Compounds and compositions for ocular treatment

Abstract

The present disclosure features a cross-linked chemical entity (e.g., a compound or a pharmaceutically acceptable salt and / or hydrate and / or prodrug of a compound) in the cornea in response to exposure to electromagnetic radiation. The disclosure also features compositions comprising the chemical entities as well as other methods of use and preparation thereof. The chemical entities may be used, for example, to treat a subject (e.g., a person) having a disease, disorder or condition in which abnormal shapes 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 steepage (e.g., protuberance), resulting in a pathology and / or symptom and / or progression of a disease, disorder or condition. Non-limiting examples of such diseases, disorders or conditions include: (i) corneal dilation disease; (ii) a visual condition; (iii) is a disease, disorder or condition after or coexisting with any of the above-described or any of the disease, disorder or condition described herein. More specific non-limiting examples of such diseases, disorders or conditions include cornea conus, corneal globe, transparent edge degeneration, corneal dilation (e.g., post-operative dilation, e.g., LASIK post-operative dilation), Terrien edge degeneration, myopia, hyperopia, astigmatism, irregular astigmatism, and presbyopia.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 775,305, filed December 4, 2018, which is incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure is characterized by the formation of a cross-linked chemical entity (e.g., a compound or a pharmaceutically acceptable salt and / or hydrate and / or prodrug of a compound) in the cornea in response to exposure to electromagnetic radiation. This disclosure is also characterized by compositions comprising the chemical entity and other methods of using and preparing it. The chemical entity can be used, for example, to treat an object (e.g., a person) suffering from a disease, condition, or symptom, wherein an abnormal shape of the cornea (e.g., corneal thinning, such as bilateral corneal thinning, such as bilateral thinning of the central, paracentral, or peripheral cornea; or corneal steepening (e.g., bulging)) causes pathology and / or symptoms and / or progression of the disease, condition, or symptom. Non-limiting examples of such diseases, conditions, or symptom include: (i) corneal ectatic disorders; (ii) visual conditions; and (iii) diseases, conditions, or symptom that are a consequence of or coexist with any of the foregoing or any of the disclosures herein. More specific, non-limiting examples of such diseases, conditions, or symptoms include keratoconus, corneal bulb, clear marginal degeneration, corneal ectasia (e.g., postoperative ectasia, such as LASIK postoperative ectasia), Terrien marginal degeneration, myopia, hyperopia, astigmatism, irregular astigmatism, and presbyopia. Background Technology

[0004] Various eye conditions, such as myopia, keratoconus, and hyperopia, involve abnormal corneal shapes. For example, laser-assisted in situ keratomileusis (LASIK) is one of many corrective treatments that reshape the cornea so that light passing through the cornea is properly focused onto the retina located at the back of the eye. The success of a specific treatment to correct corneal abnormalities depends on the stability of the changes in corneal structure after the treatment.

[0005] Although treatment may initially achieve the desired corneal remodeling, the desired effect may be at least partially diminished or reversed if the collagen fibrils within the cornea continue to change after the desired remodeling is achieved. For example, a complication called LASIK postoperative ectasia may occur due to corneal thinning and weakening caused by LASIK surgery. In LASIK postoperative ectasia, the cornea gradually steepens (bulges). To strengthen and stabilize the corneal structure after remodeling, some treatments can also induce cross-linking in the corneal tissue. For example, photosensitizers (such as riboflavin) are applied to the cornea as cross-linking agents. Once the cross-linking agent is applied to the cornea, it is activated by a light source (such as ultraviolet (UV) light), causing the cross-linking agent to absorb sufficient energy to release free oxygen radicals (such as singlet oxygen) and / or other free radicals within the cornea. Once released, these free radicals form covalent bonds between corneal collagen fibrils, thereby cross-linking the corneal collagen fibrils and strengthening and stabilizing the corneal structure.

[0006] Cross-linking agents can be used as a primary treatment method due to the beneficial structural changes they induce. For example, they can be used to treat keratoconus. Cross-linking therapy can also be used to induce corneal refractive changes to correct myopia, hyperopia, astigmatism, irregular astigmatism, presbyopia, and other conditions.

[0007] 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; and International Patent Application Publication No. 2011 / 130356, filed April 13, 2011. International Patent Application Publication No. 2015 / 130944, filed February 26, 2015, and International Patent Application Publication No. 2016 / 090016, filed December 2, 2015, describe systems and compositions (e.g., riboflavin or riboflavin phosphate eye drops) that can generate cross-linking activity in the cornea with or without removal of corneal epithelial cells in the treatment of eye diseases such as keratoconus (e.g., progressive keratoconus) or corneal ectasia following refractive surgery. VISCOUS (20% riboflavin 5′-phosphate dextran eye drops) 0.146% and (Riboflavin 5′-phosphate eye drops) 0.146% is suitable for KXL TM The system's light-enhancing agent is used for corneal collagen cross-linking to treat progressive keratoconus. Summary of the Invention

[0008] This disclosure is characterized by the formation of a cross-linked chemical entity (e.g., a compound or a pharmaceutically acceptable salt and / or hydrate and / or prodrug of a compound) in the cornea in response to exposure to electromagnetic radiation. This disclosure is also characterized by compositions comprising the chemical entity and other methods of using and preparing it. The chemical entity can be used, for example, to treat an object (e.g., a person) suffering from a disease, condition, or symptom, wherein an abnormal shape of the cornea (e.g., corneal thinning, such as bilateral corneal thinning, such as bilateral thinning of the central, paracentral, or peripheral cornea; or corneal steepening (e.g., bulging)) causes pathology and / or symptoms and / or progression of the disease, condition, or symptom. Non-limiting examples of such diseases, conditions, or symptom include: (i) corneal ectasia; (ii) visual conditions; (iii) diseases, conditions, or symptom that are a consequence of or coexist with any of the foregoing or any of the disclosures herein. More specific, non-limiting examples of such diseases, conditions, or symptoms include keratoconus, corneal bulb, clear marginal degeneration, corneal ectasia (e.g., postoperative ectasia, such as LASIK postoperative ectasia), Terrien marginal degeneration, myopia, hyperopia, astigmatism, irregular astigmatism, and presbyopia.

[0009] On the one hand, characteristic chemical entities include compounds of formula I or their pharmaceutically acceptable salts:

[0010]

[0011] Where R 1 R 2 R 3 X, Y, Z and Z X It can be defined as anywhere in this document.

[0012] On the one hand, the pharmaceutical composition is characterized by comprising the chemical entity described herein (e.g., a compound or a pharmaceutically acceptable salt thereof, or a composition comprising such a compound) and one or more pharmaceutically acceptable excipients.

[0013] On the one hand, a method for generating crosslinks in the cornea is characterized by contacting the cornea with a chemical entity described herein (e.g., a compound or a pharmaceutically acceptable salt thereof, or a composition comprising the same, as generally or specifically described herein); and applying electromagnetic radiation to the cornea. The method may include, for example, applying a chemical entity to the cornea of ​​an object (e.g., a person) suffering from a disease, condition, or symptom in which an abnormal shape of the cornea (e.g., corneal thinning, such as bilateral corneal thinning, such as bilateral thinning of the central, paracentral, or peripheral cornea; or corneal steepening (e.g., bulging)) leads to the pathology and / or symptoms and / or progression of the disease, condition, or symptom (e.g., keratoconus, globus keratoconus, clear marginal degeneration, corneal ectasia (e.g., postoperative ectasia, such as 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 (e.g., by imparting mechanical stiffness) and strengthening and stabilizing the structure of the cornea.

[0014] On the other hand, a method for treating a disease, condition, or symptom is characterized in that an abnormal shape of the cornea (e.g., corneal thinning, such as bilateral corneal thinning, such as bilateral thinning of the central, paracentral, or peripheral cornea; or corneal steepening (e.g., bulging)) leads to the pathology and / or symptoms and / or progression of the disease, condition, or symptom. The method includes administering, in an amount effective for treating the disease, condition, or symptom, a chemical entity described herein (e.g., a compound generally or specifically described herein, a pharmaceutically acceptable salt thereof, or a composition comprising thereof).

[0015] On the other hand, a method for treating a disease, condition, or symptom is characterized in that an abnormal shape of the cornea (e.g., corneal thinning, such as bilateral corneal thinning, such as bilateral thinning of the central, paracentral, or peripheral cornea; or corneal steepening (e.g., bulging)) leads to the pathology and / or symptoms and / or progression of the disease, condition, or symptom. The method includes administering an effective amount of the chemical entity described herein (e.g., a compound generally or specifically described herein, a pharmaceutically acceptable salt thereof, or a composition containing such a compound) to the cornea of ​​the object requiring such treatment; and applying electromagnetic radiation to the cornea.

[0016] Non-limiting examples of this disease, condition, and symptom are corneal ectasia. In some embodiments, corneal ectasia is keratoconus. In some embodiments, corneal ectasia is globus keratitis. In some embodiments, corneal ectasia is clear marginal degeneration. In some embodiments, corneal ectasia is corneal ectasia (e.g., postoperative ectasia, such as LASIK postoperative ectasia). In some embodiments, corneal ectasia is Terrien marginal degeneration.

[0017] Another non-limiting example of such diseases, conditions, and symptoms is visual acuity. In some embodiments, the visual acuity is myopia. In some embodiments, the visual acuity is hyperopia. In some embodiments, the visual acuity is myopia. In some embodiments, the visual acuity is hyperopia. In some embodiments, the visual acuity is astigmatism. In some embodiments, the visual acuity is irregular astigmatism. In some embodiments, the visual acuity is presbyopia.

[0018] The implementation may include one or more of the following advantageous features.

[0019] 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.

[0020] In some embodiments, the chemical entities and compositions described herein can be cross-linked in the cornea using a relatively short duration of electromagnetic radiation.

[0021] Other implementations include those described in the specific implementation and / or claims.

[0022] Other definitions

[0023] To facilitate understanding of the disclosures set forth herein, several 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 one of ordinary skill in the art to which this applies. Every patent, application, published application, and other publication mentioned throughout this specification, as well as any appendices, is incorporated herein by reference in its entirety.

[0024] As used herein, the term “acceptable” means, with respect to a formulation, composition, or ingredient, that has no lasting harmful effect on the overall health of the person being treated.

[0025] As used herein, the terms "effective amount" or "therapeutic effective amount" mean that a sufficient amount of a chemical entity (e.g., a pharmaceutically acceptable salt of a compound generally or specifically described herein, or a composition comprising such a compound) administered will, to some extent, alleviate one or more symptoms of the disease or condition being treated. Results include a reduction and / or alleviation of the signs, symptoms, or cause of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is, for instance, the amount of a composition comprising a compound disclosed herein that provides a clinically significant reduction in the symptoms of a disease. In any individual case, any suitable technique (e.g., dose escalation studies) may be used to determine an appropriate "effective" amount.

[0026] The term "excipient" or "pharmaceuticalally acceptable excipient" refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, diluent, support, solvent, or encapsulating material. In one embodiment, a component being "pharmaceutically acceptable" means that it is compatible with other components of a pharmaceutical preparation and is suitable for contact with human or animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, and is proportionate to a reasonable benefit / risk ratio. For example, see Remington: The Science and Practice of Pharmacy, 21st edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th edition; Rowe et al., eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd edition, eds. Ash and Ash, Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd edition, ed. Gibson, CRC Press LLC: Boca Raton, FL, 2009.

[0027] The term "pharmaceutically acceptable salt" refers to a formulation 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, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In other cases, pharmaceutically acceptable salts are obtained by reacting compounds having acidic groups described herein with a base to form a salt, such as ammonium salts, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), organic bases (e.g., dicyclohexylamine, N-methyl-D-glucosamine, tris(hydroxymethyl)methylamine), and salts formed with amino acids (e.g., arginine, lysine, etc.), or by other methods previously identified. There are no specific limitations on pharmacologically acceptable salts, provided they can be used in pharmaceuticals. Examples of salts formed by the compounds described herein with bases include: 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, specific examples of which are acid 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; and acidic amino acids, such as aspartic acid and glutamic acid.

[0028] The term "pharmaceutical composition" refers to a mixture of the compound described herein with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickeners. Pharmaceutical compositions facilitate the administration of the compound to a living organism. Various techniques for administering compounds exist in the art, including but not limited to rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0029] The term "object" can refer to an animal, including but not limited to primates (e.g., humans), monkeys, cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "object" and "patient" are used interchangeably herein, for example, to refer to a mammalian object, such as a human.

[0030] In the context of treating a disease, symptom, or condition, the term “treatment” is intended to include alleviating or eliminating a disease, symptom, or condition or one or more symptoms associated with a disease, symptom, or condition; or slowing the progression, spread, or worsening of a disease, symptom, or condition or one or more symptoms thereof.

[0031] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0032] The term "alkyl" refers to a hydrocarbon chain that can be straight-chain or branched, containing an indicated number of carbon atoms. For example, C 1-10 This indicates that the group may have 1 to 10 (inclusive) carbon atoms. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl.

[0033] The term "halogenated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by independently selected halogens.

[0034] The term "alkoxy" refers to -O-alkyl (e.g., -OCH3).

[0035] The term "haloalkoxy" refers to -O-haloalkyl (e.g., -OCF3).

[0036] The term "alkylene" refers to branched or unbranched divalent alkyl groups (e.g., -CH2-).

[0037] The term "triaryl" refers to the divalent form of a ring system, which in this case is a divalent aryl.

[0038] The term "alkenyl" refers to a straight-chain or branched hydrocarbon chain that can have one or more carbon-carbon double bonds. The alkenyl moiety contains an indicated number of carbon atoms. For example, C 2-6 This indicates that the group can have 2 to 6 (inclusive) carbon atoms.

[0039] The term "alkynyl" refers to a straight-chain or branched hydrocarbon chain that can have one or more carbon-carbon triple bonds. The alkynyl moiety contains an indicated number of carbon atoms. For example, C 2-6 This indicates that the group can have 2 to 6 (inclusive) carbon atoms.

[0040] 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 can be substituted with substituents, 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 groups also include phenyl, naphthyl, etc.

[0041] As used herein, the term "cycloalkyl" includes saturated cycloalkyl groups having 3 to 10 carbons, preferably 3 to 8 carbons, more preferably 3 to 6 carbons, wherein the cycloalkyl group may optionally be substituted. Preferred cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0042] The term "heteroaryl" refers to an aromatic 5-8 member monocyclic, 8-12 member bicyclic, or 11-14 member tricyclic system, having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, wherein the heteroatoms are selected from O, N, or S (e.g., carbon atom and 1-3, 1-6, or 1-9 N, O, or S heteroatoms corresponding to monocyclic, bicyclic, or tricyclic rings, respectively), wherein 0, 1, 2, 3, or 4 atoms of each ring can be substituted by substituents, 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, but not necessarily a ring containing heteroatoms, such as tetrahydroisoquinoline. 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, tetrazolium, pyridine, pyridazine , pyrimidines, pyrazines, [1,2,3]triazines, [1,2,4]triazines, [1,3,5]triazines, indole, isoindole, benzofuran, benzothiophene [1,3]benzoxazole, [1,3]benzothiazole, benzimidazole, indole, quinoline, isoquinoline, cinnamoline, quinazoline, quinoxaline, phthalazines, various naphthyridines, such as [1,8]naphthyridines, various thienopyridines, such as thieno[2,3-b]pyridine, and purines.

[0043] The term "heterocyclic group" refers to a non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic system, having 1-3 heteroatoms in the monocyclic form, 1-6 heteroatoms in the bicyclic form, or 1-9 heteroatoms in the tricyclic form. The heteroatoms are selected from O, N, or S (e.g., a carbon atom and 1-3, 1-6, or 1-9 N, O, or S heteroatoms corresponding to the monocyclic, bicyclic, or tricyclic forms, respectively). O, 1, 2, or 3 atoms in each ring can be substituted with substituents. Examples of heterocyclic groups include piperazine, pyrrolyl, dioxyl, morpholinyl, tetrahydrofuranyl, etc.

[0044] As used herein, the term "heterocyclic alkenyl" refers to a partially unsaturated cyclic system having 3-16 ring atoms (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic system), having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic), wherein the heteroatoms are selected from O, N, or S (e.g., a carbon atom and 1-3, 1-6, or 1-9 N, O, or S heteroatoms corresponding to monocyclic, bicyclic, or tricyclic systems, respectively), wherein 0, 1, 2, or 3 atoms of each ring may be substituted with substituents. Examples of heterocyclic alkenyl groups include, but are not limited to, imidazolinyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, and dihydropyrroleyl.

[0045] As used herein, when a ring is described as “partially unsaturated,” it means that the ring has one or more additional degrees of unsaturation (in addition to the unsaturation attributable to the ring itself; for example, one or more double or triple bonds between the atoms constituting the ring), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, etc.

[0046] Furthermore, the atoms constituting the compounds of the embodiments of the present invention are intended to include all isotopic forms of said atoms. Isotopes as used herein include those atoms having the same atomic number but different mass numbers. As a general example and not a limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include… 13 C and 14 C.

[0047] Details of one or more embodiments of the present invention are set forth in the following description and the appendix, which is expressly considered part of this disclosure. Further features and advantages will also be apparent from the claims. Invention Details

[0049] Compound of formula (I)

[0050] On the one hand, this disclosure is characterized by compounds of formula (I):

[0051]

[0052] Or its pharmaceutically acceptable salt;

[0053] in:

[0054] X is selected from H, NR 4X R 5X and optionally by 1-3 R a Substituted C1-C6 alkyl groups;

[0055] Y is selected from the following group:

[0056] (i)CO2R 6Y ;

[0057] (ii)C(O)NR 4Y R 5Y ;

[0058] (iii) A heteroaryl group containing 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected R c Replace; and

[0059] (iv) Heterocyclic alkenyl groups comprising 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d O and S, and one or more of the heterocyclic alkenyl ring carbon atoms are optionally separated by 1-2 independently selected R b replace;

[0060] Z is selected from the following group:

[0061] (i)H,

[0062] (ii)C 1-6 alkyl,

[0063] (iii)NR 4Z R 5Z ,

[0064] (iv)OR 6Z ,

[0065] (v)OC(O)R 7Z ,

[0066] (vi)OP(O)OR 8Z OR 9Z ,and

[0067] (vii); Heterocyclic groups containing 4-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R). d And O, and one or more of the heterocyclic group carbon atoms are optionally separated by 1-4 independently selected R h replace;

[0068] Each Z x It is H; or each of the Zs. x Together with the carbon atoms they are attached to, they form C=O;

[0069] R 1 R 2 and R3 Each independently selected from R 6A C(O)R 7A and P(O)OR 8A OR 9A ;

[0070] R 4X and R 5X Each is independently selected from: 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;

[0071] R 4Y and R 5Y Each person independently selects from the following groups:

[0072] (i)H;

[0073] (ii)C 1-12 Alkyl groups, optionally surrounded by 1-6 R groups a replace;

[0074] (iii) A heteroaryl group comprising 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-4 independently selected R h replace;

[0075] (iv)-(W 1 -W 2 ) n -W 3 ,in:

[0076] • Each time it appears, W 1 Independently for C 1-3 Alkylene, which is optionally surrounded by 1-4 R a replace;

[0077] • Each time it appears, W 2 Independently -N(H)-, -N(R) d -, -O-, or -S-;

[0078] ·W 3 Is it H or C? 1-7 Alkyl groups, optionally surrounded by 1-4 R groupsa Replace; and

[0079] n is 2-4;

[0080] or

[0081] (v)R 4Y and R 5Y Together with their respective nitrogen atoms, they form a ring comprising 3-8 ring atoms, wherein the ring comprises: (a) 1-7 ring carbon atoms, each ring carbon atom being separated by 1-2 independently selected H and C atoms. 1-3 Alkyl substituents; (b) 0-3 cyclic heteroatoms (except for R) 4Y and R 5Y (The ring heteroatoms other than the nitrogen atom that are connected) are each independently selected from N(H), N(R) d ), O and S;

[0082] R 4Z and R 5Z Each person independently selects from the following groups:

[0083] (i)H;

[0084] (ii)C 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groups. a replace;

[0085] (iii)C 3-6 cycloalkyl;

[0086] (iv)-C(O)(C 1-4 alkyl);

[0087] (v)-C(O)O(C 1-4 alkyl);

[0088] (vi)-CON(R')(R”);

[0089] (vii)-S(O) 1-2 (NR'R”);

[0090] (viii)-S(O) 1-2 (C 1-4 alkyl);

[0091] (ix)-OH;

[0092] (x)C 1-4 alkoxy groups; and

[0093] (xi)-(Q 1 -Q 2 ) q -Q 3 ,in:

[0094] • Each time Q appears 1 Independently for C 1-3 Alkylene, which is optionally surrounded by 1-4 R a replace;

[0095] • Each time Q appears 2 Independently -N(H)-, -N(R) d -, -O-, or -S-;

[0096] ·Q 3 Is it H or C? 1-7 Alkyl groups, optionally surrounded by 1-4 R groups a Replace; and

[0097] ·q is 2-4;

[0098] Each time it appears, R 6A Select independently from the following groups:

[0099] (i)H; and

[0100] (ii)C 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groups a replace;

[0101] R 6Z Select independently from the following groups:

[0102] (i)H;

[0103] (ii)C 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groups a replace;

[0104] (iii)-(C 0-2 alkylene)-(C 6-10 Aryl), of which C 6-10 The aryl group is optionally selected by 1-2 independently chosen R groups. h replace;

[0105] (iv)-(C 0-2 Alkylene-(heteroaryl), wherein the heteroaryl group comprises 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(C) 1-3 Alkyl), O and S, and one or more of the heteroaryl ring carbon atoms are optionally surrounded by 1-4 independently selected R h replace;

[0106] (v)-(C 1-2 alkylene)-C(=O)NH-(C 1-3 (alkylene)-R 6Z’ ,and

[0107] (vi)-(T 1 -T 2 ) t -T 3 ,in:

[0108] • Each time it appears, T 1 Independently for C 1-3 Alkylene, which is optionally surrounded by 1-4 R a replace;

[0109] • Each time it appears, T 2 Independently -N(H)-, -N(R) d -, -O-, or -S-;

[0110] ·T 3 Is it H or C? 1-7 Alkyl groups, optionally surrounded by 1-4 R groups a Replace; and

[0111] ·t is 2-4;

[0112] R 6Z’ Selected from the following group:

[0113] C(=O)OH,N(C 1-4 Alkyl)2, NH2, NH(C 1-4 Alkyl groups, and heterocyclic groups comprising 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d And O, and one or more of the heterocyclic group carbon atoms are optionally separated by 1-4 independently selected C atoms. 1-3 Alkyl substitution;

[0114] Each time it appears, R 6Y Select independently from the following groups:

[0115] (i)H;

[0116] (ii)-(Y 1 ) m -Y 2 ,in:

[0117] ·m is 0 or 1;

[0118] ·Y 1 It is C 1-6 Alkylenes, which are optionally surrounded by 1-6 R... a Replace; and

[0119] ·Y 2 yes:

[0120] (a)C 3-10cycloalkyl groups, optionally surrounded by 1-4 R groups. b replace,

[0121] (b)C 6-10 Aryl groups, which are optionally bounded by 1-4 R groups c replace;

[0122] (c) A heteroaryl group comprising 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-4 independently selected R c Replace, or

[0123] (d) Heterocyclic groups containing 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d And O, and one or more of the heterocyclic group carbon atoms are optionally separated by 1-4 independently selected R b replace;

[0124] (iii)C 1-12 Alkyl groups, optionally composed of 1-6 independently selected R groups a replace;

[0125] (iv)-(Z 1 -Z 2 ) p -Z 3 ,in:

[0126] • Each time Z appears 1 Independently for C 1-3 Alkylene, which is optionally surrounded by 1-4 R a replace;

[0127] • Each time Z appears 2 Independently -N(H)-, -N(R) d -, -O-, or -S-;

[0128] ·Z 3 Is it H or C? 1-7 Alkyl groups, optionally surrounded by 1-4 R groups a Replace; and

[0129] p is 2-4;

[0130] Each time it appears, R 7Z and R 7A Each person independently selects from the following groups:

[0131] (i)H;

[0132] (ii)C 1-10Alkyl groups, optionally composed of 1-6 independently selected R groups a replace;

[0133] (iii)C6- 10 Aryl groups, which are optionally bounded by 1-4 R groups c Replace; and

[0134] (iv)C 3-6 cycloalkyl groups, optionally surrounded by 1-4 R groups. b replace;

[0135] Each time it appears, R 8A R 8Z R 9A and R 9Z Each independently

[0136] (i)H; or

[0137] (ii)C 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groups a replace;

[0138] Each occurrence of R a Independently selected from the following groups: -OH; -F; -Cl; -Br; -NR e R f C 1-4 Alkoxy; C 1-4 Haloalkoxy group; -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); C(=NH)N(R')(R”); Cyano; and C 3-6 Cycloalkyl groups, optionally composed of 1-4 independently selected C atoms. 1-4 Alkyl substitution;

[0139] Each occurrence of R b Select independently from the following group: C 1-6 Alkyl; C 1-4 Halogenated alkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f C 1-4 Alkoxy; C 1-4 Haloalkoxy group; -C(=O)(C 1-4 Alkyl); -C(=O)O(C 1-4 Alkyl); -C(=O)OH; -C(=O)N(R')(R”); -S(O)1-2 (NR'R”);-S(O) 1-2 (C 1-4 Alkyl); cyano; and C 3-6 Cycloalkyl groups, optionally composed of 1-4 independently selected C atoms. 1-4 Alkyl substitution;

[0140] Each occurrence of R c Select independently from the following groups:

[0141] (i) Halogens;

[0142] (ii) Cyano group;

[0143] (iii)C 1-10 alkyl;

[0144] (iv) R selected by 1-6 independent choices a Replacement C 1-10 alkyl;

[0145] (v) R, which is arbitrarily selected by 1-3 independent choices b Replacement C 3-6 cycloalkyl;

[0146] (vi)C 2-6 alkenyl;

[0147] (vii)C 2-6 alkynyl group;

[0148] (viii)C 1-4 Alkoxy;

[0149] (ix)C 1-4 Halogenated alkoxy groups;

[0150] (x) C is arbitrarily selected by 1-4 independent choices. 1-4 Alkyl-substituted -(C 0-3 (alkylene)-C 3-6 cycloalkyl;

[0151] (xi)-S(O) 1-2 (C 1-4 alkyl);

[0152] (xii)-NR e R f ;

[0153] (xiii)-OH;

[0154] (xiv)-S(O) 1-2 (NR'R”);

[0155] (xv)-C 1-4 Thioalkoxy groups;

[0156] (xvi)-NO2;

[0157] (xvii)-C(=O)(C 1-4 alkyl);

[0158] (xviii)-C(=O)O(C 1-4 alkyl);

[0159] (xix)-C(=O)OH; and

[0160] (xx)-C(=O)N(R')(R”);

[0161] R d Selected from the following group: R selected arbitrarily by 1-3 independent choices g Replacement 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;

[0162] Each occurrence of R e and R f Independently selected from the following groups: 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;

[0163] Or, R e and R f Together with their respective nitrogen atoms, they form a ring comprising 3-8 ring atoms, wherein the ring comprises: (a) 1-7 ring carbon atoms, each ring carbon atom being separated by 1-2 independently selected H and C atoms. 1-3 Alkyl substituents; (b) 0-3 cyclic heteroatoms (except for R) e and R f (The ring heteroatoms other than the nitrogen atom that are connected) are each independently selected from N(H), N(R) d ), O and S;

[0164] Each occurrence of R g Independently selected from the following groups: -OH, -F, NR'R", C 1-3 Alkoxy group, -CON(R')(R”), -CONHS(O)2(C 1-4 Alkyl groups and -C(O)OH;

[0165] Each occurrence of R h Select independently from the following group: C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and halogens;

[0166] as well as

[0167] Each occurrence of R' and R” is independently selected from the following groups: H and C. 1-4 Alkyl; or R' and R" together with their respective attached nitrogen atoms form a ring comprising 3-8 ring atoms, wherein the ring comprises: (a) 1-7 ring carbon atoms, each ring carbon atom being supported by 1-2 independently selected H and C atoms. 1-3 Alkyl substituents; and (b) 0-3 cyclic heteroatoms (excluding nitrogen atoms bonded to R' and R''), each independently selected from N(H), N(R'', and N'''). d ), O and S.

[0168] In some embodiments, the compound is not one or more of the following:

[0169]

[0170] Or its pharmaceutically acceptable salt.

[0171] In some embodiments, the compound is not one or more of the following: Or its pharmaceutically acceptable salt.

[0172] On the other hand, this article provides compounds of formula (I):

[0173]

[0174] Or its pharmaceutically acceptable salt;

[0175] in:

[0176] X is selected from H, NR 4X R 5X and optionally by 1-3 R a Substituted C1-C6 alkyl groups;

[0177] Y is selected from the following group:

[0178] (i)CO2R 6Y ;

[0179] (ii)C(O)NR 4Y R 5Y ;and

[0180] (iii) A heteroaryl group containing 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected R c replace;

[0181] Z is selected from H and C. 1-6 Alkyl, NR 4Z R 5Z OR 6Z OC(O)R 7Z and OP(O)OR 8Z OR 9Z ;

[0182] Each Z x It is H; or each of the Zs. x Together with the carbon atoms they are attached to, they form C=O;

[0183] R 1 R 2 and R 3 Each independently selected from R 6A C(O)R 7A and P(O)OR 8A OR 9A ;

[0184] R 4X and R 5X Each is independently selected from the following groups: 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;

[0185] R 4Y and R 5Y Each person independently selects from the following groups:

[0186] (i)H;

[0187] (ii)C 1-12 Alkyl groups, optionally surrounded by 1-6 R groups a replace;

[0188] (iii)-(W 1 -W 2 ) n -W 3 ,in:

[0189] • Each time W appears 1 Independently for C 1-3 Alkylene, which is optionally surrounded by 1-4 R a replace;

[0190] • Each time W appears 2 Independently -N(H)-, -N(R) d -, -O-, or -S-;

[0191] ·W 3 Is it H or C? 1-7 Alkyl groups, optionally surrounded by 1-4 R groups a Replace; and

[0192] n is 2-4;

[0193] or

[0194] (iv)R 4Y and R 5Y Together with their respective nitrogen atoms, they form a ring comprising 3-8 ring atoms, wherein the ring comprises: (a) 1-7 ring carbon atoms, each ring carbon atom being separated by 1-2 independently selected H and C atoms. 1-3 Alkyl substituents; (b) 0-3 cyclic heteroatoms (except for R) 4Y and R 5Y (The ring heteroatoms other than the nitrogen atom that are connected) are each independently selected from N(H), N(R) d ), O and S;

[0195] R 4Z and R 5Z Each person independently selects from the following groups:

[0196] (i)H;

[0197] (ii)C 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groups. a replace;

[0198] (iii)C 3-6 cycloalkyl;

[0199] (iv)-C(O)(C 1-4 alkyl);

[0200] (v)-C(O)O(C 1-4 alkyl);

[0201] (vi)-CON(R')(R”);

[0202] (vii)-S(O) 1-2 (NR'R”);

[0203] (viii)-S(O) 1-2 (C 1-4 alkyl);

[0204] (ix)-OH;

[0205] (x)C 1-4 alkoxy groups; and

[0206] (xi)-(Q 1 -Q 2 ) q -Q 3 ,in:

[0207] Q appears each time 1 Independently for C 1-3 Alkylene, which is optionally surrounded by 1-4 R a replace;

[0208] Q appears each time 2 Independently -N(H)-, -N(R) d -, -O-, or -S-;

[0209] ·Q 3 Is it H or C? 1-7 Alkyl groups, optionally surrounded by 1-4 R groups a Replace; and

[0210] ·q is 2-4;

[0211] R each time it appears 6A Select independently from the following groups:

[0212] (i)H; and

[0213] (ii)C 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groups a replace;

[0214] R 6Z Select independently from the following groups:

[0215] (i)H;

[0216] (ii)C 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groupsa Replace; and

[0217] (iii)-(T 1 -T 2 ) t -T 3 ,in:

[0218] • Each time T appears 1 Independently for C 1-3 Alkylene, which is optionally surrounded by 1-4 R a replace;

[0219] • Each time T appears 2 Independently -N(H)-, -N(R) d -, -O-, or -S-;

[0220] ·T 3 Is it H or C? 1-7 Alkyl groups, optionally surrounded by 1-4 R groups a Replace; and

[0221] ·t is 2-4;

[0222] R each time it appears 6Y Select independently from the following groups:

[0223] (i)H;

[0224] (ii)-(Y 1 ) m -Y 2 ,in:

[0225] ·m is 0 or 1;

[0226] ·Y 1 It is C 1-6 Alkylenes, which are optionally surrounded by 1-6 R... a Replace; and

[0227] ·Y 2 yes:

[0228] (a)C 3-10 cycloalkyl groups, optionally surrounded by 1-4 R groups. b replace,

[0229] (b)C 6-10 Aryl groups, which are optionally bounded by 1-4 R groups c replace;

[0230] (c) A heteroaryl group comprising 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-4 independently selected R c Replace, or

[0231] (d) Heterocyclic groups containing 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d And O, and one or more of the heterocyclic group carbon atoms are optionally separated by 1-4 independently selected R b replace;

[0232] (iii)C 1-12 Alkyl groups, optionally composed of 1-6 independently selected R groups a Replace; and

[0233] (iv)-(Z 1 -Z 2 ) p -Z 3 ,in:

[0234] • Each time Z appears 1 Independently for C 1-3 Alkylene, which is optionally surrounded by 1-4 R a replace;

[0235] • Each time Z appears 2 Independently -N(H)-, -N(R) d -, -O-, or -S-;

[0236] ·Z 3 Is it H or C? 1-7 Alkyl groups, optionally surrounded by 1-4 R groups a Replace; and

[0237] p is 2-4;

[0238] Each time it appears, R 7Z and R 7A Each person independently selects from the following groups:

[0239] (i)H;

[0240] (ii)C 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groups a replace;

[0241] (iii)C 6-10 Aryl groups, which are optionally bounded by 1-4 R groups c Replace; and

[0242] (iv)C 3-6 cycloalkyl groups, optionally surrounded by 1-4 R groups. b replace;

[0243] Each time it appears, R 8A R 8Z R 9A and R 9Z Each independently

[0244] (i)H; or

[0245] (ii)C 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groups a replace;

[0246] Each occurrence of R a Independently selected from the following groups: -OH; -F; -Cl; -Br; -NR e R f C 1-4 Alkoxy; C 1-4 Haloalkoxy group; -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; and C 3-6 Cycloalkyl groups, optionally composed of 1-4 independently selected C atoms. 1-4 Alkyl substitution;

[0247] Each occurrence of R b Select independently from the following group: C 1-6 Alkyl; C 1-4 Halogenated alkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f C 1-4 Alkoxy; C 1-4 Haloalkoxy group; -C(=O)(C 1-4 Alkyl); -C(=O)O(C 1-4 Alkyl); -C(=O)OH; -C(=O)N(R')(R”); -S(O) 1-2 (NR'R”);-S(O) 1-2 (C 1-4 Alkyl); cyano; and C 3-6 Cycloalkyl groups, optionally composed of 1-4 independently selected C atoms. 1-4 Alkyl substitution;

[0248] Each occurrence of R c Select independently from the following groups:

[0249] (i) Halogens;

[0250] (ii) Cyano group;

[0251] (iii)C 1-10 alkyl;

[0252] (iv) R selected by 1-6 independent choices a Replacement C 1-10 alkyl;

[0253] (v) R, which is arbitrarily selected by 1-3 independent choices b Replacement C 3-6 cycloalkyl;

[0254] (vi)C 2-6 alkenyl;

[0255] (vii)C 2-6 alkynyl group;

[0256] (viii)C 1-4 Alkoxy;

[0257] (ix)C 1-4 Halogenated alkoxy groups;

[0258] (x) C is arbitrarily selected by 1-4 independent choices. 1-4 Alkyl-substituted -(C 0-3 (alkylene)-C 3-6 cycloalkyl;

[0259] (xi)-S(O) 1-2 (C 1-4 alkyl);

[0260] (xii)-NR e R f ;

[0261] (xiii)-OH;

[0262] (xiv)-S(O) 1-2 (NR'R”);

[0263] (xv)-C 1-4 Thioalkoxy groups;

[0264] (xvi)-NO2;

[0265] (xvii)-C(=O)(C 1-4 alkyl);

[0266] (xviii)-C(=O)O(C 1-4 alkyl);

[0267] (xix)-C(=O)OH; and

[0268] (xx)-C(=O)N(R')(R”);

[0269] R d Selected from the following group: 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;

[0270] Each occurrence of R e and R f Independently selected from the following groups: 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 groups; and

[0271] Each occurrence of R' and R” is independently selected from the following groups: H and C. 1-4 Alkyl; or R' and R" together with their respective attached nitrogen atoms form a ring comprising 3-8 ring atoms, wherein the ring comprises: (a) 1-7 ring carbon atoms, each ring carbon atom being supported by 1-2 independently selected H and C atoms. 1-3 Alkyl substituents; and (b) 0-3 cyclic heteroatoms (excluding nitrogen atoms bonded to R' and R''), each independently selected from N(H), N(R'', and N'''). d ), O and S.

[0272] In some embodiments, the compound is not one or more of the following: Or its pharmaceutically acceptable salt.

[0273] In some embodiments, the compound is not one or more of the following: Or its pharmaceutically acceptable salt.

[0274] In some implementations, X is optionally divided by 1-3 R aWhen the substituted C1-C6 alkyl group (e.g., X is an unsubstituted C1-C6 (e.g., C1-C3) alkyl group, for example, X is CH3) is substituted, Y is not CO2H, CO2Me, CO2Et or CO2NH2; or Y is not CO2H or CO2NH2.

[0275] In some implementations, X is optionally divided by 1-3 R a When the substituted C1-C6 alkyl group (e.g., X is an unsubstituted C1-C6 (e.g., C1-C3) alkyl group, for example, X is CH3) and Z is OH, Y is not CO2H, CO2Me, CO2Et or CO2NH2.

[0276] In some implementations, X is optionally divided by 1-3 R a Substituted C1-C6 alkyl (e.g., X is an unsubstituted C1-C6 (e.g., C1-C3) alkyl, e.g., X is CH3), R 1 R 2 and R 3 When each of them is H and Z is OH, Y is not CO2H, CO2Me, CO2Et or CO2NH2.

[0277] In some implementations, X is optionally divided by 1-3 R a When the substituted C1-C6 alkyl group (e.g., X is an unsubstituted C1-C6 (e.g., C1-C3) alkyl group, for example, X is CH3) and Z is OAc, Y is not CO2H or CO2NH2.

[0278] In some implementations, X is optionally divided by 1-3 R a Substituted C1-C6 alkyl (e.g., X is an unsubstituted C1-C6 (e.g., C1-C3) alkyl, e.g., X is CH3), R 1 R 2 and R 3 When each is C(O)Me and Z is OAc, Y is neither CO2H nor CO2NH2.

[0279] In some implementations, when X is NR 4X R 5X (For example, R) 4X and R 5X Each is independent of the other. 1-6 Alkyl; for example, R 4X and R 5X When each is CH3 and Z is OH, Y is not CO2H.

[0280] In some implementations, when X is NR 4X R 5X (For example, R) 4Xand R 5X Each is independent of the other. 1-6 Alkyl; for example, R 4X and R 5X Each is CH3), R 1 R 2 and R 3 When each of them is H and Z is OH, Y is not CO2H.

[0281] In some implementations, when X is NR 4X R 5X (For example, R) 4X and R 5X Each is independent of the other. 1-6 Alkyl; for example, R 4X and R 5X When each is CH3 and Z is OAc, Y is not CO2H.

[0282] In some implementations, when X is NR 4X R 5X (For example, R) 4X and R 5X Each is independent of the other. 1-6 Alkyl; for example, R 4X and R 5X Each is CH3), R 1 R 2 and R 3 When each is C(O)Me and Z is OAc, Y is not CO2H.

[0283] In some implementations, when R 1 R 2 and R 3 When each is H, and when Z is OH, Y is not CO2H, CO2Me, CO2Et, or CO2NH2.

[0284] In some implementations, when R 1 R 2 and R 3 When each is C(O)Me, and when Z is OAc (i.e. OC(O)Me), Y is neither CO2H nor CONH2.

[0285] VARIABLE X

[0286] In some implementations, X is H.

[0287] In some embodiments, X is a C1-C6 alkyl group, optionally surrounded by 1-3 R groups. a replace.

[0288] In some embodiments, X is an unsubstituted C1-C6 alkyl group (e.g., an unsubstituted C1-C3 alkyl group). In some embodiments, X is CH3.

[0289] In some embodiments, X is a C1-C6 alkyl group, which is surrounded by 1-3 R groups. a replace.

[0290] In some implementations, X is composed of 1-3 Rs a Substituted methyl groups (e.g., X is trifluoromethyl or difluoromethyl).

[0291] In some embodiments, X is a C2-C6 alkyl group, optionally surrounded by 1-3 R groups. a replace.

[0292] In some embodiments, X is a C2-C6 alkyl group, which is surrounded by 1-3 R groups. a replace.

[0293] In some of the foregoing embodiments, X is optionally represented by 1-3 R. a Replacement C 1- C6 alkyl group, R in each occurrence a Independently selected from the following groups: -OH; -F; -Cl; -Br; -NR e R f C 1-4 Alkoxy; C 1-4 Haloalkoxy group; -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) 1-2 (C 1-4 Alkyl); cyano; and optionally C1-4 independently selected C2 groups. 1-4 Alkyl-substituted C 3-6 Cycloalkyl.

[0294] In some of the foregoing embodiments, each occurrence of R a Independently selected from the following groups: -OH; -F; -Cl; -Br; -NR e R f C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and optionally C 1-4 independently selected 1-4 Alkyl-substituted C 3-6 Cycloalkyl.

[0295] In some implementations, X is NR 4X R 5X .

[0296] In some implementations, R 4X and R 5X None of them are H (e.g., R) 4X and R 5X Each is an independently selected C1-C6 alkyl group.

[0297] In some implementations, R 4X and R 5X One of them is H; and R 4X and R 5X The other one in is not H (e.g., R). 4X and R 5X One of them is H; and R 4X and R 5X The other one is an independently selected C1-C6 alkyl group.

[0298] In some implementations, R 4x and R 5X All are H.

[0299] In some implementations, R 4X and R 5X Each is independently selected from the following groups: H; C 1-6 Alkyl; C 3-6 cycloalkyl; and C 1-4 Alkyl group.

[0300] In some implementations, R 4X and R 5X One of them is independently selected from the following groups: H, C 1-6 Alkyl; C 3-6 cycloalkyl; and C 1-4 Alkoxy; R 4X and R 5X The other one is independently selected from the following group: -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.

[0301] In some implementations, when X is NR 4X R 5X At that time, R 4X and R 5X Each is independent of H or C 1-6 alkyl.

[0302] In some implementations, R 4X and R5X Each is an independent C 1-6 Alkyl groups (e.g., independent C4 groups) 1-3 Alkyl group). In some embodiments, R 4X and R 5X They are all the same C 1-6 Alkyl group. For example, R 4X and R 5X All are CH3. In other embodiments, R 4X and R 5X Each is a different C 1-6 alkyl.

[0303] variable Y

[0304] In some implementations, Y is CO2R 6Y .

[0305] variable R 6Y

[0306] In some implementations, R 6Y It is H.

[0307] In some implementations, R 6Y Yes - (Y 1 ) m -Y 2 .

[0308] In some implementations, m is 0.

[0309] In other embodiments, m is 1. In some of the foregoing embodiments, Y 1 It is C 1-6 Alkylenes, which are optionally surrounded by 1-6 R... a Replace. As a non-restrictive example, Y 1 It can be ethylene or methylene (e.g., unsubstituted ethylene or methylene).

[0310] In some implementations, Y 2 It is C 3-10 cycloalkyl groups, optionally surrounded by 1-4 R groups. b replace.

[0311] In some implementations, Y 2 It is C 3-8 cycloalkyl groups, optionally surrounded by 1-4 R groups. b replace.

[0312] In some implementations, Y 2 It is a C3 cycloalkyl group, optionally surrounded by 1-2 R groups. b replace.

[0313] In some implementations, Y 2 It is C 5-6 cycloalkyl groups, optionally surrounded by 1-4 R groups. b replace.

[0314] In some implementations, Y 2 It is a C5 cycloalkyl group, optionally surrounded by 1-4 R groups. b replace.

[0315] In some implementations, Y 2 It is a C6 cycloalkyl group, optionally surrounded by 1-4 R groups. b replace.

[0316] In some implementations, Y 2 It is C 6-10 Aryl groups, which are optionally bounded by 1-4 R groups c replace.

[0317] In some implementations, Y 2 It is a C6 aryl group, optionally bounded by 1-4 R groups. c replace.

[0318] In some implementations, Y 2 It is C 10 Aryl groups, which are optionally bounded by 1-4 R groups c replace.

[0319] In some implementations, Y 2 It is a heteroaryl group containing 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-4 independently selected R c replace.

[0320] In some implementations, Y 2 It is a heteroaryl group containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-4 independently selected R c replace.

[0321] In some implementations, Y 2 It is a heterocyclic group containing 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R). d And O, and one or more of the heterocyclic group carbon atoms are optionally separated by 1-4 independently selected R b replace.

[0322] In some implementations, Y 2 It is a heterocyclic group containing 4-6 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R). d ) and O, and one or more heterocyclic carbon atoms are optionally separated by 1-2 independently chosen R b replace.

[0323] In some implementations, R 6Y It is C 1-12 (For example, C) 1-6 C 2-6 C 2-3 ) alkyl group, which is optionally composed of 1 to 6 (e.g., unsubstituted; or 1 to 2, e.g., 1) independently selected R a replace.

[0324] In some implementations, R 6Y It is C 1-12 Alkyl group, optionally selected by 1-6 (e.g., 1-2) independently chosen R a replace.

[0325] In some implementations, R 6Y It is C 1-6 Alkyl group, optionally selected by 1-6 (e.g., 1-2) independently chosen R a replace.

[0326] In some implementations, R 6Y It is C 2-6 Alkyl group, optionally selected by 1-6 (e.g., 1-2) independently chosen R a replace.

[0327] In some implementations, R 6Y It is C 1-3 Alkyl group, optionally selected by 1-6 (e.g., 1-2) independently chosen R a replace.

[0328] In some implementations, R 6Y It is C 2-3 Alkyl group, optionally selected by 1-6 (e.g., 1-2) independently chosen R a Replace (e.g., optionally by 1 R) a Substituted C2 alkyl groups).

[0329] In some implementations, R 6Y It is C 1-3 Alkyl groups, optionally composed of 1-2 independently selected R groups a Replace (e.g., optionally by 1 R) a Substituted C2 alkyl groups).

[0330] In some implementations, R 6Y yes Where R a As defined elsewhere in this document (in some implementations, R) a Selected from the following groups: -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 (haloalkoxy group).

[0331] In some implementations, R 6Y yes And R a It is NR e R f In some of these implementations, R e and R f Each is H or C 1-6 Alkyl group. For example, R e and R f Each can be C 1-3 alkyl.

[0332] In some implementations, R e and R f Together with their respective nitrogen atoms, they form a ring comprising 3-8 (e.g., 5-6) ring atoms, wherein said ring comprises: (a) 1-7 (e.g., 1-5) ring carbon atoms, each ring carbon atom being supported by 1-2 independently selected H and C atoms. 1-3 Alkyl substituents; and (b) 0-3 cyclic heteroatoms (except for R) e and R f (The ring heteroatoms other than the nitrogen atom that are connected) are each independently selected from N(H), N(R) d ), O and S;

[0333] As a non-restrictive example, R 6Y It can be

[0334] In some of the foregoing embodiments, when R 6Y It is C 1-12 When alkyl, each occurrence of R a Independently selected from the following groups: -OH; -F; -Cl; -Br; -NR e R f C 1-4 Alkoxy; C 1-4 Haloalkoxy group; -C(=O)O(C 1-4 Alkyl); -C(=O)(C 1-4Alkyl); -C(=O)OH; -CON(R')(R”); -S(O) 1-2 (NR'R”);-S(O) 0-2 (C 1-4 Alkyl); cyano; and optionally C1-4 independently selected C2 groups. 1-4 Alkyl-substituted C 3-6 Cycloalkyl.

[0335] In some implementations, when R 6Y It is C 1-12 When alkyl, each occurrence of R a Independently selected from the following groups: -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups.

[0336] In some implementations, R 6Y It is unreplaced C 1-12 alkyl.

[0337] In some implementations, R 6Y It is unreplaced C 1-6 alkyl.

[0338] In some implementations, R 6Y It is unreplaced C 1-4 Alkyl (e.g., methyl or ethyl).

[0339] In some implementations, R 6Y It is unreplaced C 2-12 alkyl.

[0340] In some implementations, R 6Y It is unreplaced C 2-6 alkyl.

[0341] In some implementations, R 6Y It is unreplaced C 2-4 alkyl.

[0342] In some implementations, R 6Y It is unreplaced C 2-3 alkyl.

[0343] In some implementations, R 6Y It is unreplaced C 2-12 alkyl.

[0344] In some implementations, R 6Y It is unreplaced C 3-6 alkyl.

[0345] In some implementations, R 6Y It is an unsubstituted C3-4 alkyl group.

[0346] In some implementations, R 6Y Yes - (Z 1 -Z 2 ) p -Z 3 .

[0347] In some implementations, p is 2-4 (e.g., 2-3). In some of the foregoing implementations, each occurrence of Z... 1 Selected independently from C 1-3 Alkylene (e.g., C2 alkylene), optionally surrounded by 1-4 (e.g., 1-2) R a Replace. As a non-restrictive example, each Z 1 It can be an unsubstituted C2 alkylene group.

[0348] In some implementations, each occurrence of Z 2 Independently selected from -N(H)-, -N(R)- d )-, -O- and -S-.

[0349] In some implementations, each occurrence of Z 2 It is independently selected from -N(H)-, -N(Me)- and -O-.

[0350] In some implementations, Z 3 Is it H or C? 1-3 Alkyl groups, optionally surrounded by 1-4 R groups a replace.

[0351] In some implementations, Z 3 Is it H or unsubstituted C? 1-3 alkyl.

[0352] In some implementations, when R 6Y Yes - (Z 1 -Z 2 ) p -Z 3 p is 2-3; Z appears each time 1 It is an unsubstituted C2 alkylene group; each occurrence of Z 2 Independently selected from -N(H)-, -N(Me)-, and -O-; and Z 3 Is it H or unsubstituted C? 1-3 alkyl.

[0353] In some implementations, when Y is CO2R 6Y In this case, Y is selected from CO2H and CO2Me.

[0354] In some implementations, when Y is CO2R 6Y When Y is In some of the foregoing embodiments, R on Y a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 Haloalkoxy (e.g., Y can be) ).

[0355] In some implementations, when Y is CO2R 6Y When Y is not CO2H, CO2Me, or CO2Et.

[0356] In some implementations, Y is C(O)NR 4Y R 5Y .

[0357] variable R 4Y / R 5Y

[0358] In some of the foregoing embodiments, when Y is C(O)NR 4Y R 5Y At that time, R 4Y and R 5Y Each person independently selects from the following groups:

[0359] (i)H;

[0360] (ii)C 1-12 Alkyl groups, optionally surrounded by 1-4 R groups a replace;

[0361] (iii)-(W 1 -W 2 ) n -W 3 ,in:

[0362] ·W 1 It is C 1-3 Alkylene, which is optionally surrounded by 1-4 R a replace;

[0363] ·W 2 It is -N(H)-, -N(R)- d -, -O-, or -S-;

[0364] ·W 3 Is it H or C? 2-7 Alkyl groups, optionally surrounded by 1-4 R groups a Replace; and

[0365] n is 2-4;

[0366] or

[0367] (iv)R 4Y and R 5Y Together with their respective nitrogen atoms, they form a ring comprising 3-8 ring atoms, wherein the ring comprises: (a) 1-7 ring carbon atoms, each ring carbon atom being separated by 1-2 independently selected H and C atoms. 1-3 Alkyl substituents; (b) 0-3 cyclic heteroatoms (except for R) 4Y and R 5Y (The ring heteroatoms other than the nitrogen atom that are connected) are each independently selected from N(H), N(R) d ), O and S;

[0368] In some implementations, R 4Y It is H.

[0369] In some implementations, R 4Y It is C 1-12 Alkyl groups, optionally composed of 1-6 independently selected R groups a replace.

[0370] In some implementations, R 4Y It is C 1-6 Alkyl groups, optionally composed of 1-3 independently selected R groups a Replace (e.g., optionally by 1 R) a Substituted C2 alkyl groups).

[0371] In some implementations, R 4Y It is C 1-4 Alkyl groups, optionally composed of 1-2 independently selected R groups a Replace (e.g., optionally by 1 R) a Substituted C2 alkyl groups).

[0372] In some implementations, R 4Y yes Where R a As defined elsewhere herein. In some of the foregoing embodiments, R a It is -OH, -NR e R f C 1-4 Alkoxy or C 1-4 Haloalkoxy groups. As a non-limiting example, R 4Y It can be

[0373] In some of the foregoing embodiments, when R 4Y It is C 1-12 When alkyl, each occurrence of R a Independently selected from the following groups: -OH; -F; -Cl; -Br; -NR e Rf C 1-4 Alkoxy; C 1-4 Haloalkoxy group; -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) 1-2 (C 1-4 Alkyl); cyano; and C 3-6 Cycloalkyl groups, optionally composed of 1-4 independently selected C atoms. 1-4 Alkyl substitution.

[0374] In some implementations, when R 4Y It is C 1-12 When alkyl, each occurrence of R a Independently selected from the following groups: -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups.

[0375] In some implementations, R 4Y It is unreplaced C 1-12 alkyl.

[0376] In some implementations, R 4Y It is unreplaced C 1-6 alkyl.

[0377] In some implementations, R 4Y It is unreplaced C 1-4 Alkyl (e.g., methyl, ethyl, n-propyl or isopropyl).

[0378] In some implementations, R 4Y It is a heteroaryl group containing 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-4 independently selected R h Replacement. In some of these implementations, R 4Y It is a heteroaryl group containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-4 independently selected R h Replacement. For example, R 4Y It can be a tetrazolium group, wherein the cyclic nitrogen atom is optionally replaced by R. dReplacement. For example, R 4Y It can be (For example In some of the foregoing embodiments, R 5Y It is H.

[0379] In some implementations, R 5Y It is H.

[0380] In some implementations, R 5Y It is C 1-12 Alkyl groups, optionally composed of 1-6 independently selected R groups a replace.

[0381] In some implementations, R 5Y It is C 1-6 Alkyl groups, optionally composed of 1-3 independently selected R groups a Replace (e.g., optionally by 1 R) a Substituted C2 alkyl groups).

[0382] In some implementations, R 5Y It is C 1-4 Alkyl groups, optionally composed of 1-2 independently selected R groups a Replace (e.g., optionally by 1 R) a Substituted C2 alkyl groups).

[0383] In some implementations, R 5Y yes Where R a As defined elsewhere herein. In some of the foregoing embodiments, R a It is -OH, -NR e R f C 1-4 Alkoxy or C 1-4 Haloalkoxy groups. As a non-limiting example, R 5Y It can be

[0384] In some of the foregoing embodiments, when R 5Y It is C 1-12 When alkyl, each occurrence of R a Independently selected from the following groups: -OH; -F; -Cl; -Br; -NR e R f C 1-4 Alkoxy; C 1-4 Haloalkoxy group; -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)1-2 (C 1-4 Alkyl); cyano; and C 3-6 Cycloalkyl groups, optionally composed of 1-4 independently selected C atoms. 1-4 Alkyl substitution.

[0385] In some implementations, when R 5Y It is C 1-12 When alkyl, each occurrence of R a Independently selected from the following groups: -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups.

[0386] In some implementations, R 5Y It is unreplaced C 1-12 alkyl.

[0387] In some implementations, R 5Y It is unreplaced C 1-6 alkyl.

[0388] In some implementations, R 5Y It is unreplaced C 1-4 Alkyl (e.g., methyl, ethyl, n-propyl or isopropyl).

[0389] In some implementations, R 5Y It is a heteroaryl group containing 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-4 independently selected R h Replacement. In some of these implementations, R 5Y It is a heteroaryl group containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-4 independently selected R h Replacement. For example, R 5Y It can be a tetrazolium group, wherein the cyclic nitrogen atom is optionally replaced by R. d Replacement. For example, R 5Y It can be (For example In some of the foregoing embodiments, R 4Y It is H.

[0390] In some implementations, R 4Y Yes - (W 1 -W2 ) n -W 3 .

[0391] In other embodiments, n is 2-4 (e.g., 2-3). In some of the foregoing embodiments, each occurrence of W... 1 Selected independently from C 1-3 Alkylene (e.g., C2 alkylene), which is optionally surrounded by 1-4 R... a replace.

[0392] In some implementations, W occurs each time. 1 C is independent 2-3 Alkylene (e.g., C2 alkylene).

[0393] In some implementations, W occurs each time. 2 Independently -N(H)-, -N(Me)-, or -O- (e.g., a W) 2 It's -O-; another W 2 (When it exists) is -N(Me)-).

[0394] In some implementations, W 3 Selected from H and C 1-3 alkyl.

[0395] As a non-restrictive example, R 4Y You can choose from:

[0396] In some implementations, R 5Y Yes - (W 1 -W 2 ) n -W 3 .

[0397] In other embodiments, n is 2-4 (e.g., 2-3). In some of the foregoing embodiments, each occurrence of W... 1 Selected independently from C 1-3 Alkylene (e.g., C2 alkylene), which is optionally surrounded by 1-4 R... a replace.

[0398] In some implementations, W occurs each time. 1 C is independent 2-3 Alkylene (e.g., C2 alkylene).

[0399] In some implementations, W occurs each time. 2 Independently -N(H)-, -N(Me)-, or -O- (e.g., a W) 2 It's -O-; another W 2(When it exists) is -N(Me)-).

[0400] In some implementations, W 3 Selected from H and C 1-3 alkyl.

[0401] As a non-restrictive example, R 5Y You can choose from:

[0402] In some implementations, R 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 In some of the foregoing embodiments, R 4Y and R 5Y The other one is selected from H and C. 1-3 alkyl.

[0403] In some implementations, n is 2-4 (e.g., n is 2; or n is 3).

[0404] In some implementations, n is 2 or 3.

[0405] In some implementations, W occurs each time. 1 C is independent 2-3 Alkylene (e.g., C2 alkylene).

[0406] In some implementations, W occurs each time. 2 Independently -N(H)-, -N(Me)-, or -O- (e.g., a W) 2 It's -O-; another W 2 (When it exists) is -N(Me)-).

[0407] In some implementations, W 3 Selected from H and C 1-3 alkyl.

[0408] As a non-limiting example of the foregoing implementation, R 4Y and R 5Y One of them can be selected from: R 4Y and R 5Y The other one can be selected from H and C. 1-3 alkyl.

[0409] In some implementations, R 4Y and R 5Y None of them are H (e.g., R) 4Y and R 5YEach is an independently selected C1-C6 alkyl group, optionally bounded by 1-3 R... a replace).

[0410] In some implementations, R 4Y and R 5Y One of them is H; and R 4Y and R 5Y The other one in is not H (e.g., R). 4Y and R 5Y One of them is H; and R 4Y and R 5Y The other is an independently selected C1-C6 alkyl group, which is optionally surrounded by 1-3 R groups. a (Replace). As a non-restrictive example, R 4Y and R 5Y One of them can be H; R 4Y and R 5Y The other one can be an independently selected C2-C4 alkyl group (e.g., C2 alkyl), which is optionally surrounded by 1-3 R groups. a replace.

[0411] In some implementations, R 4Y and R 5Y All are H.

[0412] In some implementations, R 4Y and R 5Y Together with their respective nitrogen atoms, they form a ring comprising 3-8 ring atoms, wherein the ring comprises: (a) 1-7 ring carbon atoms, each ring carbon atom being separated by 1-2 independently selected H and C atoms. 1-3 Alkyl substituents; and (b) 0-3 cyclic heteroatoms (except for R) 4Y and R 5Y (The ring heteroatoms other than the nitrogen atom that are connected) are each independently selected from N(H), N(R) d ), O and S.

[0413] In some implementations, R 4Y and R 5Y Together with their respective nitrogen atoms, they form a ring comprising 5 ring atoms, wherein the ring comprises: (a) 1-4 ring carbon atoms, each ring carbon atom being supported by 1-2 independently selected H and C atoms. 1-3 Alkyl substituents; and (b) 0-3 cyclic heteroatoms (except for R) 4Y and R 5Y (The ring heteroatoms other than the nitrogen atom that are connected) are each independently selected from N(H), N(R) d ), O and S.

[0414] In some implementations, R4Y and R 5Y Together with their respective nitrogen atoms, they form a ring comprising 6 ring atoms, wherein the ring comprises: (a) 1-5 ring carbon atoms, each ring carbon atom being supported by 1-2 independently selected H and C atoms. 1-3 Alkyl substituents; and (b) 0-3 cyclic heteroatoms (except for R) 4Y and R 5Y (The ring heteroatoms other than the nitrogen atom that are connected) are each independently selected from N(H), N(R) d ), O and S.

[0415] As a non-restrictive example as described above, Y could be:

[0416] In some implementations, when Y is C(O)NR 4Y R 5Y When Y is CONH2.

[0417] In some implementations, when Y is C(O)NR 4Y R 5Y When, Y is selected In some of the foregoing embodiments, R a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 Haloalkoxy (e.g., Y can be) ).

[0418] In some implementations, when Y is C(O)NR 4Y R 5Y When, Y is selected from:

[0419] In some implementations, when Y is CONR 4Y R 5Y When, Y is selected from:

[0420] In some implementations, Y is C(O)NHR 5Y In some of these implementations, R 5Y It is C 1-6 Alkyl groups, optionally composed of 1-3 independently selected R groups a Replacement. In some implementations, R 5Y yes In some of these implementations, R a It is NR e R fIn some of these implementations, R e and R f Each is H or C 1-6 Alkyl group. For example, R e and R f Each can be C 1-3 alkyl.

[0421] In some implementations, R e and R f Together with their respective nitrogen atoms, they form a ring comprising 3-8 (e.g., 5-6) ring atoms, wherein said ring comprises: (a) 1-7 (e.g., 1-5) ring carbon atoms, each ring carbon atom being supported by 1-2 independently selected H and C atoms. 1-3 Alkyl substituents; and (b) 0-3 cyclic heteroatoms (except for R) e and R f (The ring heteroatoms other than the nitrogen atom that are connected) are each independently selected from N(H), N(R) d ), O and S;

[0422] As a non-restrictive example, R 5Y It can be

[0423] In some implementations, Y is C(O)NHR 5Y And R 5Y It is a heteroaryl group containing 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-4 independently selected R h Replacement. In some of these implementations, R 5Y It is a heteroaryl group containing 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-4 independently selected R h Replacement. For example, R 5Y It can be a tetrazolium group, wherein the cyclic nitrogen atom is optionally replaced by R. d Replacement. For example, R 5Y It can be (For example, ).

[0424] In some embodiments, Y is a heteroaryl group comprising 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected R c replace.

[0425] In some embodiments, Y is a heteroaryl group comprising 5 ring atoms, wherein 2-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected R c replace.

[0426] In some embodiments, Y is a heteroaryl group comprising 5 ring atoms, wherein 3-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected R c replace.

[0427] In some of the foregoing embodiments, when Y is a heteroaryl group containing 5 ring atoms, each occurrence of R c Select independently from the following groups:

[0428] (i) Halogens;

[0429] (ii) Cyano group;

[0430] (iii)C 1-10 alkyl;

[0431] (iv) R selected by 1-6 independent choices a Replacement C 1-10 alkyl;

[0432] (v) R, which is arbitrarily selected by 1-3 independent choices b Replacement C 3-6 cycloalkyl;

[0433] (vi)C 2-6 alkenyl;

[0434] (vii)C 2-6 alkynyl group;

[0435] (viii)C 1-4 Alkoxy;

[0436] (ix)C 1-4 Halogenated alkoxy groups;

[0437] (x) C is arbitrarily selected by 1-4 independent choices. 1-4 Alkyl-substituted -(C 0-3 (alkylene)-C 3-6 cycloalkyl;

[0438] (xi)-S(O) 1-2 (C 1-4 alkyl);

[0439] (xii)-NR e R f ;

[0440] (xiii)-OH;

[0441] In some of the foregoing embodiments, when Y is a heteroaryl group containing 5 ring atoms, each occurrence of R d Selected from the following group: C 1-6 Alkyl; with 1-6 independently selected R a Replacement C 1-10 Alkyl; optionally composed of 1-3 independently selected R b Replacement 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).

[0442] In some embodiments, when Y is a heteroaryl group containing 5 ring atoms, Y is selected from tetrazolyl, triazolyl, oxadiazolyl, imidazolyl, and oxazolyl, wherein one or more heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected R atoms. c Substitution; and one of the heteroaryl ring nitrogen atoms is optionally replaced by R d replace.

[0443] In some embodiments, when Y is a heteroaryl group comprising 5 ring atoms, Y is selected from tetrazolyl, triazolyl, oxadiazolyl, and oxazolyl, wherein one or more heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected R atoms. c Substitution; and one of the heteroaryl ring nitrogen atoms is optionally replaced by R d replace.

[0444] In some of the foregoing embodiments, each R c When it exists, it is selected independently:

[0445] (i) Halogens;

[0446] (iii)C 1-10 alkyl;

[0447] (iv) R selected independently by 1-6 (e.g., 1) a Replacement C 1-10 Alkyl; and

[0448] (v) R, which is arbitrarily selected by 1-3 independent choices b Replacement C 3-6 cycloalkyl (e.g., each R) c It can be (iii)C independently 1-10 Alkyl or (iv) by 1-6 independently selected R a Replacement C 1-10 alkyl).

[0449] In some of the foregoing embodiments, R d It is C 1-6 Alkyl groups, which are optionally composed of 1-3 independently selected R groups. g Replacement. In some of these implementations, R d It is unreplaced C 1-3 alkyl.

[0450] In some other implementations, R d It is C 1-3 Alkyl groups, which are optionally composed of 1-3 independently selected R groups. g Replacement. In some of these implementations, R g Selected from the following groups: -OH, -F, N(C) 1-3 Alkyl)2,C 1-3 Alkoxy group, -CONH2, -CONHS(O)2(C 1-4 Alkyl groups and -C(O)OH.

[0451] R d Non-restrictive examples may include the following:

[0452]

[0453] In some of the foregoing embodiments, Y is selected from the group consisting of: (For example, R) a It can be selected from -OH, -OMe, and -NMe2). For example, Y can be...

[0454] In some implementations, Y is selected from the group consisting of: For example, Y could be In some implementations, R d It is unreplaced C 1-3 Alkyl groups, such as methyl groups.

[0455] In some other of the foregoing embodiments, R d It is C 1-3 Alkyl groups, which are optionally composed of 1-3 independently selected R groups. g Replacement. In some of these implementations, R gSelected from the following groups: -OH, -F, N(C) 1-3 Alkyl)2,C 1-3 Alkoxy group, -CONH2, -CONHS(O)2(C 1-4 Alkyl groups and -C(O)OH. R d Non-restrictive examples may include the following:

[0456]

[0457] In some implementations, Y is In some of these implementations, R c It is NH2, C(=O)N(R')(R”), C(=O)OH, or optionally R a Replacement C 1-3 Alkyl (e.g., R) c It can be ).

[0458] In some embodiments, Y is a heteroaryl group comprising 6 ring atoms, wherein 1-3 ring atoms are cyclic nitrogen atoms, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected R atoms. c Substitution. As a non-limiting example, Y can be pyridinyl or pyrimidinyl, each optionally replaced by one or two independently chosen R. c Replace. As a non-restrictive example, Y could be...

[0459] In some embodiments, Y is a heterocyclic alkenyl group comprising 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d O and S, and one or more of the heterocyclic alkenyl ring carbon atoms are optionally separated by 1-2 independently selected R b Substitution. In some of these embodiments, Y is an imidazolinyl group, wherein the cyclic nitrogen is optionally replaced by R. d Replace (e.g., ).

[0460] variable Z

[0461] In some implementations, Z is selected from H and NR. 4Z R 5Z OR 6Z and OC(O)R 7Z .

[0462] In some implementations, Z is NR 4Z R 5Z .

[0463] variable R 4Z / R5Z

[0464] In some implementations, R 4Z It is H.

[0465] In some implementations, R 4Z It is C 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groups. a Replacement. In some of the foregoing embodiments, R 4Z It is C 1-6 Alkyl groups, which are optionally composed of 1-2 independently selected R groups. a replace.

[0466] In some implementations, R 4Z It is C 1-3 Alkyl group, optionally marked with one R a Replace. As a non-restrictive example, R 4Z It can be (in some implementations, R) a Selected from -OH, -NR e R f C 1-4 Alkoxy and C 1-4 Haloalkoxy groups, for example, R 4Z It can be ).

[0467] In some implementations, R 4Z It is unreplaced C 1-10 Alkyl group. In some of the foregoing embodiments, R 4Z It is unreplaced C 1-10 Alkyl (e.g., unsubstituted C) 1-6 Alkyl groups, such as unsubstituted C4 groups 1-3 Alkyl groups, such as methyl groups.

[0468] In some implementations, R 4Z Selected from the following group: -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).

[0469] In some implementations, R 5Z It is H.

[0470] In some implementations, R 5Z It is C 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groups. aReplacement. In some of the foregoing embodiments, R 5Z It is C 1-6 Alkyl groups, which are optionally composed of 1-2 independently selected R groups. a replace.

[0471] In some implementations, R 5Z It is C 1-3 Alkyl group, optionally marked with one R a Replace. As a non-restrictive example, R 5Z It can be (in some implementations, R) a Selected from -OH, -NR e R f C 1-4 Alkoxy and C 1-4 Haloalkoxy groups, for example, R 5Z It can be ).

[0472] In some implementations, R 5Z It is unreplaced C 1-10 Alkyl group. In some of the foregoing embodiments, R 5Z It is unreplaced C 1-10 Alkyl (e.g., unsubstituted C) 1-6 Alkyl groups, such as unsubstituted C4 groups 1-3 Alkyl groups, such as methyl groups.

[0473] In some implementations, R 5Z Selected from the following group: -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).

[0474] In some implementations, R 4Z and R 5Z None of them are H (e.g., R) 4Z and R 5Z Each is an independently selected C1-C6 alkyl group, optionally bounded by 1-3 R... a Replacement, for example, R 4Z and R 5Z Each is an independently selected unsubstituted C1-C6 alkyl group.

[0475] In some implementations, R 4Z and R 5Z One of them is H; and R 4Z and R 5ZThe other one in is not H (e.g., R). 4Z and R 5Z One of them is H; and R 4Z and R 5Z The other is an independently selected C1-C6 alkyl group, which is optionally surrounded by 1-3 R groups. a Replacement, for example, R 5Z (It is an independently selected unsubstituted C1-C6 alkyl group).

[0476] In some implementations, R 4Z and R 5Z All are H.

[0477] In some implementations, when Z is NR 4Z R 5Z At that time, R 4Z and R 5Z Each is independently selected from H and optionally selected from 1-6 independently chosen R. a Replacement C 1-10 alkyl.

[0478] In some implementations, when Z is NR 4Z R 5Z At that time, R 4Z and R 5Z Each is independently selected from H and optionally from 1-2 independently selected R. a Replacement C 1-6 alkyl.

[0479] In some implementations, when Z is NR 4Z R 5Z At that time, R 4Z and R 5Z Each is independently selected from H and arbitrarily selected by 1 R. a Replacement C 1-3 alkyl.

[0480] In some implementations, when Z is NR 4Z R 5Z At that time, R 4Z and R 5Z Each is independently selected from H and unsubstituted C. 1-10 alkyl.

[0481] In some of the foregoing embodiments, R 4Z and R 5Z Each is independent of the H or methyl group.

[0482] In some implementations, when Z is NR 4Z R 5Z At that time, R 4Z and R 5Z Each is independently selected from H and As a non-restrictive example, R 4Z and R 5Z R on a It can be selected from -OH, -NR e R f C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups. For example, R 4Z and R 5Z Each can be independently selected from H and

[0483] In some implementations, R 4Z and R 5Z One or two of them are H.

[0484] In some implementations, R 4Z and R 5Z Each is independently H or unsubstituted C 1-10 Alkyl (e.g., unsubstituted C) 1-6 Alkyl groups, such as unsubstituted C4 groups 1-3 Alkyl groups, such as methyl groups.

[0485] In some implementations, Z is OR 6Z .

[0486] In some implementations, R 6Z Selected from H and R, which are optionally chosen independently from 1 to 6. a Replacement C 1-10 alkyl.

[0487] In some implementations, R 6Z It is H.

[0488] In some implementations, R 6Z It is C 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groups a replace.

[0489] In some implementations, R 6Z It is C 1-6 Alkyl groups, optionally composed of 1-6 independently selected R groups a replace.

[0490] In some implementations, R 6Z It is C 1-3 Alkyl group, optionally selected by one or two (e.g., one) independently chosen R a Replace (in some implementations, R) 6Z R on a Selected from -OH, -NR e R f C1-4 Alkoxy and C 1-4 (haloalkoxy group).

[0491] As a non-restrictive example as described above, R 6Z It can be (For example ).

[0492] In some implementations, when Z is OR 6Z At that time, R 6Z Selected from H and R, which are optionally chosen independently from 1 to 6. a Replacement C 1-10 alkyl.

[0493] In some implementations, Z is OH.

[0494] In some implementations, Z is -O(C) 1-3 Alkyl), wherein C 1-3 The alkyl portion is optionally separated by 1-2 independently selected R a replace.

[0495] As a non-limiting example of the foregoing implementation, Z can be:

[0496]

[0497] In some implementations, when Z is OR 6Z At that time, R 6Z Yes - (T) 1 -T 2 ) t -T 3 .

[0498] In some of the foregoing embodiments, t is 2-3 (e.g., t is 2).

[0499] In some implementations, T occurs each time. 1 C is independent 2-3 Alkylene (e.g., C2 alkylene).

[0500] In some implementations, T occurs each time. 2 It can be -N(H)-, -N(Me)-, or -O- independently.

[0501] In some implementations, T 3 Is it H or C? 1-3 Alkyl (e.g., H or methyl).

[0502] As a non-limiting example of the foregoing implementation, Z can be:

[0503]

[0504] In some implementations, Z is OC(O)R 7Z .

[0505] In some implementations, R 7Z It is H.

[0506] In some implementations, R 7Z It is C 1-10 Alkyl (e.g., C10) 1-6 Alkyl groups, optionally selected by 1 to 6 (e.g., 1 to 4, 1 to 3, 1) independently chosen R groups. a Replacement. In some of the foregoing embodiments, R 7Z It is C 1-6 Alkyl group, optionally selected by 1 to 3 (e.g., 1 or 2) independently chosen R a replace.

[0507] In some of the foregoing embodiments, when R 7Z R is arbitrarily selected by 1-6 independent choices. a Replacement C 1-10 When alkyl, each occurrence of R a Independently selected from the following groups: -OH; -F; -NR e R f (For example, NMe2); C(=O)OH; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups.

[0508] In some of the foregoing embodiments, when R 7Z R is arbitrarily selected by 1-6 independent choices. a Replacement C 1-10 When alkyl, each occurrence of R a Independently selected from the following groups: -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups.

[0509] In some implementations, R 7Z It is unreplaced C 1-10 Alkyl (e.g., unsubstituted C) 1-6 Alkyl groups, for example, unsubstituted C4 groups 1-4 Alkyl group). As a non-limiting example, R 7Z It can be methyl, ethyl, or isopropyl.

[0510] In some implementations, R 7Z It is C 6-10 Aryl groups, which are optionally bounded by 1-4 R groupsc replace.

[0511] In some implementations, R 7Z It is a C6 aryl group, optionally bounded by 1-4 R groups. c replace.

[0512] In some of the foregoing embodiments, when R 7Z It can be arbitrarily divided by 1-4 Rs c Replacement C 6-10 When aryl, each occurrence of R c Select independently from the following groups:

[0513] (i) Halogens;

[0514] (ii) Cyano group;

[0515] (iii)C 1-6 alkyl;

[0516] (iv)C 2-6 alkenyl;

[0517] (v)C 2-6 alkynyl group;

[0518] (vi)C 1-4 Halogenated alkyl groups;

[0519] (vii)C 1-4 Alkoxy;

[0520] (viii)C 1-4 Halogenated alkoxy groups;

[0521] (ix) C can be arbitrarily selected from 1 to 4 independent choices. 1-4 Alkyl-substituted -(C 0-3 (alkylene)-C 3-6 cycloalkyl;

[0522] (xi)-NR e R f ;and

[0523] (xii)-OH.

[0524] In some implementations, R 7Z It is C 3-6 cycloalkyl groups, optionally surrounded by 1-4 R groups. b replace.

[0525] In some of the foregoing embodiments, when R 7Z It can be arbitrarily divided by 1-4 Rs b Replacement C 3-6 In cycloalkyl groups, the R that appears each time b Select independently from the following group: C1-6 Alkyl; C 1-4 Halogenated alkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and optionally C 1-4 independently selected 1-4 Alkyl-substituted C 3-6 Cycloalkyl.

[0526] In some implementations, Z is OP(O)OR 8Z OR 9Z For example, Z could be OP(O)OH(OH).

[0527] In some implementations, R 8Z It is H.

[0528] In some implementations, R 8Z It is C 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groups a replace.

[0529] In some implementations, R 9Z It is H.

[0530] In some implementations, R 9Z It is C 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groups a replace.

[0531] In some implementations, Z is H.

[0532] In some embodiments, Z is a heterocyclic group comprising 4-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R) d And O, and one or more of the heterocyclic group carbon atoms are optionally separated by 1-4 independently selected R h replace.

[0533] In some of these embodiments, Z is a heterocyclic group comprising 5-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R). d And O, and one or more of the heterocyclic group carbon atoms are optionally separated by 1-4 independently selected R h Substitution. For example, Z can be piperidinyl, pyrrolidinyl, piperazinyl, or morpholinyl, each optionally substituted as described above. As a non-limiting example, Z can be morpholino-4-yl.

[0534] In some implementations, Z is OR6Z , where R 6Z yes:

[0535] (iii)-(C 0-2 alkylene)-(C 6-10 Aryl), of which C 6-10 The aryl group is optionally selected by 1-2 independently chosen R groups. h Replace; or

[0536] (iv)-(C 0-2 Alkylene-(heteroaryl), wherein the heteroaryl group comprises 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(C) 1-3 Alkyl), O and S, and one or more of the heteroaryl ring carbon atoms are optionally surrounded by 1-4 independently selected R h replace.

[0537] In some of these implementations, R 6Z It is (iv)-(C) 0-2 Alkylene-(heteroaryl), wherein the heteroaryl group comprises 5-6 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(C) 1-3 Alkyl), O and S, and one or more of the heteroaryl ring carbon atoms are optionally surrounded by 1 to 4 (e.g., 1, 2, 3 or 4) independently selected R h Replacement. For example, Z could be...

[0538] In some implementations, Z is R 6Z , where R 6Z Yes: -(C 1-2 alkylene)-C(=O)NH-(C 1-3 (alkylene)-R 6Z’ .

[0539] In some of these implementations, R 6Z’ Selected from the following group:

[0540] C(=O)OH,N(C 1-4 Alkyl)2, NH2 and NH(C) 1-4 alkyl).

[0541] As a non-restrictive example, Z could be:

[0542]

[0543] In some implementations, R 6Z’ It is a heterocyclic group containing 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R).d And O, and one or more of the heterocyclic group carbon atoms are optionally separated by 1-4 independently selected C atoms. 1-3 Alkyl substitution.

[0544] In some of these implementations, R 6Z’ It is a heterocyclic group containing 5-6 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R). d And O, and one or more of the heterocyclic group carbon atoms are optionally separated by 1-4 independently selected C atoms. 1-3 Alkyl substitution.

[0545] As a non-restrictive example, Z could be:

[0546]

[0547] variable R 1 R 2 and R 3

[0548] In some implementations, R 1 It is R 6A .

[0549] In some implementations, R 1 It is R 6A And R 2 and R 3 None of them are R 6A .

[0550] In some implementations, R 1 It is R 6A ;R 2 It is R 6A And R 3 Not R 6A .

[0551] In some implementations, R 1 It is R 6A ;R 3 It is R 6A And R 2 Not R 6A .

[0552] In some implementations, R 1 It is R 6A And R 2 and R 3 Each is an independently chosen R 6A .

[0553] In some implementations, R 2 It is R 6A .

[0554] In some implementations, R2 It is R 6A And R 1 and R 3 None of them are R 6A .

[0555] In some implementations, R 2 It is R 6A ;R 3 It is R 6A And R 1 Not R 6A .

[0556] In some implementations, R 3 It is R 6A .

[0557] In some implementations, R 3 It is R 6A And R 1 and R 3 None of them are R 6A .

[0558] In some implementations, R 6A It is H.

[0559] In some implementations, R 6A It is C 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groups a replace.

[0560] In some implementations, R 1 It is C(O)R 7A .

[0561] In some implementations, R 1 It is C(O)R 7A And R 2 and R 3 None of them are C(O)R 7A .

[0562] In some implementations, R 1 It is C(O)R 7A ;R 2 It is C(O)R 7A And R 3 Not C(O)R 7A .

[0563] In some implementations, R 1 It is C(O)R 7A ;R 3 It is C(O)R 7A And R 2 Not C(O)R 7A.

[0564] In some implementations, R 1 It is C(O)R 7A And R 2 and R 3 Both are C(O)R 7A .

[0565] In some implementations, R 2 It is C(O)R 7A .

[0566] In some implementations, R 2 It is C(O)R 7A And R 1 and R 3 None of them are C(O)R 7A .

[0567] In some implementations, R 2 It is C(O)R 7A ;R 3 It is C(O)R 7A And R 1 Not C(O)R 7A .

[0568] In some implementations, R 3 It is C(O)R 7A .

[0569] In some implementations, R 3 It is C(O)R 7A And R 1 and R 3 None of them are C(O)R 7A .

[0570] In some implementations, R 7A It is H.

[0571] In some implementations, R 7A It is C 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groups a Replace (e.g., optionally by 1-6 independently selected R) a Replacement C 1-6 Or C 1-3 Alkyl; for example, C 1-10 Or C 1-6 Or C 1-3 Unsubstituted alkyl groups (e.g., CH3)). In some of the foregoing embodiments, R 7A It is C 1-6 Alkyl group, optionally selected by 1 to 6 (e.g., 1 to 3) independently chosen R a replace.

[0572] In some of the foregoing embodiments, when R 7A R is arbitrarily selected by 1-6 independent choices. a Replacement C 1-10 When alkyl, each occurrence of R a Independently selected from the following groups: -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups.

[0573] In some implementations, R 7A It is C 6-10 Aryl groups, which are optionally bounded by 1-4 R groups c replace.

[0574] In some implementations, R 7A It is a C6 aryl group, optionally bounded by 1-4 R groups. c replace.

[0575] In some of the foregoing embodiments, when R 7A It can be arbitrarily divided by 1-4 Rs c Replacement C 6-10 When aryl, each occurrence of R c Select independently from the following groups:

[0576] (i) Halogens;

[0577] (ii) Cyano group;

[0578] (iii)C 1-6 alkyl;

[0579] (iv)C 2-6 alkenyl;

[0580] (v)C 2-6 alkynyl group;

[0581] (vi)C 1-4 Halogenated alkyl groups;

[0582] (vii)C 1-4 Alkoxy;

[0583] (viii)C 1-4 Halogenated alkoxy groups;

[0584] (ix) C can be arbitrarily selected from 1 to 4 independent choices. 1-4 Alkyl-substituted -(C 0-3 (alkylene)-C 3-6 cycloalkyl;

[0585] (xi)-NRe R f ;and

[0586] (xii)-OH.

[0587] In some implementations, R 7A It is C 3-6 cycloalkyl groups, optionally surrounded by 1-4 R groups. b replace.

[0588] In some of the foregoing embodiments, when R 7A It can be arbitrarily divided by 1-4 Rs b Replacement C 3-6 In cycloalkyl groups, the R that appears each time b Select independently from the following group: C 1-6 Alkyl; C 1-4 Halogenated alkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f C 1-4 Alkoxy; C 1-4 Haloalkoxy; cyano; and optionally C 1-4 independently selected 1-4 Alkyl-substituted C 3-6 Cycloalkyl.

[0589] In some implementations, R 1 Is it OP(O)OR 8A OR 9A .

[0590] In some implementations, R 1 Is it OP(O)OR 8A OR 9A And R 2 and R 3 Neither is OP(O)OR 8A OR 9A .

[0591] In some implementations, R 1 Is it OP(O)OR 8A OR 9A ;R 2 Is it OP(O)OR 8A OR 9A And R 3 Not OP(O)OR 8A OR 9A .

[0592] In some implementations, R 1 Is it OP(O)OR 8A OR 9A ;R 3 Is it OP(O)OR8A OR 9A And R 2 Not OP(O)OR 8A OR 9A .

[0593] In some implementations, R 1 Is it OP(O)OR 8A OR 9A And R 2 and R 3 Both are OP(O)OR 8A OR 9A .

[0594] In some implementations, R 2 Is it OP(O)OR 8A OR 9A .

[0595] In some implementations, R 2 Is it OP(O)OR 8A OR 9A And R 1 and R 3 Neither is OP(O)OR 8A OR 9A .

[0596] In some implementations, R 2 Is it OP(O)OR 8A OR 9A ;R 3 Is it OP(O)OR 8A OR 9A And R 1 Not OP(O)OR 8A OR 9A .

[0597] In some implementations, R 3 Is it OP(O)OR 8A OR 9A .

[0598] In some implementations, R 3 Is it OP(O)OR 8A OR 9A And R 1 and R 3 Neither is OP(O)OR 8A OR 9A .

[0599] In some implementations, R 8A It is H.

[0600] In some implementations, R8A It is C 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groups a replace.

[0601] In some implementations, R 9A It is H.

[0602] In some implementations, R 9A It is C 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groups a replace.

[0603] In some implementations, R 1 R 2 and R 3 Each is independently selected from H and C(O)R 7A .

[0604] In some of the foregoing embodiments, each occurrence of R 7A C is independent 1-10 Alkyl groups, optionally composed of 1-6 independently selected R groups a Replace (e.g., optionally by 1-6 independently selected R) a Replacement C 1-6 Or C 1-3 Alkyl; for example, C 1-10 Or C 1-6 Or C 1-3 Unsubstituted alkyl groups (e.g., CH3)).

[0605] In some implementations, R 1 R 2 and R 3 Each is independently selected from H and C(O)Me (e.g., R). 1 R 2 and R 3 Both are H; or R 1 R 2 and R 3 All are C(O)Me).

[0606] In some implementations, R 1 R 2 and R 3 One or more of them are H. In some of these implementations, R 1 R 2 and R 3 Each one in the list is H.

[0607] In some other implementations, R 1 R 2 and R 3 Each of them is C(O)Me.

[0608] variable Z x

[0609] In some implementations, Z x All are H.

[0610] In some implementations, each Z x Together with the carbon atoms they are attached to, they form C=O.

[0611] Leek Restricted Combinations

[0612] Leek restricted combinations[1]

[0613] In some embodiments, the compound of formula (I) is a compound having formula (Ia):

[0614]

[0615] Where X, Y, Z, Z x R 1 R 2 and R 3 As defined elsewhere in this document.

[0616] Unrestricted combinations [2]

[0617] In some implementation methods:

[0618] X is arbitrarily divided by 1-3 Rs a Substituted C1-C6 alkyl groups; and

[0619] Y is CO2R 6Y .

[0620] In some embodiments of [2], R 6Y It is C 1-12 Alkyl groups, optionally composed of 1-6 independently selected R groups a Replacement. In some implementations, R 6Y It is C 1-6 Alkyl groups, optionally composed of 1-3 independently selected R groups a Replace (e.g., optionally by 1 R) a (Substituted C2 alkyl). In some embodiments, R 6Y It is C 1-4 Alkyl groups, optionally composed of 1-2 independently selected R groups a Replace (e.g., optionally by 1 R) a (Substituted C2 alkyl). In some embodiments, R 6Y yes Where R a As defined elsewhere in this document (in some implementations, R)a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 (Haloalkoxy). For example, R 6Y It is methyl, 2-(dimethylamino)-ethyl-1-yl or 2-(hydroxy)-ethyl-1-yl. In some embodiments of [2], R 6Y It is unreplaced C 1-12 alkyl.

[0621] In some other embodiments of [2], R 6Y It is H.

[0622] In some embodiments of [2], R 6Y It is H.

[0623] In some embodiments of [2], R 6Y It is C 1-12 (For example, C) 1-6 C 2-6 C 2-3 ) alkyl groups, which are optionally composed of 1-6 independently selected R groups a Substitution (e.g., unsubstituted; or R selected by 1-2, e.g., 1 independently) a replace).

[0624] In some embodiments of [2], Y is selected from CO2H and CO2Me.

[0625] In some embodiments of [2], Y is For example, Y could be

[0626] In some embodiments of [2], Y is Where R a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 Haloalkoxy (e.g., Y can be) As a non-restrictive example, Y could be... And R a It can be -OH or -NR e R f (e.g., NMe2).

[0627] In some embodiments of [2], X is C 1-3 Alkyl; and Y is In some of these embodiments, X is a methyl group. In some embodiments, R... a Is it -OH or -NR? e R f (For example, NMe2).

[0628] In some implementations of [2], Z is OR 6Z For example, Z can be OH.

[0629] In some embodiments of [2], each Z x It is H.

[0630] In some embodiments of [2], each Z x Together with the carbon atoms they are attached to, they form C=O.

[0631] In some embodiments of [2], R 1 R 2 and R 3 Each is independently selected from H and C(O)R 7A For example, R 1 R 2 and R 3 Each can be H. In another non-restrictive example, R 1 R 2 and R 3 Each can be an independently chosen C(O)R 7A (e.g., C(O)Me).

[0632] Leek restricted combinations [3]

[0633] In some implementation methods:

[0634] X is arbitrarily divided by 1-3 Rs a Substituted C1-C6 alkyl groups; and

[0635] Y is C(O)NR 4Y R 5Y .

[0636] In some embodiments of [3], R 4Y It is H. In some other embodiments of [3], R 4Y It is C 1-12 (For example, C) 1-6 C 1-4 )alkyl group, optionally with 1-6 independently selected R a Replacement. In some of the foregoing embodiments, R 4Y It is C 1-6 Alkyl groups, optionally composed of 1-3 independently selected R groups a Replace (e.g., optionally by 1 R) a(Substituted C2 alkyl). In some of the foregoing embodiments, R 4Y It is C 1-4 Alkyl groups, optionally composed of 1-2 independently selected R groups a Replace (e.g., optionally by 1 R) a (Substituted C2 alkyl). In some embodiments, R 4Y yes Where R a As defined elsewhere in this document (in some implementations, R) a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 (Haloalkoxy). For example, R 4Y It is methyl, 2-(dimethylamino)-ethyl-1-yl or 2-(hydroxy)-ethyl-1-yl. In some embodiments of [3], R 4Y It is unreplaced C 1-12 Alkyl (e.g., C10) 1-6 C 2-6 C 2-3 ).

[0637] In some embodiments of [3], R 5Y It is H. In some other embodiments of [3], R 5Y It is C 1-12 (For example, C) 1-6 C 1-4 )alkyl group, optionally with 1-6 independently selected R a Replacement. In some of the foregoing embodiments, R 5Y It is C 1-6 Alkyl groups, optionally composed of 1-3 independently selected R groups a Replace (e.g., optionally by 1 R) a (Substituted C2 alkyl). In some of the foregoing embodiments, R 5Y It is C 1-4 Alkyl groups, optionally composed of 1-2 independently selected R groups a Replace (e.g., optionally by 1 R) a (Substituted C2 alkyl). In some embodiments, R 5Y yes Where R a As defined elsewhere in this document (in some implementations, R) a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 (Haloalkoxy). For example, R5Y It is methyl, 2-(dimethylamino)-ethyl-1-yl or 2-(hydroxy)-ethyl-1-yl. In some embodiments of [3], R 5Y It is unreplaced C 1-12 Alkyl (e.g., C10) 1-6 C 2-6 C 2-3 ).

[0638] In some embodiments of [3], R 4Y and R 5Y None of them are H (e.g., R) 4Y and R 5Y Each is an independently selected C1-C6 alkyl group.

[0639] In some embodiments of [3], R 4Y and R 5Y One of them is H; and R 4Y and R 5Y The other one in is not H (e.g., R). 4Y and R 5Y One of them is H; and R 4Y and R 5Y The other one is an independently selected C1-C6 alkyl group.

[0640] In some embodiments of [3], R 4Y and R 5Y All are H.

[0641] In some embodiments of [3], R 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 .

[0642] In some of the aforementioned embodiments of [3], n is 2-3 (e.g., n is 2; or n is 3).

[0643] In some embodiments of [3], W occurs each time. 1 C is independent 2-3 Alkylene (e.g., C2 alkylene).

[0644] In some embodiments of [3], W occurs each time. 2 Independently -N(H)-, -N(Me)-, or -O- (e.g., a W) 2 It's -O-; another W 2 (When it exists) is -N(Me)-).

[0645] In some embodiments of [3], W 3 Selected from H and C 1-3 alkyl.

[0646] As a non-limiting example of the foregoing implementation, R 4Y and R 5Y One of them can be selected from:

[0647] In some embodiments of [3], when R 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 At that time, R 4Y and R 5Y The other one is selected from H and C. 1-3 alkyl.

[0648] In some implementations, R 4Y and R 5Y One of them is not H.

[0649] In some embodiments of [3], R 4Y and R 5Y are each independently H or C 1-12 Alkyl (e.g., C10) 1-6 C 1-4 ), which is optionally selected independently by 1-6 (e.g., 1-3 or 1-2) R a replace.

[0650] In some embodiments of [3], R 4Y and R 5Y Each is H or independently

[0651] In some of these implementations, R 4Y and R 5Y One of them is H; R 4Y and R 5Y The other one is

[0652] In some of the foregoing embodiments of [3] (when R) 4Y and R 5Y Each is H or independently ), R a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups.

[0653] In some of these implementations (e.g., when R...) 4Y and R 5Y One of them is H; and R 4Y and R 5Y The other one is ), R a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups.

[0654] In some embodiments of [3], R 4Y and R 5Y H, each independently

[0655] In some implementations of [3], Y is CONH2.

[0656] In some other embodiments of [3], Y is (For example, R) a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 (Haloalkoxy). As a non-limiting example, Y could be...

[0657] In some embodiments of [3], R 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 And R 4Y and R 5Y The other one is selected from H and C. 1-3 alkyl.

[0658] In some embodiments of [3], R 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 And R 4Y and R 5Y The other one is selected from H and C. 1-3 Alkyl; n is 2 or 3.

[0659] In some embodiments of [3] (when R) 4Y and R5Y One of them is -(W) 1 -W 2 ) n -W 3 And R 4Y and R 5Y The other one is selected from H and C. 1-3 Alkyl), W 1 Each time it appears, it is C independently. 2-3 Alkylene (e.g., C2 alkylene).

[0660] In some embodiments of [3] (when R) 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 And R 4Y and R 5Y The other one is selected from H and C. 1-3 Alkyl), W 2 Each time it appears, it is independently -N(H)-, -N(Me)-, or -O-.

[0661] In some embodiments of [3] (when R) 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 And R 4Y and R 5Y The other one is selected from H and C. 1-3 Alkyl), W 3 Selected from H and C 1-3 alkyl.

[0662] In some embodiments of [3], R 4Y and R 5Y One of them is selected from:

[0663] In some embodiments of [3], R 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 And R 4Y and R 5Y The other one is H, where n is 2 or 3; W 1 Each time it appears, it is C independently. 2-3 Alkylene (e.g., C2 alkylene); W 2Each occurrence is independently -N(H)-, -N(Me)-, or -O-; W 3 Selected from H and C 1-3 alkyl.

[0664] As a non-limiting example of the foregoing implementation, when Y is C(O)NR 4Y R 5Y Y can be

[0665] In some embodiments of [3], R 4Y and R 5Y Together with their respective nitrogen atoms, they form a ring comprising 3-8 ring atoms, wherein the ring comprises: (a) 1-7 ring carbon atoms, each ring carbon atom being separated by 1-2 independently selected H and C atoms. 1-3 Alkyl substituents; and (b) 0-3 cyclic heteroatoms (except for R) 4Y and R 5Y (The ring heteroatoms other than the nitrogen atom that are connected) are each independently selected from N(H), N(R) d ), O and S.

[0666] In some of the foregoing embodiments, R 4Y and R 5Y Together with their respective nitrogen atoms, they form a ring comprising 6 ring atoms, wherein the ring comprises: (a) 1-5 ring carbon atoms, each ring carbon atom being supported by 1-2 independently selected H and C atoms. 1-3 Alkyl substituents; and (b) 0-3 cyclic heteroatoms (except for R) 4Y and R 5Y (The ring heteroatoms other than the nitrogen atom that are connected) are each independently selected from N(H), N(R) d ), O and S.

[0667] As a non-restrictive example as described above, Y could be:

[0668] In some embodiments of [3], X is a C1-C3 alkyl group; Y is a C(O)NHR group. 5Y In some of these embodiments, X is a methyl group. In some of the foregoing embodiments, R... 5Y It is C 1-12 Alkyl (e.g., C10) 1-6 C 1-4 ), optionally selected by 1-6 (e.g., 1-3 or 1-2) independently selected R a Replace. As a non-restrictive example, R 5Y It can be (e.g. R) a It can be -OH; -F; -NRe R f (e.g., NMe2); C 1-4 alkoxy; or C 1-4 (Haloalkoxy). For example, R 5Y It can be

[0669] In some embodiments of [3], X is a C1-C3 alkyl group; Y is a C(O)NHR group. 5Y ;R 5Y Yes - (W 1 -W 2 ) n -W 3 Where n is 2 or 3; W appears each time. 1 C is independent 2-3 Alkylene (e.g., C2 alkylene); W each time it appears 2 Independently -N(H)-, -N(Me)-, or -O-; and W 3 Selected from H and C 1-3 alkyl.

[0670] In some implementations of [3], Z is OR 6Z For example, Z can be OH.

[0671] In some embodiments of [3], each Z x It is H.

[0672] In some embodiments of [3], each Z x Together with the carbon atoms they are attached to, they form C=O.

[0673] In some embodiments of [3], R 1 R 2 and R 3 Each is independently selected from H and C(O)R 7A For example, R 1 R 2 and R 3 Each can be H. In another non-restrictive example, R 1 R 2 and R 3 Each can be an independently chosen C(O)R 7A (e.g., C(O)Me).

[0674] Unrestricted combinations [4]

[0675] In some implementation methods:

[0676] X is arbitrarily divided by 1-3 Rs a Substituted C1-C6 alkyl groups; and

[0677] Y is a heteroaryl group containing 5 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), and N(R). d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected R c replace.

[0678] In some embodiments of [4], Y is a heteroaryl group comprising 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R). d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected R c replace.

[0679] In some embodiments of [4], Y is a heteroaryl group comprising 5 ring atoms, wherein one ring atom is a heteroatom selected from N, N(H), N(R). d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected R c replace.

[0680] In some embodiments of [4], Y is a heteroaryl group containing 5 ring atoms, of which 3-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R). d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected R c replace.

[0681] In some embodiments of [4], Y is selected from tetrazolyl, triazolyl, oxadiazolyl, and oxazolyl, wherein one or more heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected Rs. c Substitution; and one of the heteroaryl ring nitrogen atoms is optionally replaced by R d replace.

[0682] In some of the foregoing embodiments, each R c When it exists, it is selected independently:

[0683] (i) Halogens;

[0684] (iii)C 1-10 alkyl;

[0685] (iv) R selected independently by 1-6 (e.g., 1) a Replacement C 1-10 Alkyl; and

[0686] (v) R, which is arbitrarily selected by 1-3 independent choices b Replacement C 3-6cycloalkyl (e.g., each R) c It can be (iii)C independently 1-10 Alkyl or (iv) by 1-6 independently selected R a Replacement C 1-10 alkyl).

[0687] In some of the foregoing embodiments, Y is selected from the group consisting of: (For example, R) a It can be selected from -OH, -OMe and -NMe2).

[0688] In some embodiments of [4], Y is selected from tetrazolyl, triazolyl, oxadiazolyl, and oxazolyl, wherein one or more heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected Rs. c Substitution; and one of the heteroaryl ring nitrogen atoms is optionally replaced by R d replace.

[0689] In some embodiments of [4], Y is selected from the group consisting of: (For example, R) a It can be selected from -OH, -OMe and -NMe2).

[0690] In some embodiments of [4], X is C 1-3 Alkyl; Y is selected from tetrazolyl and trizolyl, wherein one or more heteroaryl ring carbon atoms are optionally surrounded by 1-2 independently selected R. c Substitution; and one of the heteroaryl ring nitrogen atoms is optionally replaced by R d replace.

[0691] In some of these embodiments, X is a methyl group.

[0692] In some of the foregoing embodiments, Y is As a non-restrictive example, Y is (For example ).

[0693] In some implementations of [4], Z is OR 6Z For example, Z can be OH.

[0694] In some embodiments of [4], each Z x It is H.

[0695] In some embodiments of [4], each Z x Together with the carbon atoms they are attached to, they form C=O.

[0696] In some embodiments of [4], R 1 R 2and R 3 Each is independently selected from H and C(O)R 7A For example, R 1 R 2 and R 3 Each can be H. In another non-restrictive example, R 1 R 2 and R 3 Each can be an independently chosen C(O)R 7A (e.g., C(O)Me).

[0697] Unrestricted combinations [5]

[0698] In some implementation methods:

[0699] X is NR 4X R 5X ;and

[0700] Y is CO2R 6Y .

[0701] In some embodiments of [5], R 4X and R 5X None of them are H (e.g., R) 4X and R 5X Each is an independently selected C1-C6 alkyl group, such as R 4X and R 5X Each is a methyl group.

[0702] In some embodiments of [5], R 4X and R 5X One of them is H; and R 4X and R 5X The other one in is not H (e.g., R). 4X and R 5X One of them is H; and R 4X and R 5X The other one is an independently selected C1-C6 alkyl group.

[0703] In some embodiments of [5], R 4X and R 5X All are H.

[0704] In some embodiments of [5], R 6Y R is arbitrarily selected by 1-6 independent choices. a Replacement C 1-12 Alkyl group. In some embodiments, R 6Y It is C 1-6 Alkyl groups, optionally composed of 1-3 independently selected R groups a Replace (e.g., optionally by 1 R) a(Substituted C2 alkyl). In some embodiments, R 6Y It is C 1-4 Alkyl groups, optionally composed of 1-2 independently selected R groups a Replace (e.g., optionally by 1 R) a (Substituted C2 alkyl). In some embodiments, R 6Y yes Where R a As defined elsewhere in this document (in some implementations, R) a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 (Haloalkoxy). For example, R 6Y It is methyl, 2-(dimethylamino)-ethyl-1-yl or 2-(hydroxy)-ethyl-1-yl. In some embodiments of [5], R 6Y It is unreplaced C 1-12 alkyl.

[0705] In some other embodiments of [5], R 6Y It is H.

[0706] In some embodiments of [5], R 6Y It is H.

[0707] In some embodiments of [5], R 6Y It is C 1-12 (For example, C) 1-6 C 2-6 C 2-3 ) alkyl groups, which are optionally composed of 1-6 independently selected R groups a Substitution (e.g., unsubstituted; or R selected by 1-2, e.g., 1 independently) a replace).

[0708] In some embodiments of [5], Y is selected from CO2H and CO2Me.

[0709] In some embodiments of [5], Y is For example, Y could be

[0710] In some embodiments of [5], Y is Where R a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 Haloalkoxy (e.g., Y can be) As a non-restrictive example, Y could be... And R a It can be -OH or -NR e R f (e.g., NMe2).

[0711] In some embodiments of [5], X is N(C 1-3 Alkyl)2; Y is In some of these implementations, X is NMe2. In some implementations, Y is... Where R a It can be -OH or -NR e R f (e.g., NMe2).

[0712] In some implementations of [5], Z is OR 6Z For example, Z can be OH.

[0713] In some embodiments of [5], each Z x It is H.

[0714] In some embodiments of [5], each Z x Together with the carbon atoms they are attached to, they form C=O.

[0715] In some embodiments of [5], R 1 R 2 and R 3 Each is independently selected from H and C(O)R 7A For example, R 1 R 2 and R 3 Each can be H. In another non-restrictive example, R 1 R 2 and R 3 Each can be an independently chosen C(O)R 7A (e.g., C(O)Me).

[0716] Leek restricted combinations[6]

[0717] In some implementation methods:

[0718] X is NR 4X R 5X ;and

[0719] Y is C(O)NR 4Y R 5Y .

[0720] In some embodiments of [6], R 4Xand R 5X None of them are H (e.g., R) 4X and R 5X Each is an independently selected C1-C6 alkyl group.

[0721] In some embodiments of [6], R 4X and R 5X One of them is H; and R 4X and R 5X The other one in is not H (e.g., R). 4X and R 5X One of them is H; and R 4X and R 5X The other one is an independently selected C1-C6 alkyl group.

[0722] In some embodiments of [6], R 4X and R 5X All are H.

[0723] In some embodiments of [6], R 4Y It is H. In some other embodiments of [6], R 4Y It is C 1-12 (For example, C) 1-6 C 1-4 )alkyl group, optionally with 1-6 independently selected R a Replacement. In some of the foregoing embodiments, R 4Y It is C 1-6 Alkyl groups, optionally composed of 1-3 independently selected R groups a Replace (e.g., optionally by 1 R) a (Substituted C2 alkyl). In some of the foregoing embodiments, R 4Y It is C 1-4 Alkyl groups, optionally composed of 1-2 independently selected R groups a Replace (e.g., optionally by 1 R) a (Substituted C2 alkyl). In some embodiments, R 4Y yes Where R a As defined elsewhere in this document (in some implementations, R) a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 (Haloalkoxy). For example, R 4Y It is methyl, 2-(dimethylamino)-ethyl-1-yl or 2-(hydroxy)-ethyl-1-yl. In some embodiments of [6], R 4Y It is unreplaced C 1-12 Alkyl (e.g., C10)1-6 C 2-6 C 2-3 ).

[0724] In some embodiments of [6], R 5Y It is H. In some other embodiments of [6], R 5Y It is C 1-12 (For example, C) 1-6 C 1-4 )alkyl group, optionally with 1-6 independently selected R a Replacement. In some of the foregoing embodiments, R 5Y It is C 1-6 Alkyl groups, optionally composed of 1-3 independently selected R groups a Replace (e.g., optionally by 1 R) a (Substituted C2 alkyl). In some of the foregoing embodiments, R 5Y It is C 1-4 Alkyl groups, optionally composed of 1-2 independently selected R groups a Replace (e.g., optionally by 1 R) a (Substituted C2 alkyl). In some embodiments, R 5Y yes Where R a As defined elsewhere in this document (in some implementations, R) a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 (Haloalkoxy). For example, R 5Y It is methyl, 2-(dimethylamino)-ethyl-1-yl-2-(hydroxy)-ethyl-1-yl. In some embodiments of [6], R 5Y It is unreplaced C 1-12 Alkyl (e.g., C10) 1-6 C 2-6 C 2-3 ).

[0725] In some embodiments of [6], R 4Y and R 5Y None of them are H (e.g., R) 4Y and R 5Y Each is an independently selected C1-C6 alkyl group.

[0726] In some embodiments of [6], R 4Y and R 5Y One of them is H; and R 4Y and R 5Y The other one in is not H (e.g., R). 4Y and R5Y One of them is H; and R 4Y and R 5Y The other one is an independently selected C1-C6 alkyl group.

[0727] In some embodiments of [6], R 4Y and R 5Y All are H.

[0728] In some embodiments of [6], R 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 .

[0729] In some of the aforementioned embodiments of [6], n is 2-3 (e.g., n is 2; or n is 3).

[0730] In some embodiments of [6], W occurs each time. 1 C is independent 2-3 Alkylene (e.g., C2 alkylene).

[0731] In some embodiments of [6], W occurs each time. 2 Independently -N(H)-, -N(Me)-, or -O- (e.g., a W) 2 It's -O-; another W 2 (When it exists) is -N(Me)-).

[0732] In some embodiments of [6], W 3 Selected from H and C 1-3 alkyl.

[0733] As a non-limiting example of the foregoing implementation, R 4Y and R 5Y One of them can be selected from:

[0734] In some embodiments of [6], when R 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 At that time, R 4Y and R 5Y The other one is selected from H and C. 1-3 alkyl.

[0735] In some implementations, R 4Y and R 5Y One of them is not H.

[0736] In some embodiments of [6], R 4Y and R 5Y are each independently H or C 1-12 Alkyl (e.g., C10) 1-6 C 1-4 ), which is optionally selected independently by 1-6 (e.g., 1-3 or 1-2) R a replace.

[0737] In some embodiments of [6], R 4Y and R 5Y Each is H or independently

[0738] In some of these implementations, R 4Y and R 5Y One of them is H; R 4Y and R 5Y The other one is

[0739] In some of the foregoing embodiments of [6] (when R) 4Y and R 5Y Each is H or independently ), R 4Y or R 5Y R on a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups.

[0740] In some of these implementations (e.g., when R...) 4Y and R 5Y One of them is H; R 4Y and R 5Y The other one is ), R a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups.

[0741] In some embodiments of [6], R 4Y and R 5Y H, each independently

[0742] In some embodiments of [6], Y is CONH2.

[0743] In some other embodiments of [6], Y is (For example, R) a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 (Haloalkoxy). As a non-limiting example, Y could be...

[0744] In some embodiments of [6], R 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 And R 4Y and R 5Y The other one is selected from H and C. 1-3 alkyl.

[0745] In some embodiments of [6], R 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 And R 4Y and R 5Y The other one is selected from H and C. 1-3 Alkyl; n is 2 or 3.

[0746] In some embodiments of [6] (when R) 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 And R 4Y and R 5Y The other one is selected from H and C. 1-3 Alkyl), W 1 Each time it appears, it is C independently. 2-3 Alkylene (e.g., C2 alkylene).

[0747] In some embodiments of [6] (when R) 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 And R 4Y and R 5Y The other one is selected from H and C. 1-3 Alkyl), W2 Each time it appears, it is independently -N(H)-, -N(Me)-, or -O-.

[0748] In some embodiments of [6] (when R) 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 And R 4Y and R 5Y The other one is selected from H and C. 1-3 Alkyl), W 3 Selected from H and C 1-3 alkyl.

[0749] In some embodiments of [6], R 4Y and R 5Y One of them is selected from:

[0750] In some embodiments of [6], R 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 And R 4Y and R 5Y The other one is H, where n is 2 or 3; W 1 Each time it appears, it is C independently. 2-3 Alkylene (e.g., C2 alkylene); W 2 Each occurrence is independently -N(H)-, -N(Me)-, or -O-; W 3 Selected from H and C 1-3 alkyl.

[0751] As a non-limiting example of the foregoing implementation, when Y is C(O)NR 4Y R 5Y When; Y can be

[0752] In some embodiments of [6], R 4Y and R 5Y Together with their respective nitrogen atoms, they form a ring comprising 3-8 ring atoms, wherein the ring comprises: (a) 1-7 ring carbon atoms, each ring carbon atom being separated by 1-2 independently selected H and C atoms. 1-3 Alkyl substituents; and (b) 0-3 cyclic heteroatoms (except for R) 4Y and R 5Y(The ring heteroatoms other than the nitrogen atom that are connected) are each independently selected from N(H), N(R) d ), O and S.

[0753] In some of the foregoing embodiments, R 4Y and R 5Y Together with their respective nitrogen atoms, they form a ring comprising 6 ring atoms, wherein the ring comprises: (a) 1-5 ring carbon atoms, each ring carbon atom being supported by 1-2 independently selected H and C atoms. 1-3 Alkyl substituents; and (b) 0-3 cyclic heteroatoms (except for R) 4Y and R 5Y (The ring heteroatoms other than the nitrogen atom that are connected) are each independently selected from N(H), N(R) d ), O and S.

[0754] As a non-restrictive example as described above, Y could be:

[0755] In some embodiments of [5], X is N(C 1-3 Alkyl)2; Y is C(O)NHR 5Y In some of these implementations, X is NMe2.

[0756] In some of the foregoing embodiments, Y is (For example, R) a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 (Haloalkoxy). As a non-limiting example, Y could be...

[0757] In some embodiments of [6], R 5Y Yes - (W 1 -W 2 ) n -W 3 Where n is 2 or 3; W appears each time. 1 C is independent 2-3 Alkylene (e.g., C2 alkylene); W each time it appears 2 Independently -N(H)-, -N(Me)-, or -O-; and W 3 Selected from H and C 1-3 alkyl.

[0758] In some implementations of [6], Z is OR 6Z For example, Z can be OH.

[0759] In some embodiments of [6], each Z x It is H.

[0760] In some embodiments of [6], each Z x Together with the carbon atoms they are attached to, they form C=O.

[0761] In some embodiments of [6], R 1 R 2 and R 3 Each is independently selected from H and C(O)R 7A For example, R 1 R 2 and R 3 Each can be H. In another non-restrictive example, R 1 R 2 and R 3 Each can be an independently chosen C(O)R 7A (e.g., C(O)Me).

[0762] Unrestricted combinations [7]

[0763] In some implementation methods:

[0764] X is NR 4X R 5X ;and

[0765] Y is a heteroaryl group containing 5 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), and N(R). d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected R c replace.

[0766] In some embodiments of [7], R 4X and R 5X None of them are H (e.g., R) 4X and R 5X Each is an independently chosen C1-C6 alkyl group. As a non-limiting example, R 4X and R 5X Each can be a methyl group.

[0767] In some embodiments of [7], R 4X and R 5X One of them is H; and R 4X and R 5X The other one in is not H (e.g., R). 4X and R 5X One of them is H; and R 4X and R 5XThe other one is an independently selected C1-C6 alkyl group.

[0768] In some embodiments of [7], R 4X and R 5X All are H.

[0769] In some embodiments of [7], Y is a heteroaryl group comprising 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R). d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected R c replace.

[0770] In some embodiments of [7], Y is a heteroaryl group comprising 5 ring atoms, wherein one ring atom is a heteroatom selected from N, N(H), N(R). d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected R c replace.

[0771] In some embodiments of [7], Y is a heteroaryl group comprising 5 ring atoms, wherein 3-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R). d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected R c replace.

[0772] In some embodiments of [7], Y is selected from tetrazolyl, triazolyl, oxadiazolyl, and oxazolyl, wherein one or more heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected Rs. c Substitution; and one of the heteroaryl ring nitrogen atoms is optionally replaced by R d replace.

[0773] In some of the foregoing embodiments, each R c When it exists, it is selected independently:

[0774] (i) Halogens;

[0775] (iii)C 1-10 alkyl;

[0776] (iv) R selected independently by 1-6 (e.g., 1) a Replacement C 1-10 Alkyl; and

[0777] (v) R, which is arbitrarily selected by 1-3 independent choices b Replacement C 3-6 cycloalkyl (e.g., each R) a It can be (iii)C independently1-10 Alkyl or (iv) by 1-6 independently selected R a Replacement C 1-10 alkyl).

[0778] In some of the foregoing embodiments, Y is selected from the group consisting of: (For example, R) a It can be selected from -OH, -OMe and -NMe2).

[0779] In some embodiments of [7], Y is selected from tetrazolyl, triazolyl, oxadiazolyl, and oxazolyl, wherein one or more heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected Rs. c Substitution; and one of the heteroaryl ring nitrogen atoms is optionally replaced by R d replace.

[0780] In some embodiments of [4], Y is selected from the group consisting of: (For example, R) a It can be selected from -OH, -OMe and -NMe2).

[0781] In some embodiments of [7], X is N(C 1-3 Alkyl)2; Y is selected from tetrazolyl and trizolyl, wherein one or more heteroaryl ring carbon atoms are optionally surrounded by 1-2 independently selected R c Substitution; and one of the heteroaryl ring nitrogen atoms is optionally replaced by R d replace.

[0782] In some of these implementations, X is NMe2.

[0783] In some of the foregoing embodiments, Y is As a non-restrictive example, Y is (For example, ).

[0784] In some implementations of [7], Z is OR 6Z For example, Z can be OH.

[0785] In some embodiments of [7], each Z x It is H.

[0786] In some embodiments of [7], each Z x Together with the carbon atoms they are attached to, they form C=O.

[0787] In some embodiments of [7], R 1 R 2 and R 3 Each is independently selected from H and C(O)R7A For example, R 1 R 2 and R 3 Each can be H. In another non-restrictive example, R 1 R 2 and R 3 Each can be an independently chosen C(O)R 7A (e.g., C(O)Me).

[0788] Z and R in unrestricted combinations [1]-[7] 1 R 2 and R 3 Further exemplary implementation

[0789] In some embodiments of [1]-[7], Z is selected from H, NR 4Z R 5Z OR 6Z and OC(O)R 7Z .

[0790] In some embodiments of [1]-[7], Z is NR 4Z R 5Z .

[0791] In some of these implementations, R 4Z and R 5Z Each is independently selected from H and optionally selected from 1-6 independently chosen R. a Replacement C 1-10 Alkyl group. In some of these embodiments, R 4Z and R 5Z Each is independently selected from H and optionally from 1-2 independently selected R. a Replacement C 1-6 Alkyl group. In some of these embodiments, R 4Z and R 5Z Each is independently selected from H and arbitrarily selected by 1 R. a Replacement C 1-3 Alkyl group. In some of these embodiments, R 4Z and R 5Z Each is independently selected from H and In some of the foregoing embodiments, when R 4Z and R 5Z Each is independently selected from H and At that time, R a Selected from -OH, -NR e R f C 1-4 Alkoxy and C 1-4 Haloalkoxy. In some embodiments of [1]-[7], R 4Z and R 5Z Each is independently selected from H and

[0792] In some embodiments of [1]-[7], Z is NR 4Z R 5Z And R 4Z and R 5Z One or two of them are H.

[0793] In some embodiments of [1]-[7], Z is NR 4Z R 5Z And R 4Z and R 5Z Each is independently H or unsubstituted C 1-10 Alkyl (e.g., unsubstituted C) 1-6 Alkyl groups, such as unsubstituted C4 groups 1-3 Alkyl groups, such as methyl groups.

[0794] In some implementations of [1]-[7], Z is OR 6Z In some of these implementations, R 6Z It is H. In some other implementations, R 6Z It is C 1-6 Alkyl groups, optionally composed of 1-6 independently selected R groups a Replacement. For example, R 6Z R is arbitrarily selected by 1-6 independent choices. a Replacement C 1-6 Alkyl, or R 6Z R is optionally selected independently by 1-2 (e.g., 1) a Replacement C 1-3 Alkyl group. As a non-limiting example, R 6Z It can be

[0795] In some implementations of [1]-[7], Z is OR 6Z ;R 6Z yes And R 6Z R on a Selected from -OH, -NR e R f C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups. For example, R 6Z Can be selected

[0796] In some embodiments of [1]-[7], Z is OC(O)R 7Z In some of these implementations, R 7Z R is arbitrarily selected by 1-6 independent choices. a Replacement C 1-10Alkyl group. For example, R 7Z It is unreplaced C 1-10 Alkyl groups (e.g., methyl, ethyl, and isopropyl).

[0797] In some of these implementations, R 1 R 2 and R 3 Each is independently selected from H and C(O)R 7A .

[0798] In some of these implementations, each occurrence of R 7A Independently, R is arbitrarily selected by 1-6 independent choices. a Replacement C 1-10 Alkyl groups (e.g., optionally composed of 1-6 independently selected R groups) a Replacement C 1-6 Or C 1-3 Alkyl; for example, C 1-10 Or C 1-6 Or C 1-3 Unsubstituted alkyl groups (e.g., CH3)).

[0799] In some of the foregoing embodiments, R 1 R 2 and R 3 Each is independently selected from H and C(O)Me (e.g., R). 1 R 2 and R 3 Each is H; or R 1 R 2 and R 3 Each is C(O)Me).

[0800] In some embodiments of [1]-[7], R 1 R 2 and R 3 Each is independently selected from H and C(O)Me. For example, R 1 R 2 and R 3 Each can be H. For example, R. 1 R 2 and R 3 Each can be C(O)Me).

[0801] Unrestricted combinations [8]

[0802] In some implementation methods:

[0803] X is arbitrarily divided by 1-3 Rs a Substituted C1-C6 alkyl groups; and

[0804] Z is OR6Z .

[0805] In some implementations, R 6Z It is H.

[0806] In some embodiments of [8], X is C 1-3 Alkyl groups, optionally surrounded by 1-3 R groups a Substitution. For example, X is methyl or trifluoromethyl. In some of these embodiments, Z is OH.

[0807] Unrestricted combinations[9]

[0808] In some implementation methods:

[0809] X is arbitrarily divided by 1-3 Rs a Substituted C1-C6 alkyl groups; and

[0810] Z is OC(O)R 7Z .

[0811] In some embodiments of [9], R 7Z It is H.

[0812] In some embodiments of [9], R 7Z R is arbitrarily selected by 1-6 independent choices. a Replacement C 1-10 Alkyl group. In some of the foregoing embodiments, R 7Z It is C 1-6 Alkyl group, optionally selected by 1 to 6 (e.g., 1 to 3) independently chosen R a replace.

[0813] In some of the foregoing embodiments of [9], when R 7Z R is arbitrarily selected by 1-6 independent choices. a Replacement C 1-10 When alkyl, each occurrence of R a Independently selected from the following groups: -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups.

[0814] In some embodiments of [9], when R 7Z It is unreplaced C 1-10 Alkyl (e.g., unsubstituted C) 1-6 alkyl).

[0815] Unrestricted combinations

[10]

[0816] In some implementation methods:

[0817] X is NR 4X R 5X ;and

[0818] Z is OR 6Z .

[0819] In some implementations, R 6Z It is H.

[0820] In some embodiments of

[10] , R 4X and R 5X None of them are H (e.g., R) 4X and R 5X Each is an independently chosen C1-C6 alkyl group. As a non-limiting example, R 4X and R 5X Each can be a methyl group.

[0821] In some embodiments of

[10] , R 4X and R 5X One of them is H; and R 4X and R 5X The other one in is not H (e.g., R). 4X and R 5X One of them is H; and R 4X and R 5X The other one is an independently selected C1-C6 alkyl group.

[0822] In some embodiments of

[10] , R 4X and R 5X All are H.

[0823] Unrestricted combinations

[11]

[0824] In some implementation methods:

[0825] X is NR 4X R 5X ;and

[0826] Z is OC(O)R 7Z .

[0827] In some embodiments of

[11] , R 4X and R 5X None of them are H (e.g., R) 4X and R 5X Each is an independently chosen C1-C6 alkyl group. As a non-limiting example, R 4X and R 5X Each can be a methyl group.

[0828] In some embodiments of

[11] , R4X and R 5X One of them is H; and R 4X and R 5X The other one in is not H (e.g., R). 4X and R 5X One of them is H; and R 4X and R 5X The other one is an independently selected C1-C6 alkyl group. As a non-limiting example, R 4X and R 5X Each can be a methyl group.

[0829] In some embodiments of

[11] , R 4X and R 5X All are H.

[0830] In some embodiments of

[11] , R 7Z It is H.

[0831] In some embodiments of

[11] , R 7Z R is arbitrarily selected by 1-6 independent choices. a Replacement C 1-10 Alkyl group. In some of the foregoing embodiments, R 7Z It is C 1-6 Alkyl group, optionally selected by 1 to 6 (e.g., 1 to 3) independently chosen R a replace.

[0832] In some of the foregoing embodiments of

[11] , when R 7Z R is arbitrarily selected by 1-6 independent choices. a Replacement C 1-10 When alkyl, each occurrence of R a Independently selected from the following groups: -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups.

[0833] In some embodiments of [8]-

[11] , Y is CO2R 6Y .

[0834] In some embodiments of [8]-

[11] , R 6Y It is H. In some other implementations, R 6Y It is C 1-12 (For example, C) 1-6 C 2-6 C 2-3 ) alkyl groups, which are optionally composed of 1-6 independently selected R groups aSubstitution (e.g., unsubstituted; or R selected by 1-2, e.g., 1 independently) a replace).

[0835] In some embodiments of [8]-

[11] , Y is selected from CO2H and CO2Me.

[0836] In some embodiments of [8]-

[11] , Y is

[0837] In some embodiments of [8]-

[11] , Y is And R a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 Haloalkoxy groups. For example, Y could be... ).

[0838] In some embodiments of [8]-

[11] , Y is CONR 4Y R 5Y In some of these implementations, R 4Y and R 5Y are each independently H or C 1-12 Alkyl (e.g., C10) 1-6 C 1-4 ), which is optionally selected independently by 1-6 (e.g., 1-3 or 1-2) R a Replacement. In some of the foregoing embodiments, R 4Y and R 5Y Each is H or independently In some of these implementations, R a Selected from -OH; -F; -NR e R f (e.g., NMe2); C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy groups.

[0839] In some embodiments of [8]-

[11] , Y is CONR 4Y R 5Y And R 4Y and R 5Y H, each independently For example, Y could be CONH2.

[0840] As another non-restrictive example, Y is (For example, R) a Selected from -OH; -F; -NR e R f(e.g., NMe2); C 1-4 Alkoxy; and C 1-4 (haloalkoxy group).

[0841] In some embodiments of [8]-

[11] , Y is CONR 4Y R 5Y , where R 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 And R 4Y and R 5Y The other one is selected from H and C. 1-3 alkyl.

[0842] In some of these implementations, n is 2 or 3.

[0843] In some implementations, when R 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 At that time, W 1 Each time it appears, it is C independently. 2-3 Alkylene (e.g., C2 alkylene).

[0844] In some implementations, when R 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 At that time, W 2 Each time it appears, it is independently -N(H)-, -N(Me)-, or -O-.

[0845] In some implementations, when R 4Y and R 5Y One of them is -(W) 1 -W 2 ) n -W 3 At that time, W 3 Selected from H and C 1-3 alkyl.

[0846] In some embodiments of [8]-

[11] , Y is CONR 4Y R 5Y ;R 4Y and R 5Y One of them is -(W) 1 -W 2 )n -W 3 And R 4Y and R 5Y The other one is selected from H and C. 1-3 Alkyl groups, wherein:

[0847] n is 2 or 3; W appears each time. 1 C is independent 2-3 Alkylene (e.g., C2 alkylene); W each time it appears 2 Independently -N(H)-, -N(Me)-, or -O-; and W 3 Selected from H and C 1-3 alkyl.

[0848] As a non-restrictive example, R 4Y and R 5Y One of them can be selected from:

[0849] **

[0850] In some of these embodiments, Y is selected from tetrazolyl, triazolyl, oxadiazolyl, and oxazolyl, wherein one or more heteroaryl ring carbon atoms are optionally separated by 1-2 independently selected Rs. c Substitution; and one of the heteroaryl ring nitrogen atoms is optionally replaced by R d replace.

[0851] In some of the foregoing embodiments, Y is selected from the group consisting of: (For example, R) a It can be selected from -OH, -OMe and -NMe2).

[0852] As a non-restrictive example, Y could be

[0853] In some of these implementations, R 1 R 2 and R 3 Each is independently selected from H and C(O)R 7A .

[0854] In some of these implementations, each occurrence of R 7A Independently, R is arbitrarily selected by 1-6 independent choices. a Replacement C 1-10 Alkyl groups (e.g., optionally composed of 1-6 independently selected R groups) a Replacement C 1-6 Or C 1-3 Alkyl; for example, C 1-10 Or C 1-6 Or C 1-3Unsubstituted alkyl groups (e.g., CH3)).

[0855] In some of the foregoing embodiments, R 1 R 2 and R 3 Each is independently selected from H and C(O)Me (e.g., R). 1 R 2 and R 3 Each is H; or R 1 R 2 and R 3 Each is C(O)Me).

[0856] In some embodiments of [8]-

[11] , R 1 R 2 and R 3 Each is independently selected from H and C(O)Me. For example, R 1 R 2 and R 3 Each can be H. For example, R. 1 R 2 and R 3 Each can be C(O)Me).

[0857] In some embodiments of [1]-

[11] , each Z x It is H.

[0858] In some other embodiments of [1]-

[11] , each Z x Together with the carbon atoms they are attached to, they form C=O.

[0859] In some embodiments, the compounds are selected from Table A-1 below:

[0860] Table A-1.

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873]

[0874]

[0875]

[0876]

[0877]

[0878]

[0879] Or its pharmaceutically acceptable salt.

[0880] In some embodiments, the compounds are selected from Table A-2 below:

[0881] Table A-2.

[0882]

[0883]

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892]

[0893]

[0894]

[0895]

[0896]

[0897]

[0898]

[0899]

[0900] Or its pharmaceutically acceptable salt.

[0901] Pharmaceutical composition and administration

[0902] Overview

[0903] In some embodiments, a chemical entity (e.g., a compound or a pharmaceutically acceptable salt and / or hydrate and / or prodrug) that generates crosslinks in the cornea in response to exposure to photoactivated light is administered as a pharmaceutical composition comprising the chemical entity and one or more pharmaceutically acceptable excipients and optionally one or more other therapeutic agents described herein.

[0904] In some embodiments, the pharmaceutical composition is as described in US2018 / 0236077, which is incorporated herein by reference in its entirety.

[0905] In some embodiments, the chemical entities described herein may be administered in combination with one or more delivery agents. Delivery agents include, but are not limited to, anesthetics, analgesics, tonics, shear thinners, viscosity increasers, surfactants (e.g., ionic or nonionic surfactants), or chelating agents. Non-limiting examples of anesthetics may include pilocarpine, paracaine, tetracaine, or oxybuprocaine. Non-limiting examples of analgesics include menthol, benzyl alcohol, or phenethyl alcohol. Non-limiting examples of tonics include glycerol, propylene glycol, polyethylene glycol (PEG)-8, ethanol, benzyl alcohol, phenethyl alcohol, or glyceryl triacetate. Non-limiting examples of shear thinners and viscosity increasers include carbomer, polycarbofil, gellan gum, xanthan gum, sodium carboxymethyl cellulose, 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.

[0906] In some embodiments, the chemical entities described herein may be combined with one or more preparative formulations to be administered to the corneal epithelium. In some embodiments, the preparative formulations increase the permeability of the corneal epithelium. As a non-limiting example of the foregoing, the preparative formulations may include one or more of the following: zinc metalloproteinases, copper metalloproteinases, papain, bromelain, actinidin, ficain, N-acetylcysteine, ambroxol, carbocysteine, or erdocysteine. In some embodiments, one or more preparative formulations may also include one or more anesthetics (e.g., pilocarpine, paracaine, tetracaine, or oxybuprofen).

[0907] In some embodiments, the chemical entities described herein may be administered in combination with one or more enhancing agents configured to: (i) remove one or more therapeutic agents from the corneal epithelium without diluting one or more therapeutic agents delivered to the stroma; (ii) close the tight junctions of the epithelium to control corneal hydration; (iii) promote the 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 a non-limiting example 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.

[0908] In some embodiments, the chemical entities described herein may be administered in combination with one or more post-treatment formulations in response to the application of one or more enhancement formulations, and the one or more post-treatment formulations may include at least one of the following: one or more divalent metal salts, one or more viscosity modifiers, one or more glycosaminoglycans, or one or more antibiotics.

[0909] In some embodiments, the chemical entity may 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, poloxamer, or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffering substances such as phosphates, tris(hydroxymethyl)aminomethane (tris), glycine, sorbic acid, potassium sorbate, partially glycerol ester 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 silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and lanolin. Cyclodextrins such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives, may also be used to improve the delivery of the compounds described herein. Dosage forms or compositions comprising 0.005% to 100% of the chemical entities described herein can be prepared, with the balance made up by nontoxic excipients. The compositions considered may comprise 0.001% to 100% of the chemical entities provided herein, 0.1% to 95% in one embodiment, 75% to 85% in another, and 20% to 80% in yet another. Practical methods for preparing such dosage forms are known or understood by those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22nd edition (Pharmaceutical Press, London, 2012).

[0910] Route of administration and composition components

[0911] The composition can be formulated as a liquid solution or suspension; it can also be prepared in a solid form suitable for addition to a liquid prior to administration to prepare a solution or suspension; and the formulation can also be emulsified. According to this disclosure, the preparation of such formulations is known to those skilled in the art.

[0912] The composition can be administered topically (e.g., intraocularly via topical drops).

[0913] Suitable forms of medicines for intraocular use include sterile aqueous solutions (e.g., buffer solutions, such as citrate buffer; e.g., ophthalmic solutions, such as 20% dextran ophthalmic solution) or dispersions; formulations including aqueous solutions of sesame oil, peanut oil, or propylene glycol; and sterile powders for the ad hoc preparation of sterile solutions or dispersions. Generally, the form must be sterile and must be a fluid readily injectable. It should also be stable under manufacturing and storage conditions and must be resistant to contamination by microorganisms such as bacteria and fungi during storage.

[0914] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Suitable flowability can be maintained, for example, by using coatings such as lecithin, maintaining the desired particle size in the dispersion case, and by using surfactants. Microbial action can be prevented by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, isotonic agents, such as sugars or sodium chloride, are preferred. The absorption of the composition can be prolonged by using delaying absorption agents such as aluminum monostearate and gelatin in the composition.

[0915] A sterile solution is prepared by incorporating the desired amount of the active compound and any other components described above as needed into a suitable solvent, followed by filtration and sterilization. Typically, a dispersion is prepared by incorporating various sterilized active ingredients into a sterile carrier containing an alkaline dispersion medium and the other desired components described above. When preparing a sterile powder from a sterile solution, a preferred method is vacuum drying and freeze-drying techniques to obtain a powder of the active component and any other desired components from a previously sterile filtered solution.

[0916] In some embodiments, the excipients are sterile and generally free of undesirable substances. The composition can be sterilized using conventional, well-known sterilization techniques. For various oral dosage form excipients, such as tablets and capsules, sterility is not required. USP / NF standards are usually sufficient.

[0917] Ophthalmic compositions may contain, but are not limited to, any one or more of the following: dextran, viscogens (e.g., carboxymethyl cellulose, glycerin, 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.)).

[0918] Compositions may include ointments and creams. Ointments are semi-solid formulations, typically based on petrolatum or other petroleum derivatives. Creams containing selected active agents are typically viscous liquids or semi-solid emulsions, usually oil-in-water or water-in-oil. Cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes referred to as the "internal" phase, typically consists of petrolatum and fatty alcohols (such as cetyl alcohol or stearyl alcohol); although not always, the aqueous phase usually exceeds the volume of the oil phase and typically contains a wetting agent. Emulsifiers in cream formulations are typically nonionic, anionic, cationic, or amphoteric surfactants. Like other carriers or loadings, ointment bases should be inert, stable, non-irritating, and non-allergenic.

[0919] In some embodiments, the compounds and compositions disclosed herein can be applied to the cornea using an applicator. Non-limiting examples of applicators may include an eyedropper or a syringe.

[0920] In some embodiments, the compounds and compositions described herein can be administered in a formulation that allows the compounds of the composition to penetrate the corneal epithelium and reach the underlying region of the corneal stroma. In other embodiments, the corneal epithelium may be removed or otherwise incised to allow for more direct application of the compounds or compositions provided herein to the underlying tissue.

[0921] Therefore, in some embodiments, the compounds and compositions described herein are applied directly to the cornea (e.g., without removing or otherwise incising the corneal epithelium). In other embodiments, the corneal epithelium is removed or otherwise incised prior to the application of the compounds and compositions described herein.

[0922] dose

[0923] Dosage can vary depending on the patient's needs, the severity of the disease being treated, and the specific compound used. The appropriate dosage for a particular situation can be determined by a physician in the medical field. In some cases, the total dose may be administered in divided doses throughout the treatment or by providing continuous delivery.

[0924] In some embodiments, the composition is a solution (e.g., a buffer solution, such as citrate buffer; e.g., an ophthalmic solution, such as 20% dextran ophthalmic solution) containing 0.01-100 mg / mL of the 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 some of the foregoing embodiments, 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).

[0925] In some embodiments, the composition is a solution (e.g., a buffer, such as citrate buffer; e.g., an ophthalmic solution, such as 20% dextran ophthalmic solution) containing 0.001%-20% of the chemical entities described herein (e.g., 0.002%-10%, 0.004%-5%, 0.008%-2.5%). In some of the foregoing embodiments, 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).

[0926] Dosing regimen

[0927] The above-mentioned dosage can be administered periodically over a specific duration. In some embodiments, a unit dose can be given 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 foregoing embodiments, the dose is administered over a time period of 1-1200 minutes (e.g., 1-600 minutes, 5-120 minutes, 10-120 minutes).

[0928] Treatment

[0929] Overview

[0930] This disclosure is characterized by a method for treating an object (e.g., a person) suffering from a disease, condition, or symptom, in which an abnormal shape of the cornea (e.g., corneal thinning, such as bilateral corneal thinning, such as bilateral thinning of the central, paracentral, or peripheral cornea; or corneal steepening (e.g., bulging)) contributes to the pathology and / or symptoms and / or progression of the disease, condition, or symptom. In some embodiments, the method described herein may include or further include treating one or more conditions associated with, co-occurring with, or consequential to any one or more of the conditions described herein.

[0931] In some implementations, the method also includes identifying objects.

[0932] In some embodiments, the chemical entities described herein provide refractive correction to the cornea (e.g., by imparting mechanical stiffness). In some embodiments, the chemical entities described herein reinforce and stabilize corneal structures. In some embodiments, the chemical entities described herein can be used for vision correction.

[0933] method

[0934] In some embodiments, the method includes administering the disclosed compound or a pharmaceutical composition thereof to the cornea of ​​a subject in need; and applying electromagnetic radiation (e.g., light) to the cornea to induce cross-linking in the cornea.

[0935] In some of the foregoing embodiments, the method includes administering the disclosed compound or a pharmaceutical composition thereof to the corneal stroma of a subject in need.

[0936] In some embodiments, the compounds or pharmaceutical compositions thereof disclosed herein are administered to the cornea without the need to remove corneal epithelial cells.

[0937] In some embodiments, the method further includes increasing or decreasing the O2 concentration on the cornea during irradiation.

[0938] In some embodiments, the method further includes administering one or more delivery agents to the cornea, wherein the one or more delivery agents are described elsewhere herein.

[0939] In some embodiments, the method further includes administering one or more preparative agents to an object in need (e.g., the cornea of ​​the object in need), said preparative agents increasing the permeability of the corneal epithelium, wherein one or more preparative agents are as described elsewhere herein.

[0940] In some embodiments, the method further includes administering one or more enhancing agents to the corneal epithelium, wherein the one or more enhancing agents are configured as one or more of the following:

[0941] (i) Removing one or more therapeutic agents from the corneal epithelium without diluting one or more therapeutic agents delivered to the matrix;

[0942] (ii) Close the tight junctions of the epithelium to control corneal hydration;

[0943] (iii) Promoting the oxidation of one or more therapeutic agents delivered to the matrix; or

[0944] (iv) Further delivery of one or more therapeutic agents from the epithelium to the matrix.

[0945] The one or more of the aforementioned enhancing agents are described elsewhere in this document.

[0946] In some embodiments, the method further includes administering one or more post-treatment agents to a subject in need of such application in response to the application of one or more enhancement agents, wherein the one or more enhancement agents are as described elsewhere herein.

[0947] Electromagnetic radiation

[0948] In some embodiments, the electromagnetic radiation applied to the cornea of ​​the object in need is light radiation. In some embodiments, the light radiation has a suitable wavelength, energy, and duration to induce a reaction in the compounds described herein (e.g., photoinduced electron transfer and / or breakage), thereby allowing crosslinking.

[0949] In some embodiments, the wavelength of light can be selected such that it corresponds to or covers the absorption of the compound described herein and reaches tissue areas that have been in contact with the compound described herein, for example, penetrating into areas where the compound described herein is present.

[0950] In some implementations, the energy of the applied electromagnetic radiation is below 2000 J / cm². 2 In some of the foregoing embodiments, the applied electromagnetic energy is between 1 and 500 J / cm². 2 The total energy dose absorbed in the cornea can be described as the effective dose, which is the energy absorbed through the corneal epithelium. For example, the effective dose for a region of the corneal surface could be, for instance, at 5 J / cm². 2 and 20J / cm 2 Or 30J / cm 2 Between (e.g., 5.4 J / cm) 2 ).

[0951] In some embodiments, the electromagnetic radiation is at a rate of approximately 1-100 mW / cm². 2 The electromagnetic radiation is applied at a rate of approximately 1-5 mW / cm². In some embodiments, the electromagnetic radiation is applied at a rate of approximately 1-5 mW / cm². 2 (For example, 3mW / cm) 2 The radiance is applied.

[0952] In some embodiments, the electromagnetic radiation has wavelengths within the visible, infrared, or ultraviolet spectrum. In some embodiments, the electromagnetic radiation includes radiation with wavelengths from about 300 nm to about 800 nm (e.g., from 300 nm to 700 nm). In some embodiments, the electromagnetic radiation includes ultraviolet A (UVA) light (e.g., wavelengths between 350 and 380 nm, e.g., 360-370 nm, e.g., 365 nm). In some embodiments, the electromagnetic radiation includes visible wavelengths (e.g., wavelengths between 400 nm and 550 nm, e.g., about 452 nm). In some embodiments, the electromagnetic radiation is laser radiation. In some embodiments, the laser radiation is applied with an average power of 1-100 mW.

[0953] In some implementations, the radiation duration is between 30 seconds and 1 hour. In other implementations, the irradiation duration is between 1 minute and 1 hour (e.g., 30 minutes).

[0954] In some embodiments, the cornea can be treated more extensively with the compounds or compositions described herein; and radiation can be selectively directed to the treated corneal area according to a specific pattern.

[0955] In some implementations, electromagnetic radiation can be guided and focused onto a specific pattern on the cornea using one or more mirrors or lenses (e.g., at a specific focal plane within the cornea, or at a specific depth in the underlying region where crosslinking activity is required).

[0956] In some implementations, specific electromagnetic radiation patterns can be modulated to achieve a desired degree of crosslinking in selected regions of the cornea. For example, electromagnetic radiation can be delivered based on any combination of the following: wavelength, bandwidth, intensity, power, location, penetration depth, and / or treatment duration (duration of the exposure cycle, duration of the dark cycle, and the ratio of the exposure cycle duration to the dark cycle duration).

[0957] In some embodiments, a system incorporating a digital micromirror device (DMD) is used to deliver electromagnetic irradiation to modulate the application of electromagnetic radiation spatially and temporally. In some of the foregoing embodiments, light is projected in a precise spatial pattern generated by micromirrors in a matrix laid out on a semiconductor chip. Each mirror represents one or more pixels in the pattern of projected light. Topography-guided crosslinking can be performed using the DMD. Several different spatial and temporal irradiance and dose distributions can be employed depending on the topography of the DMD. These spatial and temporal dose distributions can be generated using continuous wave irradiation, but can also be modulated by pulsed irradiation, by pulsed irradiation of the irradiation source at varying frequencies and duty cycles as described above. Alternatively, the DMD can modulate different frequencies and duty cycles pixel-by-pixel to achieve maximum flexibility using continuous wave irradiation. Alternatively, combinations of pulsed irradiation and modulated DMD frequencies and duty cycles can be combined. This allows for spatially determined corneal crosslinking of specific amounts. Such 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.

[0958] In some embodiments, multiphoton excitation microscopy is used to deliver electromagnetic radiation. 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 initiate crosslinking. Advantageously, longer wavelengths are scattered less within the cornea compared to shorter wavelengths, allowing longer wavelengths to penetrate the cornea more efficiently than shorter wavelengths. Because the photosensitizer absorbs much less of the longer wavelengths, the shielding effect of incident radiation deeper within the cornea is also reduced compared to conventional short-wavelength irradiation. This allows for enhanced control over depth-specific crosslinking. For example, in some embodiments, two photons may be used, each carrying approximately half the energy required to excite the molecules of the compounds or compositions disclosed herein to produce the photochemical kinetics described further below. When the compounds disclosed herein absorb both photons simultaneously, they absorb sufficient energy to release active free radicals in the corneal tissue. The implementation can also utilize lower-energy photons, requiring the molecules of the compounds disclosed herein to simultaneously absorb, for example, three, four, or five photons to release active radicals. The probability of multiple photons absorbing almost simultaneously is low, therefore a high-throughput excitation photon may be required, and this high throughput can be delivered via a femtosecond laser.

[0959] In some embodiments, electromagnetic radiation is applied continuously (continuous wave (CW)) or as pulsed radiation. In some embodiments, this choice affects the amount, rate, and extent of crosslinking. In some embodiments, when electromagnetic radiation is applied as pulsed radiation, the duration of the exposure cycle, the duration of the dark cycle, and the ratio of the exposure cycle to the dark cycle duration affect the resulting corneal sclerosis. For the same amount or dose of delivered energy, pulsed radiation can be used to produce more or less corneal tissue sclerosis compared to continuous wave irradiation. Appropriate lengths and frequencies of light pulses can be used to achieve more desirable 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 0.1 mW / cm². 2 Approximately 1000 mW / cm 2 Between average irradiance, the pulse rate can be between about 0.01 Hz and about 1000 Hz or between about 1000 Hz and about 100,000 Hz.

[0960] In some implementations, pulsed radiation can be delivered using a DMD, electronically turning the light source 110 on and off, and / or using a mechanical or photoelectric (e.g., Pockels cells) shutter or mechanical chopper or rotating aperture. Due to the pixel-specific modulation capabilities of the DMD and the subsequent stiffness imparted based on the modulation frequency, duty cycle, irradiance, and dose delivered to the cornea, complex biomechanical stiffness patterns can be imparted to the cornea to allow for various degrees of refractive correction. For example, these refractive corrections may involve combinations of myopia, hyperopia, astigmatism, irregular astigmatism, presbyopia, and complex corneal refractive surface corrections due to ophthalmic conditions such as keratoconus, clear limbal diseases, post-laser vision correction ectasia, and other changes / degenerations of corneal biomechanical conditions. A particular advantage of DMD systems and methods is that they allow for randomized asynchronous pulsed topographic patterning, creating non-periodic and uniformly occurring illumination, eliminating the possibility of triggering photosensitive seizures or flickering vertigo at pulse frequencies between 2 Hz and 84 Hz.

[0961] Examples of systems and methods for delivering electromagnetic radiation are described herein, for example, U.S. Patent Application Publication No. 2011 / 0237999, filed March 18, 2011, entitled "Systems and Methods for Applying and Monitoring Eye Therapy"; U.S. Patent Application Publication No. 2012 / 0215155, filed April 3, 2012, entitled "Systems and Methods for Applying and Monitoring Eye Therapy"; and U.S. Patent Application Publication No. 2013 / 0245536, filed 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.

[0962] oxygen

[0963] 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 applied in different ways during the crosslinking treatment. In some embodiments, pharmaceutical compositions comprising compounds as described herein can be supersaturated with O2. Thus, when the compounds described herein are used in the eye, higher concentrations of O2 are delivered directly to the cornea along with riboflavin, and the exposure of riboflavin to electromagnetic radiation affects the O2-related responses. According to another approach, a stable 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. Exemplary systems and methods for applying oxygen during crosslinking processes are described, for example, U.S. Patent No. 8,574,277, filed October 21, 2010, entitled "Eye Therapy," and U.S. Patent Application Publication No. 2013 / 0060187, filed 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.

[0964] Therefore, in some embodiments, the method may further include applying a selected concentration of oxygen to the eye, wherein the selected concentration is greater than the concentration of oxygen in the atmosphere.

[0965] Indications

[0966] In some implementations, the symptom, disease, or condition is an ophthalmic disease.

[0967] In some embodiments, the ophthalmic disease includes decreased corneal hardness.

[0968] dilated disease

[0969] In some embodiments, the symptom, disease, or condition is a corneal ectasia. Non-limiting examples of ectasia include keratoconus (e.g., keratoconus with a papillary cone, elliptical cone, or bulbous cone; e.g., progressive keratoconus), globus keratoconus, clear marginal degeneration, corneal ectasia (e.g., postoperative ectasia, such as LASIK postoperative ectasia), and Terrien marginal degeneration.

[0970] In some embodiments, the symptom, disease, or condition is a corneal ectasia that occurs after refractive surgery (e.g., postoperative corneal ectasia). Non-limiting examples of refractive surgeries include radial keratotomy (RK), refractive keratotomy (PRK), or laser-assisted in situ keratomileusis (LASIK).

[0971] In some embodiments, the symptom, disease, or condition is bacterial keratitis.

[0972] Vision condition

[0973] In some implementations, the disease, symptom, or condition is myopia, hyperopia, astigmatism, irregular astigmatism, or presbyopia.

[0974] In some implementations, the ophthalmic condition is cataract (e.g., nuclear, cortical, posterior polar, secondary, traumatic, or radiation-induced cataract) or lens condition.

[0975] Combination therapy

[0976] This disclosure covers both single-therapy regimens and combination therapy regimens.

[0977] In some embodiments, the methods described herein may further include administration in combination with the compounds described herein of one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more treatment regimens).

[0978] In some embodiments, the compounds described herein may be administered in combination with one or more other therapeutic agents. Representative other therapeutic agents include, but are not limited to, those for conditions such as inflammation, cataracts, lens disorders or ectasia, including but not limited to keratoconus (e.g., keratoconus with a papillary cone, elliptical cone, or bulbous cone), globus keratitis, clear marginal degeneration, corneal ectasia (e.g., postoperative ectasia, such as LASIK postoperative ectasia), and Terrien marginal degeneration.

[0979] In some embodiments, one or more additional therapeutic agents include those that can be used as, for example, crosslinking 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:

[0980] Riboflavin (e.g., riboflavin or riboflavin phosphate);

[0981] ·2,3-Butanedione;

[0982] Folic acid;

[0983] Quinoxaline (e.g., Olaquidox);

[0984] Quinoline (e.g., chloroquine, hydroxychloroquine, and quinine);

[0985] • Debucaine;

[0986] Methotrexate;

[0987] • Menaquinone; and

[0988] Vertepofen

[0989] And their derivatives.

[0990] Other non-limiting examples of crosslinking agents may include photosensitizers such as Rose Bengal, Methylene Blue, and N-hydroxypyridine-2-(1H)-thione. Other non-limiting examples of crosslinking agents may also include photosensitizers such as Photofrin.RTM, synthetic diporphyrins and dichlorins, phthalocyanines with or without metal substituents, aluminum chlorophthalocyanines with or without different substituents, O-substituted tetraphenylporphyrins, 3,1-meta-tetra(o-propionylaminophenyl)porphyrins, verdins, violet, tin and zinc derivatives of octaethylviolet, etiopurpurin, hydroporphyrins, tetra(hydroxyphenyl)porphyrin series of bacterial chlorophyll (e.g., protoporphyrin I to protoporphyrin IX, coprophyrin, uroporphyrin, mesoporphyrin, hematoporphyrin and sapphyrins), chlorins, chlorine 6, mono-1-aspartic derivatives of chlorine 6, di-1-aspartic derivatives of chlorine 6, tin ( IV) Chlorine 6, m-Tetrahydrophenyl dihydroporphyrin, benzo[a]porphyrin derivatives, benzo[a]porphyrin monoacid derivatives, tetracyanoethylidene adduct of benzo[a]porphyrin, dimethyl acetylacetyl dicarboxylate adduct of benzo[a]porphyrin, Diels-Adler adduct, monoacid ring "a" derivative of benzo[a]porphyrin, aluminum sulfonate PC, sulfonated AlPc, disulfonated and tetrasulfonated derivatives, aluminum sulfonate phthalocyanine, phthalocyanine with or without metal substituents and with or without different substituents, chlorophyll, bacterial chlorophyll A, anthraquinone, anthraquinone, aminoanthraquinone, phenoloxazine dyes, thiazides, methylene blue, phenothiazine derivatives, chalcogenapyrylium dyes, cationic selenium and tellurium derivatives. Selena and tellurapyrylium derivatives), cyclic-substituted cationic PC, pheophytic acid 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 red. Benzoquinone, eosin, erythrosine, anthocyanin, quinone-based anthocyanin 540, selenium-substituted anthocyanins, flavins, riboflavin, proflavins, quinones, anthraquinones, benzoquinones, naphthalene diimides, naphthalene diimides, Victoria blue, toluidine blue, dianthraquinones (e.g., hypericin), fullerenes, rhodamine, and their photosensitive derivatives.

[0991] In some embodiments, one or more additional reagents include metals (including elemental and ionic forms) (e.g., metal salts, such as divalent metal salts). Non-limiting examples include:

[0992] • Iron (e.g., iron(II), such as FeSO4) (in some embodiments, the iron additive may be dissolved in citrate buffer);

[0993] ·copper;

[0994] ·manganese;

[0995] ·chromium;

[0996] ·vanadium;

[0997] ·aluminum;

[0998] ·cobalt;

[0999] ·mercury;

[1000] ·cadmium;

[1001] Nickel; and

[1002] ·arsenic;

[1003] Optionally combined with hydrogen peroxide.

[1004] In some embodiments, one or more additional therapeutic agents include, for example, those that can be used as anesthetics. Non-limiting examples include pilocarpine, paracaine, tetracaine, or oxybuprocaine.

[1005] In some embodiments, one or more additional therapeutic agents include, for example, those that can be used as analgesics. Non-limiting examples include menthol, benzyl alcohol, or phenylethanol.

[1006] In some embodiments, 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, ficain, N-acetylcysteine, ambroxol, carboxycysteine, or erdosteine.

[1007] In some embodiments, one or more additional therapeutic agents include those that can be used as therapeutic agents for cataracts and / or lens disorders.

[1008] In some implementations, one or more additional therapeutic agents include, for example, those that can be used as antibiotics.

[1009] In some implementations, one or more additional therapeutic agents include, for example, those that can be used for gene therapy.

[1010] In some implementations, one or more additional treatment options include treatment options for conditions such as inflammation, cataracts, lens disorders or ectasia, including but not limited to keratoconus (e.g., keratoconus with a papillary cone, elliptical cone or bulbous cone), globus keratosis, clear marginal degeneration, corneal ectasia (e.g., postoperative ectasia, such as LASIK postoperative ectasia), and Terrien marginal degeneration.

[1011] In some implementations, one or more additional treatment options include those for myopia, hyperopia, astigmatism, irregular astigmatism, and presbyopia.

[1012] In some implementations, one or more additional treatment options include ophthalmic surgery. Non-limiting examples include:

[1013] • Corneal transplant surgery;

[1014] Cataract surgery;

[1015] Laser surgery;

[1016] • Corneal transplantation (e.g., penetrating keratoplasty or lamellar keratoplasty);

[1017] • Refractive surgery (e.g., keratotomy (RK), refractive keratotomy (PRK), or laser-assisted in situ keratomileusis (LASIK));

[1018] • Corneal reshaping; and

[1019] Treatment of corneal lacerations.

[1020] Additional, non-limiting examples of one or more alternative treatment options include contact lens therapy, amniocentesis, LASIK therapy, and antibiotic administration.

[1021] Compound preparation and biological experiments

[1022] As will be understood by those skilled in the art, the methods for synthesizing compounds of the formulas described herein will be readily apparent to those of ordinary skill in the art. Synthetic chemical transformations and protecting group methods (protection and deprotection) that can be used to synthesize the compounds described herein are known in the art and include, for example, those described in R. Larok, *Comprehensive Organic Transformations*, VCH Press (1989); T.W. Greene and R.M. Wuts, *Protective Groups in Organic Synthesis*, 2nd ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, *Fieser and Fieser's Reagents for Organic Synthesis*, John Wiley and Sons (1994); L. Paquette, ed., *Encyclopedia of Reagents for Organic Synthesis*, John Wiley and Sons (1995), and subsequent editions.

[1023] In some embodiments, intermediates that can be used to prepare the compounds described herein can be prepared using the chemical methods described in any one or more of the following schemes and non-limiting examples.

[1024] abbreviation

[1025]

[1026]

[1027]

[1028] Compound preparation

[1029] The compounds of the present invention can be obtained according to the following process.

[1030] General process

[1031] General Process 1

[1032] Step 1

[1033]

[1034] Commercially available compounds (i) such as riboflavin or rose flavonoids can be converted into compounds (ii) by treatment with a base such as NaOH or KOH in a suitable solvent such as water or ethanol at a temperature ranging from room temperature to the boiling point of the solvent, and then neutralized to pH 6 with an acid (e.g., acetic acid, citric acid, or hydrochloric acid) at a temperature ranging from 0°C to room temperature.

[1035] Where X is defined elsewhere in this document.

[1036] Step 2

[1037]

[1038] Compound (ii) can be converted into compound (iii) by treatment with A and a coupling agent (e.g., thionyl chloride, CDI or EDCI) in a suitable solvent (e.g., methanol, ethanol, THF or dioxane) at a temperature ranging from room temperature to the boiling point of the solvent.

[1039] Where X and R 6Y As defined elsewhere in this document, and A is an alcohol, such as methanol, allyl alcohol, or ethylene glycol.

[1040] General Process 2

[1041] Step 1

[1042]

[1043] Compound (ii) can be converted into compound (iv) by treatment with B and, if necessary, a base (e.g., TEA or DIPEA) in a suitable solvent (e.g., DCM, THF or dioxane) at a temperature ranging from room temperature to the boiling point of the solvent.

[1044] Where X is defined elsewhere in this document, B is a hydroxyl protecting group reagent, such as acetic anhydride, MOM-Cl, or MEM-Cl, and P is a hydroxyl protecting group, such as acetyl, MOM, or MEM.

[1045] Step 2

[1046]

[1047] Compound (iv) can be converted into compound (vi) by treatment with amine (v) such as methylamine, dimethylamine or N,N-dimethylethane-1,2-diamine, C and, if necessary, a base (e.g., TEA or DIPEA) in a suitable solvent (e.g., DMF, DCM, THF or dioxane) at a temperature in the range of room temperature to the boiling point of the solvent.

[1048] Among them, X and R 4Y R 5YAs defined elsewhere in the text, C is a coupling agent, such as EDCI, CDI, or PyBOP.

[1049] Step 3

[1050]

[1051] Compound (vi) can be converted into compound (vii) by treating D in a suitable solvent (e.g., MeOH, DCM, THF or dioxane) at a temperature ranging from 0°C to the boiling point of the solvent.

[1052] Among them, X and R 4Y and R 5Y As defined elsewhere in this document, D is a reagent capable of removing the protecting group P, such as sodium methoxide, HCl (gas) in dioxane, HBr, or NH4OH.

[1053] General Process 3

[1054] Step 1

[1055]

[1056] The compound (viii) obtained using general procedure 1 can be converted into compound (ix) by treatment with E and, if necessary, a base (e.g., TEA or DIPEA) in a suitable solvent (e.g., MeOH, DCM, THF or dioxane) at a temperature ranging from -70°C to room temperature.

[1057] Where X and R 7Z As defined elsewhere in this document, E is an acid anhydride, such as acetic anhydride, propionic anhydride, or isopropionic anhydride, or an activated ester or acid, such as pentafluorophenol acetate or acetic acid activated with CDI.

[1058] Step 2

[1059]

[1060] Compound (ix) can be converted into compound (x) by treatment with F and, if necessary, a base (e.g., TEA, pyrrolidine, or DIPEA) in a suitable solvent (e.g., MeCN, DCM, THF, or dioxane) at a temperature ranging from 0°C to room temperature.

[1061] Where X and R 7Z As defined elsewhere in this document, and F is an agent capable of selectively removing the protecting group of allyl esters, such as Pd(PPh3)4 or Pd(OAc)2.

[1062] General Process 4

[1063] Step 1

[1064]

[1065] The compound (xi) obtained using general process 1 can be converted into compound (xii) by treatment with G and, if necessary, a base (e.g., TEA, N,N-dimethylaminopyridine or DIPEA) in a suitable solvent (e.g., pyridine, DCM, THF or dioxane) at a temperature ranging from 0°C to the boiling point of the solvent.

[1066] Where X is defined elsewhere in this document, G is a protecting group reagent capable of selectively reacting with the primary hydroxyl group, such as triphenylmethyl chloride or 2-chlorotriphenylmethyl chloride, and P 1 It is a primary hydroxyl protecting group, such as triphenylmethyl or 2-chlorotriphenylmethyl.

[1067] Step 2

[1068]

[1069] Compound (xii) can be converted into compound (xiii) by treatment with B according to step 1 of general process 2.

[1070] Among them, X, P and P 1 As defined elsewhere in this document.

[1071] Step 3

[1072]

[1073] Compound (xiii) can be converted into compound (xix) by treatment with H in a suitable solvent (e.g., water, MeOH, THF or dioxane) at a temperature ranging from 0°C to the boiling point of the solvent.

[1074] Among them, X, P and P 1 As defined elsewhere in this document, and H is a reagent capable of hydrolyzing methyl esters, such as NaOH, LiOH, or NH4OH.

[1075] Step 4

[1076]

[1077] Compound (xix) can be converted into compound (xx) by treating it with C according to step 2 of general process 2.

[1078] Among them, X and R 4Y R 5Y P, P 1 C is defined elsewhere in this document.

[1079] Step 5

[1080]

[1081] Compound (xx) can be converted into compound (xxi) by processing with D according to step 3 of general process 2.

[1082] Among them, X and R 4Y R 5Y P, P 1 And D as defined elsewhere in this document.

[1083] General Process 5

[1084] Step 1

[1085]

[1086] Compound (xx) can be converted into compound (xxii) by treatment with J in a suitable solvent (e.g., diethyl ether, MeOH, THF or dioxane) at a temperature ranging from 0°C to room temperature.

[1087] Among them, X and R 4Y R 5Y P and P 1 As defined elsewhere in this document, J is an agent capable of selectively removing the protecting group of triphenylmethyl or 2-chlorotriphenylmethyl, such as pentafluoroethanol, silica-supported cerium ammonium formic acid, or acetic acid.

[1088] Step 2

[1089]

[1090] Compound (xxii) can be converted into compound (xxiii) by treatment with K and, if necessary, a base (e.g., TEA, N,N-dimethylaminopyridine or DIPEA) in a suitable solvent (e.g., DMF, DCM, MeOH, THF or dioxane) at a temperature ranging from 0°C to room temperature.

[1091] Among them, X and R 4Y R 5Y As defined elsewhere in this document, K is an agent capable of converting a hydroxyl group into a leaving group, such as Ms-Cl, TsCl, or methyltriphenoxyphosphonium iodide. LG is a leaving group, such as a methanesulfonate, toluenesulfonate, or iodine.

[1092] Step 3

[1093]

[1094] Compound (xxiii) can be converted to compound (xxv) by treatment with an amine (xxiv) such as methylamine, dimethylamine, morpholine or N,N-dimethylethane-1,2-diamine and, if necessary, a base (e.g., TEA, N,N-dimethylaminopyridine or DIPEA) in a suitable solvent (e.g., DMF, DCM, MeOH, THF or dioxane) at a temperature ranging from 0°C to the boiling point of the solvent.

[1095] Among them, X and R 4Y R 5Y R 4Z R 5Z LG and P are as defined elsewhere in this document.

[1096] Step 4

[1097]

[1098] Compound (xxv) can be converted into compound (xxvi) by treatment with D according to step 3 of general process 2.

[1099] Among them, X and R 4Y R 5Y R 4Z R 5Z P and D are defined elsewhere in this document.

[1100] Reactions sensitive to moisture or air are carried out under nitrogen or argon atmospheres using anhydrous solvents and reagents. The progress of the reaction is determined by analytical thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS), typically using pre-coated Sanpont TLC plates, silica gel GF-254, with a layer thickness of 0.25 mm.

[1101] Typically, the analytical LC-MS system used consists of an Agilent 6120 platform with electrospray ionization capability in positive ion detection mode and an Agilent 1260 series HPLC with an autosampler. The column is typically a 3.0 × 50 mm, 2.7 μm Agilent Poroshell C18. The flow rate is 0.6 mL / min, and the injection volume is 5 μL. The UV detection range is 190–400 nm. The mobile phase consists of solvent A (water + 0.1% TFA) and solvent B (acetonitrile + 0.05% TFA), with a gradient of 90% solvent A to 95% solvent B over 1.7 min, held for 1.8 min, then reverting to 90% solvent A over 0.1 min and held for 1.4 min.

[1102] Preparative HPLC purification was typically performed on a Waters 2555-2767 system equipped with a 2489 UV detector. The column was a Welch C-18, 21.2 x 150 mm, 5 μm. The mobile phase consisted of a mixture of acetonitrile (5-95%) in water containing 0.05% TFA. The flow rate was maintained at 20 mL / min, with an injection volume of 1800 μL. Two channels of the UV detector, 254 nm and 280 nm, were used. The mobile phase gradient was optimized for each compound.

[1103] Reactions using microwave radiation are typically carried out using an initiator manufactured by Biotage. Solution concentration is then performed under reduced pressure using a rotary evaporator. Rapid chromatography is usually performed using a Biotage rapid chromatograph (Dyax), with silica gel (40-63 mM, pore size...). The assay was performed on pre-packed columns of a specified size. Unless otherwise specified, the assay was performed in CDCl3 solution using a 400 MHz spectrometer. 1 ¹H NMR spectroscopy. Chemical shifts are reported in parts per million (ppm). Tetramethylsilane (TMS) is used as an internal standard in CD₃Cl solution, and the residual CH₃OH peak or TMS is used as an internal standard in CD₃OD solution. Coupling constants (J) are expressed in Hertz (Hz). Chiral analytical chromatography is performed on one of the following columns (250 x 4.6 mm) (Daicel Chemical Industries, Ltd.): ethanol / hexane (%Et / Hex) or isopropanol / heptane (%IPA / Hep) as the isocratic solvent system. Chiral preparative chromatography is performed on one of the following columns (20 x 250 mm) (Daicel Chemical Industries, Ltd.): the desired isocratic solvent system is identified on chiral analytical chromatography or by supercritical fluid (SFC) conditions.

[1104] Synthesis Examples

[1105] Synthesis of Compound 3 (Example 1) and Compound 4 (Example 5)

[1106] Examples 1 and 5 were synthesized according to the following schemes:

[1107]

[1108] Compound 2

[1109] 1200 mL of 1 M NaOH aqueous solution was added to riboflavin (1) (50 g, 133 mmol), and the mixture was stirred at 90 °C for 2 hours. The mixture was cooled to 20 °C, and glacial acetic acid was added to adjust the pH to 6. The mixture was partially evaporated to 800 mL and placed in a refrigerator at 5 °C overnight to allow crystallization. The particles thus formed were filtered off, washed with water, and dried to give 41 g of compound (2).

[1110] 1 H-NMR (DMSO-d6, δ, ppm): 2.25 (s, 3H), 2.31 (s, 3H), 3.42-3.48 (m, 1H), 3.55-3.66 (m, 2H), 4.53 (dd, 1H, J1=3.9Hz, J2=9.8Hz), 4.62 (br.s, 1H), 4.72 (br.d, 1H, J=6.0Hz), 5.02 (br.s, 1H), 5.14 (br.s, 1H), 7.41 (s, 1H), 7.46 (s, 1H).

[1111] LCMS, m / z: 353.4 (M+H) + .

[1112] Compound 3 (Example 1)

[1113] At ambient temperature, pure SOCl2 (0.51 g, 4.3 mmol) was added dropwise to a suspension of compound (2) (1.5 g, 4.3 mmol) in 100 mL of MeOH. The reaction mixture was stirred under reflux overnight and evaporated to dryness. The residue was passed through a silica gel pad and eluted with 20% MeOH in chloroform to give 1.0 g of compound (3) (Example 1).

[1114] 1 H-NMR (DMSO-d6, δ, ppm): 2.30 (s, 3H), 2.38 (s, 3H), 3.41-3.49 (m, 1H), 3.55-3.65 (m, 3H), 4.07-4.14 (m, 1H), 4.18 (br.d, 1H, J=14.0Hz), 4.47 (d d, 1H, J1=J2=5.8Hz), 4.59 (dd, 1H, J1=3.6Hz, J2=14.0Hz), 4.72 (d, 1H, J=5.8Hz), 4.82 (d, 1H, J=2.7Hz), 4.97 (d, 1H, J=4.3Hz), 7.61 (br.s, 2H).

[1115] 13C-NMR (DMSO-d6, δ, ppm): 18.63, 20.33, 44.50, 52.61, 63.51, 68.60, 72.76, 73. 83, 116.26, 129.66, 129.96, 132.34, 132.68, 142.20, 147.65, 152.41, 164.54.

[1116] LCMS, m / z: 367.0 (M+H) + 389.5 (M+Na) + .

[1117] Compound 4 (Example 5)

[1118] Compound (2) (2.5 g, 7.1 mmol) was suspended in 20 mL of pyridine, and acetic anhydride (7.2 g, 71 mmol) was added. The mixture was stirred overnight at 70 °C and evaporated to dryness. The residue was passed through a silica gel pad and eluted with 25% MeOH in chloroform to give 0.77 g of compound (4) (Example 5).

[1119] 1 H-NMR (DMSO-d6, δ, ppm): 1.70 (3, 3H), 2.00 (s, 3H), 2.11 (s, 3H), 2.13 (s, 3H), 2.31 (s, 3H), 2.40 (s, 3H), 4.19 (dd, 1H, J1=5.4Hz, J2 =12.2Hz), 4.32 (br.d, 1H, J=12.2Hz), 4.42 (br.d, 1H, J=14.0Hz), 4.60-4.68 (m, 1H), 5.30-5.42 (m, 3H), 7.40 (s, 1H), 7.52 (s, 1H).

[1120] 13 C-NMR (DMSO-d6, δ, ppm): 18.67, 20.10, 20.19, 20.51, 20.57, 20.73, 41.78, 61.56, 68.99, 69.15, 70.17, 11 5.00, 129.60, 130.30, 130.72, 132.48, 140.35, 152.58, 152.70, 166.26, 169.33, 169.56, 169.62, 170.16.

[1121] LCMS, m / z: 521.4 (M+H) + 543.5 (M+Na) + .

[1122] Synthesis of Compound 7 (Example 6)

[1123] Example 6 was synthesized according to the following scheme:

[1124]

[1125] Rosoflavone (5) (CAS#51093-55-1) was hydrolyzed with NaOH, and the resulting carboxylic acid ester moiety was then re-acidified with acetic acid to give compound (6). Compound (6) was subjected to esterification with methanol (e.g., with thionyl chloride) to provide compound (7) (Example 6).

[1126] Synthesis of Compound 10 (Example 2), Compound 12 (Example 3) and Compound 14 (Example 4)

[1127] Examples 2-4 were synthesized according to the following scheme:

[1128]

[1129] Compound 8

[1130] At ambient temperature, pure SOCl2 (10.6 g, 89.4 mmol) was added dropwise to a suspension of compound (2) (31.5 g, 89.4 mmol) in allyl alcohol (allOH) (200 mL). The reaction mixture was stirred at 80–90 °C for 4 hours and evaporated to dryness. The residue was purified by column chromatography on silica gel, eluting with 20–100% EtOAc / hexane → 10% i-PrOH / EtOAc to give 16.0 g of compound (8).

[1131] 1 H-NMR (DMSO-d6, δ, ppm): 2.30 (s, 3H), 2.39 (s, 3H), 3.42-3.49 (m, 1H), 3.58-3.66 (m, 3H), 4.10-4.14(m, 1H), 4.20(br.d, 1H, J=12.3Hz), 4.60(dd, 1H, J1=3.5Hz, J2=13.6H z), 4.72 (br.s, 1H), 4.82 (br.s, 1H), 4.85 (d, 2H, J=5.3Hz), 4.97 (br.s, 1H), 5.30 (d, 1H, J=10.7Hz), 5.50 (d, 1H, J=17.2Hz), 5.98-6.08 (m, 1H), 7.60 (s, 1H), 7.62 (s, 1H).

[1132] LCMS, m / z: 393.5 (M+H) + .

[1133] Compound 9

[1134] DIPEA (23.2 g, 179.5 mmol) was added to a suspension of compound (8) (14.1 g, 35.9 mmol) in DCM (500 mL). The mixture was cooled to -70 °C, and isobutyric anhydride (5.7 g, 35.9 mmol) was added in a single batch. The mixture was stirred at -70 °C for 5 h, and then stirred at ambient temperature for 48 h. The reaction mixture was quenched with 5% aqueous citric acid, the organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic extracts were dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel, eluting with 30–70% EtOAc / hexane to give 3.6 g of compound (9).

[1135] 1 H-NMR (DMSO-d6, δ, ppm): 1.10 (dd, 6H, J1=1.8Hz, J2=7.0Hz), 2.31 (s, 3H), 2.39 (s, 3H), 2.52-2.59 (m, 1H), 3 .59-3.64 (m, 1H), 3.80-3.87 (m, 1H), 4.02 (dd, 1H, J1=7.1Hz, J2=11.3Hz), 4.07-4.14 (m, 1H), 4.20-4.26 (m, 2 H), 4.55 (dd, 1H, J1=3.8Hz, J2=13.5Hz), 4.83-4.88 (m, 3H), 5.16 (dd, 1H, J1=5.4Hz, J2=16.4Hz), 5.30 (dd, 1 H, J1=1.3Hz, J2=10.5Hz), 5.49 (dd, 1H, J1=1.3Hz, J2=17.2Hz), 5.97-6.06 (m, 1H), 7.57 (s, 1H), 7.62 (s, 1H).

[1136] LCMS, m / z: 445.0(M-H2O), 463.5(M+H) + 485.3 (M+Na) + .

[1137] Compound 10 (Example 2)

[1138] Compound (9) (3.6 g, 7.7 mmol) was dissolved in MeCN (50 mL). The solution was purged with nitrogen, and Pd(PPh3)4 (0.89 g, 0.77 mmol) was added, followed by pyrrolidine (0.66 g, 9.2 mmol). After 16 hours at room temperature, the MeCN was evaporated, EtOAc was added, and the resulting particles were filtered off and washed with EtOAc. The particles were dissolved in water, and the pH was adjusted to 2 by adding 10% HCl. The resulting particles were filtered off, washed with water, and dried to give 1.56 g of compound (10) (Example 2).

[1139] 1 H-NMR (DMSO-d6, δ, ppm): 1.10 (dd, 6H, J1=1.7Hz, J2=7.1Hz), 2.32 (s, 3H), 2.40 (s, 3H ), 2.52-2.59(m, 1H), 3.60-3.62(m, 1H), 3.81-3.88(m, 1H), 4.02(dd, 6H, J1=7.0Hz, J 2=10.9Hz), 4.10-4.12(m, 1H), 4.20-4.30(m, 2H), 4.58(dd, 6H, J1=10.2Hz, J2=13.7H z), 4.82-4.89 (m, 1H), 5.12-5.23 (m, 2H), 7.60 (s, 1H), 7.65 (s, 1H), 13.98 (br.s, 1H).

[1140] 13 C-NMR (DMSO-d6, δ, ppm): 18.67, 18.91 (2×), 20.38, 33.31, 44.84, 66.28, 68.44, 69.74, 7 3.78, 116.26, 129.79, 130.41, 132.07, 132.98, 142.11, 147.51, 153.54, 165.03.176.39.

[1141] LCMS, m / z: 423.5 (M+H) + 445.3 (M+Na) + .

[1142] Compound 11

[1143] DIPEA (14.7 g, 113.5 mmol) was added to a suspension of compound (8) (8.9 g, 22.7 mmol) in DCM (400 mL). The mixture was cooled to -70 °C, and propionic anhydride (3.0 g, 22.7 mmol) was added in a single batch. The mixture was stirred at -70 °C for 5 h, and then stirred at ambient temperature for 48 h. The reaction mixture was quenched with 5% citric acid aqueous solution, the organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic extracts were dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel, eluting with 30–70% EtOAc / hexane to give 2.6 g of compound (11).

[1144] 1 H-NMR (DMSO-d6, δ, ppm): 1.02 (t, 3H, J = 7.4Hz), 2.30-2.42 (m, 8H), 3.58-3.62 (m, 1H), 3.80-3 .87 (m, 1H), 4.00-4.05 (m, 1H), 4.09-4.12 (m, 1H), 4.20-4.24 (m, 2H), 4.55 (dd, 1H, J1=3.3Hz, J 2=10.4Hz), 4.85-4.90 (m, 3H), 5.18 (dd, 1H, J1=5.9Hz, J2=16.3Hz), 5.30 (dd, 1H, J1=1.3Hz, J 2=10.5Hz), 5.49 (dd, 1H, J1=1.3Hz, J2=17.2Hz), 5.97-6.05 (m, 1H), 7.57 (s, 1H), 7.63 (s, 1H).

[1145] LCMS, m / z: 431.3(M-H2O), 449.4(M+H) + 471.0 (M+Na) + .

[1146] Compound 12 (Example 3)

[1147] Compound (11) (2.6 g, 5.8 mmol) was dissolved in MeCN (50 mL). The solution was purged with nitrogen, and Pd(PPh3)4 (0.68 g, 0.58 mmol) was added, followed by pyrrolidine (0.62 g, 8.7 mmol). After 16 hours at room temperature, the MeCN was evaporated, EtOAc was added, the resulting particles were filtered off and washed with EtOAc. The particles were dissolved in water, the pH was adjusted to 2 by adding 10% HCl, the resulting particles were filtered off, washed with water and dried to give 0.84 g of compound (12) (Example 3).

[1148] 1H-NMR (DMSO-d6, δ, ppm): 1.03 (t, 3H, J=7.4Hz), 2.30-2.43 (m, 8H), 3.60-3.6 3(m, 1H), 3.82-3.89(m, 1H), 4.03(dd, 6H, J1=7.0Hz, J2=10.9Hz), 4.10-4.13( m, 1H), 4.21-4.30 (m, 2H), 4.57 (dd, 6H, J1=10.2Hz, J2=13.7Hz), 4.82 (br.d, 1H, J=4.6Hz), 5.12-5.21 (m, 2H), 7.60 (s, 1H), 7.65 (s, 1H), 13.95 (br.s, 1H).

[1149] 13 C-NMR (DMSO-d6, δ, ppm): 9.07, 18.67, 20.38, 26.91, 44.83, 66.25, 68.45, 69.70, 73.7 9, 116.25, 129.79, 130.41, 132.07, 132.99, 142.11, 147.53, 153.53, 165.04, 173.88.

[1150] LCMS, m / z: 409.5 (M+H) + 431.5 (M+Na) + .

[1151] Compound 13

[1152] DIPEA (26.5 g, 205.0 mmol) was added to a suspension of compound (8) (16.1 g, 41.0 mmol) in DCM (600 mL). The mixture was cooled to -70 °C, and acetic anhydride (4.2 g, 41.0 mmol) was added in a single batch. The mixture was stirred at -70 °C for 5 h, and then stirred at ambient temperature for 24 h. The reaction mixture was quenched with 5% citric acid aqueous solution, the organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic extracts were dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel, eluting with 30–100% EtOAc / hexane to give 2.5 g of compound (13).

[1153] 1H-NMR (DMSO-d6, δ, ppm): 2.01 (s, 3H), 2.31 (s, 3H), 2.40 (s, 3H), 3.58-3.62 (m, 1H), 3.81-3.8 8(m, 1H), 4.00-4.05(m, 1H), 4.09-4.12(m, 1H), 4.20-4.24(m, 2H), 4.55(dd, 1H, J1=3.3Hz, J2 =10.4Hz), 4.85-4.90 (m, 3H), 5.18 (dd, 1H, J1 = 5.9Hz, J2 = 16.3Hz), 5.30 (dd, 1H, J1 = 1.3Hz, J2 =10.5Hz), 5.49 (dd, 1H, J1 = 1.3Hz, J2 = 17.2Hz), 5.97-6.05 (m, 1H), 7.57 (s, 1H), 7.62 (s, 1H).

[1154] LCMS, m / z: 417.5 (M-H2O) + 435.0 (M+H) + .

[1155] Compound 14 (Example 4)

[1156] Compound (13) (2.5 g, 5.8 mmol) was dissolved in MeCN (50 mL). The solution was purged with nitrogen, and Pd(PPh3)4 (0.68 g, 0.58 mmol) was added, followed by pyrrolidine (0.62 g, 8.7 mmol). After 16 hours at room temperature, the MeCN was evaporated, EtOAc was added, the formed particles were filtered off and washed with EtOAc. The residue was dissolved in water, the pH was adjusted to 2 by adding 10% HCl, the formed particles were filtered off, washed with water and dried to give 1.56 g of compound (14) (Example 4).

[1157] 1 H-NMR (DMSO-d6, δ, ppm): 2.02 (s, 3H), 2.32 (s, 3H), 2.39 (s, 3H), 3.60-3.6 3 (m, 1H), 3.82-3.85 (m, 1H), 4.03 (dd, 6H, J1=7.0Hz, J2=10.9Hz), 4.08-4.1 2 (m, 1H), 4.20-4.28 (m, 2H), 4.57 (dd, 6H, J1=10.2Hz, J2=13.7Hz), 4.80-4 .90 (m, 1H), 5.10-5.29 (m, 2H), 7.59 (s, 1H), 7.64 (s, 1H), 13.96 (br.s, 1H).

[1158] 13C-NMR (DMSO-d6, δ, ppm): 18.67, 20.38, 20.91, 44.83, 66.35, 68.44, 69.65, 73.78, 116.24, 129.79, 130.40, 132.07, 132.99, 142.13, 147.50, 153.53, 165.03, 170.60.

[1159] LCMS, m / z: 395.3 (M+H) + 417.5 (M+Na) + .

[1160] Synthesis of Compound 15 (Example 8), Compound 16 (Example 9) and Compound 17 (Example 13)

[1161] Examples 8, 9, and 13 were synthesized according to the following schemes:

[1162]

[1163] Compound 15 (Example 8)

[1164] Et3N (1 mL), N,N-dimethylethane-1,2-diamine (1.2 g, 4.3 mmol), and TBTU (1.68 g, 5.3 mmol) were added to a DCM solution of compound (4) (1.7 g, 3.3 mmol). The mixture was stirred at ambient temperature for 15 hours and quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel, eluted with 10–20% EtOAc / DCM, to give a mixture of di, tri, and tetraacetic acid esters of compound (12). The mixture was dissolved in MeOH, Dowex-OH resin and an aqueous solution of NH3 were added, and the mixture was stirred at ambient temperature for 15 hours. The resin was filtered off, and the filtrate was evaporated to give 0.12 g of compound (15) (Example 8).

[1165] 1H-NMR (DMSO-d6, δ, ppm): 2.30 (s, 6H), 2.32 (s, 3H), 2.40 (s, 3H), 2.56 (dd, 1H, J1=J2=5.8Hz), 3.40-3.48(m, 3H), 3.60-3.65(m, 3H), 4.10-4.15(m, 1H) , 4.24(br.d, 1H, J=13.5Hz), 4.45-4.48(m, 1H), 4.58-4.68(m, 2H), 4.82(b r.s, 1H), 4.97 (br.s, 1H), 7.61 (s, 1H), 7.66 (s, 1H), 9.19 (t, 1H, J=4.7Hz).

[1166] 13 C-NMR (DMSO-d6, δ, ppm): 18.69, 20.34, 37.06, 45.23, 57.92, 63.52, 68.73, 72.78, 73.81, 116.13, 129.95, 130.53, 132.10, 132.67, 141.90, 147.25, 154.20, 162.81.

[1167] LCMS, m / z: 378.2(M-NMe2), 423.5(M+H) + 445.3 (M+Na) + .

[1168] Compound 16 (Example 9)

[1169] Thionyl chloride (0.68 g, 5.6 mmol) was added dropwise to a solution of compound (2) (1.0 g, 2.8 mmol) in 1.76 g (28 mmol) of ethylene glycol. The mixture was stirred under reflux for 2 hours and cooled to room temperature. Excess solvent was evaporated under vacuum, and the oily residue was washed with Et2O and DCM. The residue was crystallized from THF-MeCN, and the resulting particles were washed with MeCN and Et2O and dried to give 0.70 g of compound (16) (Example 9).

[1170] 1H-NMR (DMSO-d6, δ, ppm): 2.31 (s, 3H), 2.39 (s, 3H), 3.40-3.48 (m, 1H), 3.58-3.65 (m, 3 H), 3.66-3.71 (m, 2H), 4.10-4.15 (m, 1H), 4.20 (br.d, 1H, J=12.9Hz), 4.30-4.34 (m, 2H) , 4.45-4.50 (m, 1H), 4.60 (dd, 1H, J1=2.8Hz, J2=10.4Hz), 4.74 (d, 1H, J=6.4Hz), 4.84 (b r.s, 1H), 4.92 (dd, 1H, J1=J2=5.3Hz), 4.98 (d, 1H, J=3.1Hz), 7.61 (s, 1H), 7.62 (s, 1H).

[1171] 13 C-NMR (DMSO-d6, δ, ppm): 18.65, 20.34, 44.53, 58.81, 63.51, 67.30, 68.59, 72.75, 73.84, 116.31, 129.63, 129.96, 132.32, 132.70, 142.11, 147.91, 152.43, 164.24.

[1172] LCMS, m / z: 379.5 (M-H2O) + 397.3 (M+H) + 419.5 (M+Na) + .

[1173] Compound 17 (Example 13)

[1174] Ammonium chloride (0.64 g, 11.8 mmol) was added to 5 mL of a DMF solution of compound (2) (1.0 g, 2.8 mmol), followed by EDCI (0.65 g, 3.4 mmol) and HOBt (0.5 g, 3.6 mmol). The mixture was stirred at ambient temperature for 15 hours, diluted with water, and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel, eluting with 10% EtOAc / DCM, to give 0.62 g of compound (17) (Example 13).

[1175] 1H-NMR (DMSO-d6, δ, ppm): 2.32 (s, 3H), 2.38 (s, 3H), 3.16 (br.s, 1H), 3.40-3.48 (m, 1H), 3.57-3.67 (m, 3H), 4.10-4.18 (m, 1H), 4.21 (br.d, 1H, J =13.4Hz), 4.45-4.51(m, 1H), 4.56-4.70(m, 2H), 4.82(br.s, 1H), 5.00(br.s, 1H), 7.60(s, 1H), 7.62(s, 1H), 7.79(br.s, 1H), 8.35(br.s, 1H).

[1176] 13 C-NMR (DMSO-d6, δ, ppm): 18.69, 20.32, 44.52, 63.50, 68.85, 72.76, 73.83, 116.10, 129.79, 130.38, 132.10, 132.53, 141.60, 148.83, 153.81, 164.93.

[1177] LCMS, m / z: 352.6 (M+H) + 374.5 (M+Na) + .

[1178] Synthesis of Compound 24 (Example 10)

[1179] Example 10 was synthesized according to the following scheme:

[1180]

[1181] Compound 18

[1182] Compound (3) (5.2 g, 14.2 mmol) was dissolved in pyridine (50 mL), and triphenylmethyl chloride (6.3 g, 22.7 mmol) was added. The mixture was stirred at 50 °C for 15 hours. The pyridine was evaporated, and the residue was diluted with 5% citric acid aqueous solution and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexane, 1:2 → 2:1, to give 4.1 g of compound (18).

[1183] 1H-NMR (DMSO-d6, δ, ppm): 2.30 (s, 6H), 2.32 (s, 3H), 3.06 (dd, 1H, J1=2.4Hz, J2=6.8Hz), 3.18 ( dd, 1H, J1=2.8Hz, J2=9.0Hz), 3.56-3.62(m, 1H), 4.07-4.13(m, 1H), 4.20(br.d, 1H, J=13.9Hz) , 4.58 (dd, 1H, J1=3.9Hz, J2=9.9Hz), 4.75 (d, 1H, J=6.1Hz), 4.94 (d, 1H, J=5.3Hz), 5.20 (d, 1H, J=5.8Hz), 7.22-7.28(m, 3H), 7.29-7.35(m, 6H), 7.42-7.47(m, 6H), 7.52(s, 1H), 7.62(s, 1H).

[1184] LCMS, m / z: 631.5 (M+Na) + .

[1185] Compound 19

[1186] Compound (18) (6.6 g, 10.8 mmol) was dissolved in 100 mL of DMF, followed by the addition of DIPEA (16.8 g, 129.6 mmol) and then MOM-Cl (5.2 g, 64.8 mmol). The mixture was stirred at 70 °C for 72 h. The mixture was cooled to room temperature, diluted with 5% citric acid aqueous solution, and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel, eluting with 5–30% EtOAc-hexane to give 5.2 g of compound (19).

[1187] 1 H-NMR (DMSO-d6, δ, ppm): 2.28 (s, 6H), 2.30 (s, 3H), 2.70 (s, 3H), 3.24 (s, 3H), 3.11-3.17 (m , 1H), 3.23(s, 3H), 3.29-3.31(m, 1H), 3.33(s, 3H), 3.89(s, 3H), 3.95-4.04(m, 2H), 4.15(d , 1H, J=6.9Hz), 4.21-4.35 (m, 3H), 4.56 (d, 1H, J=6.4Hz), 4.66 (d, 1H, J=6.6Hz), 4.72-4.83 (m, 3H), 7.22-7.28 (m, 3H), 7.29-7.34 (m, 6H), 7.37-7.42 (m, 6H), 7.47 (s, 1H), 7.66 (s, 1H).

[1188] LCMS, m / z: 741.8 (M+H) + 763.7 (M+Na) + .

[1189] Compound 20

[1190] Compound (19) (4.8 g, 6.5 mmol) was dissolved in 50 mL of Et₂O, and formic acid (50 mL) was added in 10 mL portions at 5 °C. The mixture was stirred at 5 °C for 1 hour, and then poured into a saturated aqueous solution of Na₂CO₃ in portions at 5 °C. The mixture was extracted with EtOAc, and the combined organic extracts were dried over Na₂SO₄ and evaporated. The residue was purified by column chromatography on silica gel, eluting with 5–30% EtOAc-hexane to give 2.6 g of compound (20).

[1191] 1 H-NMR (DMSO-d6, δ, ppm): 2.32 (s, 6H), 2.39 (s, 3H), 2.64 (s, 3H), 3.36 (s, 3H), 3.38 (s, 3H), 3.59-3.62 (m, 2H), 3.80-3.82 (m, 1H), 3.89 ( s, 3H), 4.00-4.02 (m, 1H), 4.20 (d, 1H, J=6.9Hz), 4.22-4.34 (m, 2H), 4.41 (d, 1H, J=6.4Hz), 4.72-4.85 (m, 6H), 7.50 (s, 1H), 7.64 (s, 1H).

[1192] LCMS, m / z: 499.5 (M+H) + 521.3(M+Na) + .

[1193] Compound 21

[1194] Et3N (0.58 g, 5.6 mmol) was added to 50 mL of DCM solution of compound (20) (1.4 g, 2.8 mmol), followed by dropwise addition of MsCl (0.39 g, 3.4 mmol) in 10 mL of DCM at 5–10 °C. The mixture was stirred at ambient temperature for 1 hour and quenched with a saturated aqueous solution of NaHCO3. The mixture was extracted with EtOAc, and the combined organic extracts were dried over Na2SO4 and evaporated to give 1.6 g of compound (21), which could be used in the next step without further purification.

[1195] 1H-NMR (DMSO-d6, δ, ppm): 2.33 (s, 6H), 2.41 (s, 3H), 2.71 (s, 3H), 3.06-3.12 (m, 1H), 3.23 (s, 3H), 3.37 (s, 3H), 3.38 (s, 3H), 3.89 (s, 3H), 3. 98-4.00(m, 1H), 4.08-4.12(m, 1H), 4.20-4.35(m, 4H), 4.41-4.52(m, 2H), 4.70-4.82(m, 4H), 4.85-4.89(m, 1H), 7.50(s, 1H), 7.65(s, 1H).

[1196] LCMS, m / z: 577.3 (M+H) + 599.3 (M+Na) + .

[1197] Compound 22

[1198] Sodium azide (1.9 g, 28.7 mmol) was added to 80 mL of a DMF solution of compound (21) (2.4 g, 4.1 mmol) and the mixture was stirred at 70 °C for 15 hours. Water was added, and the mixture was extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and evaporated to give 2.1 g of compound (22), which could be used in the next step without further purification.

[1199] 1 H-NMR (DMSO-d6, δ, ppm): 2.32 (s, 6H), 2.40 (s, 3H), 2.70 (s, 3H), 3.36 (s, 3H) , 3.39(s, 3H), 3.46-3.52(m, 1H), 3.72-3.77(m, 1H), 3.89(s, 3H), 3.95-4.00 (m, 2H), 4.20-4.34 (m, 3H), 4.42 (d, 1H, J=7.2Hz), 4.68-4.72 (m, 1H), 4.76 (s , 2H), 4.81 (d, 1H, J=6.2Hz), 4.88 (d, 1H, J=6.1Hz), 7.49 (s, 1H), 7.65 (s, 1H).

[1200] LCMS, m / z: 524.7 (M+H) + 546.2 (M+Na) + .

[1201] Compound 24 (Example 10)

[1202] Triphenylphosphine (0.31 g, 1.18 mmol) was added to 20 mL of a THF solution of compound (22) (0.31 g, 0.59 mmol), and the mixture was stirred at 60 °C for 4 hours. 10% HCl (5 mL) was added, and the mixture was stirred at 60 °C for 2 hours. The mixture was diluted with water, extracted with chloroform, and the combined organic extracts were discarded. The aqueous layer was evaporated to dryness, and the solid residue was washed with chloroform and Et₂O to give 0.13 g of compound (24) (Example 10).

[1203] 1 H-NMR (DMSO-d6, δ, ppm): 2.31 (s, 3H), 2.40 (s, 3H), 2.80-2.84 (m, 1H), 2.98-3.02 (m, 1H), 3.32-3.40(m, 2H), 3.60-3.65(m, 1H), 3.89(s, 3H), 3.90-3.92(m, 1H), 3.95-4.0 2 (m, 1H), 4.28 (br.d, 1H, J=13.4Hz), 4.48 (dd, 1H, J1=3.8Hz, J2=9.7Hz), 5.10 (d, 1H, J=6.5Hz), 5.48 (d, 1H, J=5.8Hz), 7.61 (s, 1H), 7.62 (s, 1H), 7.88 (br.s, 3H, NH2.HCl).

[1204] 13 C-NMR (DMSO-d6, δ, ppm): 18.63, 20.33, 41.74, 45.32, 52.64, 68.29, 68.71, 74. 62, 116.30, 129.65, 129.96, 132.45, 132.77, 142.32, 146.51, 152.34, 164.49.

[1205] LCMS, m / z: 348.6 (M-H2O) + 366.1 (M+H) + 388.3 (M+Na) + .

[1206] Synthesis of Compound 27 (Example 11) and Compound 26 (Example 12)

[1207] Examples 11-12 were synthesized according to the following scheme:

[1208]

[1209] The azide moiety on compound (22) was reduced by Staudinger with triphenylphosphine and water to give compound (23). Compound (23) was reductively amination with formaldehyde and STAB to give compound (25), and then the MOM group was removed to give compound (26) (Example 12). The ester group of compound (26) (Example 12) was hydrolyzed with aqueous HCl solution and heated to give compound (27) (Example 11).

[1210] Synthesis of Compound 31 (Example 14)

[1211] Example 14 was synthesized according to the following scheme:

[1212]

[1213] Compound 28

[1214] At ambient temperature, EDC-HCl (1.3 g, 6.8 mmol) and HOBt (1.5 g, 11.4 mmol) were added to a DMF (15 mL) solution of compound (4) (3.0 g, 5.7 mmol), followed by NH4Cl (1.3 g, 24.0 mmol). The reaction mixture was stirred at ambient temperature for 12 hours, ice-cold water was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and evaporated to dryness. The residue was passed through a silica gel pad and eluted with 4% MeOH / DCM to give 0.95 g of compound (28).

[1215] 1 H-NMR (DMSO-d6, δ, ppm): 1.70 (s, 3H), 2.00 (s, 3H), 2.11 (s, 3H), 2.13 (s, 3H), 2.33 (s, 3H), 2.42 (s, 3H), 4.18 (dd, 1H, J1=5.4Hz, J2=12. 0Hz), 4.33-4.37(m, 1H), 4.46-4.50(m, 1H), 4.64-4.70(m, 1H), 5.31-5.40(m, 3H), 7.47(s, 1H), 7.64(s, 1H), 7.80(s, 1H), 8.22(s, 1H).

[1216] LCMS, m / z: 520 (M+H) + 542.5 (M+Na) + .

[1217] Compound 29

[1218] At ambient temperature, DMFDMA (0.24 g, 2.0 mmol) was added to a 25 mL THF solution of compound (28) (0.95 g, 1.9 mmol), and the reaction mixture was heated to reflux and maintained for 3 hours. The reaction mixture was evaporated to dryness to give the desired compound (29). 1.05 g of the crude product was used in the next step without further purification.

[1219] LCMS, m / z: 575.3 (M+H) + 597.3 (M+Na) + .

[1220] Compound 30

[1221] Hydrazine hydrate (0.22 g, 4.3 mmol) was added to a solution of compound (29) (1.05 g, 1.8 mmol) in 70% AcOH (10 mL) at ambient temperature. The reaction mixture was heated to reflux and maintained for 2 hours. The reaction mixture was evaporated to dryness and co-evaporated with toluene. The residue was dissolved in EtOAc, washed with water, dried with Na2SO4, and evaporated to dryness. The residue was passed through a silica gel pad and eluted with 5% MeOH / DCM to give 0.18 g of compound (30).

[1222] 1 H-NMR (DMSO-d6, δ, ppm): 1.67 (s, 3H), 1.99 (s, 3H), 2.11 (s, 3H), 2.13 (s, 3 H), 2.35(s, 3H), 2.44(s, 3H), 4.15-4.19(m, 1H), 4.34-4.37(m, 1H), 4.56- 4.61 (m, 1H), 4.72-4.78 (m, 1H), 5.32-5.35 (m, 1H), 5.40-5.48 (m, 2H), 7.4 6-7.54(m, 1H), 7.62-7.72(m, 1H), 8.15-8.59(m, 1H), 14.32-14.47(m, 1H).

[1223] LCMS, m / z: 544.5.0 (M+H) + 566.7 (M+Na) + .

[1224] Compound 31 (Example 14)

[1225] At ambient temperature, 3.5 mL of aqueous NH3 solution was added to a MeOH solution of compound (30) (0.18 g, 0.33 mmol). The reaction mixture was stirred at ambient temperature for 12 hours. The reaction mixture was evaporated to half its volume, the resulting particles were filtered off and dried to give 0.099 g of compound (31) (Example 14).

[1226] 1 H-NMR (DMSO-d6, δ, ppm): 2.34 (s, 3H), 2.40 (s, 3H), 3.43-3.48 (m, 1H), 3.59-3.66 (m, 3H), 4.15-4.21 (m, 1H), 4.29-4.32 (m, 1H), 4.46 -4.49 (m, 1H), 4.64-4.73 (m, 2H), 4.81-4.82 (m, 1H), 4.98-4.99 (m, 1H), 7.62 (s, 1H), 7.68 (s, 1H), 8.23 ​​(br.s, 1H), 14.36 (br.s, 1H).

[1227] 13 C-NMR (DMSO-d6, δ, ppm): 18.70, 20.34, 44.68, 63.50, 68.65, 72.73, 73.83, 116.08, 12 9.82, 131.09, 131.71, 132.63, 141.53, 142.20(br), 150.16(br), 151.42(br), 153.79.

[1228] LCMS, m / z: 376.5 (M+H) + 398.4 (M+Na) + .

[1229] Synthesis of Compound 37 (Example 15)

[1230] Example 15 was synthesized according to the following scheme:

[1231]

[1232] Compound 32

[1233] Compound (3) (10.1 g, 27.5 mmol) was dissolved in DMF (100 mL), and MOM chloride (16.75 mL, 220 mmol) and DIPEA (38 mL, 220 mmol) were added. The reaction mixture was stirred overnight at 60 °C. The reaction mixture was concentrated under vacuum, diluted with water, and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and evaporated to give 12.1 g of compound (32). Compound (32) was ready for use in the next step without further purification.

[1234] 1 H-NMR (DMSO-d6, δ, ppm): 2.39 (s, 3H), 2.67 (s, 3H), 3.27 (s, 3H), 3.31 (s, 3H), 3.37 (s, 3H), 3.38 (s, 2H), 3.62-3.73 (m, 2H), 3.89 (s, 3H), 3.9 6-4.06 (m, 2H), 4.21-4.25 (m, 2H), 4.3 (br.d, 1H, J=13.2Hz), 4.41 (d, 1H, J=7.4Hz), 4.6 (s, 2H), 4.74-4.80 (m, 6H), 7.49 (s, 1H), 7.64 (s, 1H).

[1235] LCMS, m / z: 543.5 (M+H) + 565.5 (M+Na) + .

[1236] Compound 33

[1237] Compound (32) (12.1 g, 22.3 mmol) was dissolved in MeOH (150 mL), and a solution of NaOH (2.2 g, 55.75 mmol) in water (15 mL) was added. The reaction mixture was stirred overnight at room temperature. The MeOH was evaporated and the residue was diluted with water, acidified to pH 2 with 10% H2SO4, and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and evaporated to dryness to give 10.8 g of compound (33).

[1238] 1H-NMR (DMSO-d6, δ, ppm): 2.33 (s, 3H), 2.4 (s, 3H), 2.69 (s, 3H), 3.28 (s, 3H), 3.37 (s, 3H), 3.38 (s, 3H), 3.65 (dd, 1H, J1=10.5Hz, J2=4.5Hz), 3. 72(dd, 1H, J1=11Hz, J2=4Hz), 3.96-4.04(m, 2H), 4.21-4.43(m, 4H), 4.6(s, 2H), 4.74-4.80(m, 5H), 7.5(s, 1H), 7.65(s, 1H), .13.95(br.s, 1H)

[1239] LCMS, m / z: 529.5 (M+H) + 551.3(M+Na) + .

[1240] Compound 34

[1241] Compound (33) (5 g, 9.5 mmol) was dissolved in THF (100 mL), and triethylamine (1.1 g, 11.4 mmol) was added. The reaction mixture was cooled to 0 °C, and ethyl chloroformate (1.08 g, 10 mmol) was added dropwise. Stirring was continued at -5 °C for 30 minutes, then ammonia (150 mL) was added, and the mixture was stirred overnight at room temperature. The precipitate formed was filtered off, washed with water, and air-dried to give 4.4 g of compound (34).

[1242] 1 H-NMR (DMSO-d6, δ, ppm): 2.33 (s, 3H), 2.39 (s, 3H), 2.69 (s, 3H), 3.28 (s, 3 H), 3.37 (s, 3H), 3.38 (s, 3H), 3.64 (dd, 1H, J1=10.5Hz, J2=4.5Hz), 3.73 (dd , 1H, J1=11.0Hz, J2=4.0Hz), 3.89-4.08(m, 2H), 4.11-4.47(m, 4H), 4.61(s, 2H), 4.69-4.87(m, 5H), 7.48(s, 1H), 7.64(s, 1H), 7.79(s, 1H), 8.27(s, 1H)

[1243] LCMS, m / z: 528.3 (M+H) + 550.5(M+Na) + .

[1244] Compound 35

[1245] Compound (34) (2.1 g, 4 mmol) was dissolved in THF (50 mL). Pyridine (0.6 g, 8.0 mmol) was added under an inert atmosphere, followed by dropwise addition of trifluoroacetic anhydride (1.0 g, 4.8 mmol). The reaction mixture was stirred at room temperature under an inert atmosphere for 24 hours. Additional amounts of pyridine (0.6 g, 8.0 mmol) and trifluoroacetic anhydride (1 g, 4.8 mmol) were added, and stirring continued for 4 hours. The reaction mixture was poured into water, extracted with EtOAc, dried over Na2SO4, concentrated, and purified by column chromatography on silica gel, eluting with 25–30% EtOAc / DCM to give 1.5 g of compound (35).

[1246] 1 H-NMR (DMSO-d6, δ, ppm): 2.34 (s, 3H), 2.43 (s, 3H), 2.71 (s, 3H), 3.28 (s, 3H), 3.37 (s, 3H), 3.38 (s, 3H), 3.63 (dd, 1H, J1=11.5Hz, J2=5.3 Hz), 3.73 (dd, 1H, J1=11.4, Hz, J2=4Hz), 3.93-4.06 (m, 2H), 4.16-4.41 (m, 4H), 4.61 (s, 2H), 4.74-4.84 (m, 5H), 7.55 (s, 1H), 7.71 (s, 1H)

[1247] LCMS, m / z: 511.0 (M+H) + 532.0 (M+Na) + .

[1248] Compound 36

[1249] A mixture of compound (35) (1.5 g, 2.9 mmol), triethylammonium chloride (1.6 g, 11.6 mmol), and sodium azide (0.76 g, 11.6 mmol) in DMF (30 mL) was stirred at 120 °C for 5 hours. The reaction mixture was concentrated under vacuum, diluted with water, and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and evaporated to give 1.5 g of compound (36).

[1250] 1H-NMR (DMSO-d6, δ, ppm): 2.35 (s, 3H), 2.42 (s, 3H), 2.66 (s, 3H), 3.28 (s, 3H), 3.37 (s, 3H), 3.38 (s, 3H), 3.66 (dd, 1H, J1=10.5Hz, J2=5.3Hz ), 3.73 (dd, 1H, J1 = 11.4Hz, Hz, J2 = 4.0Hz), 3.93-4.11 (m, 2H), 4.14-4.49 (m, 4H), 4.61 (s, 2H), 4.71-4.99 (m, 6H), 7.53 (s, 1H), 7.72 (s, 1H)

[1251] LCMS, m / z: 553.5 (M+H) + 575.3 (M+Na) + .

[1252] Compound 37 (Example 15)

[1253] Compound (36) (1.3 g, 2.3 mmol) was dissolved in MeOH (50 mL), and concentrated HCl (10 mL) was added. The reaction mixture was heated at 60 °C for 40 minutes. The precipitate formed was filtered off and washed with water to give 0.45 g of compound (37) (Example 15).

[1254] 1 H-NMR (DMSO-d6, δ, ppm): 2.35 (s, 3H), 2.41 (s, 3H), 3.22-3.38 (m, 4H), 3.42-3.50 (m, 1H), 3.60-3.66 (m, 3H), 4.18 (m, 1H), 4 .36 (br.d, 1H, J=13.5Hz), 4.40-4.56 (m, 1H), 4.62-4.83 (m, 3H), 5.00 (br.s, 1H), 7.66 (s, 1H), 7.75 (s, 1H), 16.8 (br.s, 1H).

[1255] 13 C-NMR (DMSO-d6, δ, ppm): 18.68, 20.45, 44.88, 63.47, 68.44, 68.49, 72.71, 73. 75, 116.26, 130.06, 131.15, 132.24, 133.08, 139.99, 142.73, 150.96, 153.47.

[1256] LCMS, m / z: 377.6 (M+H) + 399.0 (M+Na) + .

[1257] Synthesis of Compound 40 (Example 16)

[1258] Example 16 was synthesized according to the following scheme:

[1259]

[1260] Compound 38

[1261] To a DMF (40 mL) solution of compound (4) (2 g, 3.8 mmol), methylamine hydrochloride (0.52 g, 7.6 mmol), EDCI (2.2 g, 11.4 mmol), and HOBt (1.17 g, 7.6 mmol) were added. The mixture was stirred at room temperature for 18 hours, diluted with water, and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and evaporated to give 0.9 g of compound (38).

[1262] 1 H-NMR (DMSO-d6, δ, ppm): 1.69 (s, 3H), 2.0 (s, 3H), 2.11 (s, 3H), 2.12 (s, 3H), 2.33 (s, 3H), 2.42 (2, 3H), 2.8 (s, 3H), 4.11-4.23 (m, 1H), 4.3-4.39(m, 1H), 4.43-4.54(m, 1H), 4.61-4.74(m, 1H), 5.26-5.44(m, 3H), 7.48(s, 1H), 7.64(s, 1H), 8.77(d, 1H, J=3.4Hz).

[1263] LCMS, m / z: 534.3.0 (M+H) + 556.3 (M+Na) + .

[1264] Compound 39

[1265] Under a nitrogen atmosphere, PCI5 (0.28 g, 1.32 mmol) was added to a stirred DCM solution of compound (38) (0.65 g, 1.2 mmol). The stirred reaction mixture was cooled to -5 °C, and TMSN3 (0.56 g, 4.8 mmol) was added dropwise. The mixture was then heated to ambient temperature and maintained for 16 hours. Subsequently, the mixture was cooled to 0 °C, and saturated NaHCO3 was added dropwise. The two layers were separated; the organic layer was washed with water, dried with Na2SO4, and evaporated to give 0.26 g of compound (39).

[1266] 1H-NMR (DMSO-d6, δ, ppm): 1.69 (s, 3H), 2.0 (s, 3H), 1.99 (s, 3H), 2.09 (s, 3H), 2.13 (s, 3H), 2.36 (2, 3H), 2.47 (s, 3H), 4 .12-4.21(m, 3H), 4.3-4.39(m, 1H), 4.51-4.6(m, 1H), 4.69-4.78(m, 1H), 5.29-5.47(m, 3H), 7.59(s, 1H), 7.75(s, 1H).

[1267] LCMS, m / z: 559.2.0(M+H) + 581.3 (M+Na) + .

[1268] Compound 40 (Example 16)

[1269] Compound (39) (0.26 g, 0.4 mmol) was dissolved in MeOH (10 mL). Ammonia (5 mL) was added and the mixture was stirred overnight at ambient temperature. The precipitate formed was filtered off and washed with water to give 0.12 g of compound (40) (Example 16).

[1270] 1 H-NMR (DMSO-d6, δ, ppm): 2.35 (s, 3H), 2.43 (s, 3H), 3.32 (s, 3H), 3.39-3.51 (m, 1H), 3.55-3.67 (m, 3H), 4.09-4.21 (m, 4H), 4.22-4.31 (d, 1 H, J=3.7Γц), 4.43-4.51 (m, 1H), 4.62-4.74 (m, 1H), 4.76-4.89 (m, 2H) , 4.99 (d, 1H, J=4.0Γц), 5.29-5.47 (m, 3H), 7.68 (s, 1H), 7.72 (s, 1H).

[1271] 13 C-NMR (DMSO-d6, δ, ppm): 18.65, 20.47, 35.32, 44.85, 63.53, 68.52, 72.79, 73. 72, 116.26, 130.04, 131.04, 132.54, 132.97, 141.58, 142.99, 151.20, 153.40.

[1272] LCMS, m / z: 391.4 (M+H) + 413.6 (M+Na) + .

[1273] Synthesis of Compound 43 (Example 17)

[1274] Example 17 was synthesized according to the following scheme:

[1275]

[1276] Compound 41

[1277] Under a nitrogen atmosphere, a solution of compound (4) (2.0 g, 3.8 mmol), EDC-HCl (1.5 g, 7.6 mmol), and 1-hydroxybenzo-triazole (1.04 g, 7.6 mmol) in anhydrous DCM (40 mL) was stirred for 30 min at ambient temperature. N-hydroxyacetamidine (0.57 g, 7.6 mmol) was added, and the reaction mixture was stirred at ambient temperature for 12 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with 10% sodium bicarbonate, water, and brine, dried over Na2SO4, filtered, and concentrated. The residue was passed through a silica gel pad and eluted with 2% MeOH / DCM to give 1.00 g of compound (41).

[1278] 1 H-NMR (DMSO-d6, δ, ppm): 1.70 (s, 3H), 1.78 (s, 3H), 2.00 (s, 3H), 2.10 (s, 3H), 2.13 (s, 3H), 2.33 (s, 3H), 2.44 (s, 3H), 4.15-4.19 (m, 1H), 4. 32-4.36(m, 1H), 4.48-4.52(m, 1H), 4.62-4.71(m, 1H), 5.29-5.33(m, 1H), 5.35-5.41(m, 2H), 6.41-6.69(m, 2H), 7.49(s, 1H), 7.66(s, 1H).

[1279] LCMS, m / z: 577.5 (M+H) + 599.2 (M+Na) + .

[1280] Compound 42

[1281] TBAF (0.077 g, 1.7 mmol) was added to a THF (30 mL) solution of compound (41) (1.00 g, 1.7 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 12 hours. The reaction mixture was dissolved in EtOAc, washed with water, 5% citric acid, water, and brine, dried over Na2SO4, filtered, and concentrated. The residue was passed through a silica gel pad and eluted with 30% EtOAc / CCl4 to give 0.26 g of compound (42).

[1282] 1 H-NMR (CDCl3, δ, ppm): 1.82 (s, 3H), 2.08 (s, 3H), 2.18 (s, 3H), 2.20 (s, 3H), 2.39 (s, 3H), 2.50 (s, 3H), 2.57 (s, 3H), 4.2 1-4.25 (m, 1H), 4.40-4.44 (m, 1H), 4.56-4.72 (m, 2H), 5.39-5.46 (m, 2H), 5.61-5.63 (m, 1H), 7.34 (s, 1H), 7.82 (s, 1H).

[1283] LCMS, m / z: 559.3 (M+H) + 581.3 (M+Na) + .

[1284] Compound 43 (Example 17)

[1285] At ambient temperature, 5 mL of aqueous NH3 solution was added to a MeOH (5 mL) solution of compound (42) (0.26 g, 0.46 mmol). The reaction mixture was stirred at ambient temperature for 12 hours. The reaction mixture was evaporated to half its volume, the resulting particles were filtered off and dried to give 0.11 g of compound (43) (Example 17).

[1286] 1 H-NMR (DMSO-d6, δ, ppm): 2.33 (s, 3H), 2.41 (s, 3H), 2.48 (s, 3H), 3.41-3.48 (m, 1H), 3.56-3.66 (m, 3H), 4.13-4.16 (m, 1H), 4.25-4 .29 (m, 1H), 4.45-4.47 (m, 1H), 4.64-4.65 (m, 1H), 4.73-4.74 (m, 1H), 4.82 (br.s, 1H), 4.98 (br.s, 1H), 7.65 (s, 1H), 7.71 (s, 1H).

[1287] 13 C-NMR (DMSO-d6, δ, ppm): 11.34, 18.62, 20.53, 44.80, 63.50, 68.58, 72.73, 73. 81, 116.25, 130.24, 130.75, 133.05, 139.61, 143.85, 152.56, 167.56, 171.70.

[1288] LCMS, m / z: 391.4 (M+H) + 413.6 (M+Na)+ .

[1289] Synthesis of Compound 44 (Example 7)

[1290] Example 7 was synthesized according to the following scheme:

[1291]

[1292] Compound (33) was converted into compound (44) by coupling with 2-dimethylaminoethanol (CAS#108-01-0) and acid-mediated removal of the MOM protecting group (Example 7).

[1293] Synthesis of Compound 50 (Example 18), Compound 52 (Example 19), and Compound 54 (Example 20)

[1294] Examples 18-20 were synthesized according to the following scheme.

[1295]

[1296] Compound 45

[1297] At 0 °C, lithium hydroxide (6.47 g, 269.96 mmol) in water (120 mL) was added dropwise to a stirred solution of compound (19) (40.0 g, 53.99 mmol) in MeOH (120 mL) and THF (120 mL). The resulting mixture was stirred at 0 °C for 3 hours. The mixture was neutralized to pH 7 with 1 M HCl and diluted with water (0.8 L). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with water (3 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give compound (45), which could be used directly in the next step without further purification.

[1298] LCMS: (ES, m / z): [M+Na] + =749.5

[1299] Compound 46

[1300] PyBOP (42.99 g, 82.55 mmol) was added in portions to a stirred solution of compound (45) (30.0 g, 41.27 mmol), (2-aminoethyl)dimethylamine (7.28 g, 82.55 mmol), and DIPEA (16.0 g, 0.124 mol) in DMF (400 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 3 h and then diluted with water (1.2 L). The resulting mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with water (3 × 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give compound (46), which could be used directly in the next step without further purification.

[1301] LCMS: (ES, m / z): [M+H] + =797.5

[1302] Compound 47

[1303] Formic acid (120 mL) was added dropwise to a THF (120 mL) solution of compound (46) (25.0 g, 31.37 mmol) stirred at 0 °C. The resulting mixture was stirred at 25 °C for 3 h and adjusted to pH 10 with saturated Na₂CO₃ aqueous solution. The mixture was then diluted with water (0.8 L) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with water (3 x 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile (0.1% formic acid), 25% to 35% gradient over 20 min; detector, UV 254 nm, yielding a yellow oily compound (47) (8 g).

[1304] LCMS: (ES, m / z): [M+H] + =555.4

[1305] Compound 48

[1306] Under an argon atmosphere, MsCl (6.20 g, 54.09 mmol) was added dropwise to a solution of compound (47) (6.00 g, 10.82 mmol) and DIPEA (13.98 mg, 108.18 mmol) in DCM, stirred at 0 °C. The resulting mixture was stirred at 25 °C for 2 h and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile (0.1% formic acid) in a 25% to 40% gradient over 20 min; detector, UV 254 nm, yielding a yellow oily compound (48) (5.2 g).

[1307] LCMS: (ES, m / z): [M+H] + =633.3

[1308] Compound 49

[1309] In a 40 mL sealed tube, compound (48) (400 mg) and 7 M NH3 (g) were mixed in MeOH (20 mL) at 25 °C. The mixture was stirred at 60 °C for 18 hours and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile (0.1% formic acid) in a 25% to 40% gradient over 20 minutes; detector, UV 254 nm, yielding a yellow oily compound (49) (300 mg).

[1310] LCMS: (ES, m / z): [M+H] + =554.4

[1311] Compound 50 (Example 18)

[1312] 4M HCl in 1,4-dioxane (10 mL) was added dropwise to a THF (1 mL) solution of compound (49) (300 mg, 0.54 mmol) stirred at 0 °C. The resulting mixture was stirred at 0 °C for 3 hours under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure and purified by preparative HPLC under the following conditions: column: X Bridge Shield RP18 OBD column, 5 μm, 19 x 150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: from 4% B to 18% B over 8 min; 220 nm; Rt: 7.8 min), yielding compound (50) (Example 18) (55 mg) as a yellow solid.

[1313] LCMS: (ES, m / z): [M+H] + =422.2

[1314] 1H NMR (300MHz, methanol-d4) δ7.82 (s, 1H), 7.66 (s, 1H), 4.64 (d, J = 24.3Hz, 2H), 4.19 (s, 1H), 4.03 (d, J = 10.2Hz, 1H), 3.76 (t, J = 6.0Hz, 1H), 3.65 (t, J=6.5Hz, 2H), 3.16 (dd, J=12.9, 3.7Hz, 1H), 3.04 (dd, J=12.9, 7.5Hz, 1H), 2.65 (t, J=6.5Hz, 2H), 2.46 (d, J=25.9Hz, 3H), 2.36 (s, 9H).

[1315] Compound 51

[1316] 2M dimethylamine in MeOH (5 mL) was added to a solution of compound (48) (300 mg, 0.47 mmol) stirred at 25 °C. The resulting mixture was stirred at 75 °C for 18 h and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile (0.1% formic acid) in a 25% to 40% gradient over 20 min; detector, UV 254 nm, yielding a yellow oily compound (51) (200 mg).

[1317] LCMS: (ES, m / z): [M+H] + =582.4

[1318] Compound 52 (Example 19)

[1319] 4M HCl in 1,4-dioxane (10 mL) was added dropwise to a THF (10 mL) solution of compound (51) (200 mg) at 0 °C, and the mixture was stirred at 0 °C for 3 hours. The mixture was then neutralized to pH 7 with a saturated aqueous NaHCO3 solution. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 5 μm, 19 x 150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: from 20% B to 50% B over 12 min; 220 nm; Rt: 11.8 min, yielding compound (52) (Example 19) (60 mg) as a yellow solid.

[1320] LCMS: (ES, m / z): [M+H] + =450.2

[1321] 1H NMR (300MHz, DMSO-d6) δ9.15 (s, 1H), 7.63 (d, J = 22.7Hz, 2H), 4.91 (s, 2H), 4.72 (s, 1H), 4.55 (t, J = 12.2Hz, 1H), 4.31 (d , J=13.8Hz, 1H), 4.05 (s, 1H), 3.77 (s, 1H), 3.58 (s, 3H), 2.41 (d, J=6.6Hz, 7H), 2.33 (s, 3H), 2.26 (s, 6H), 2.20 (s, 6H).

[1322] Compound 53

[1323] 2-Aminoethanol (10 mL) was added to a THF (10 mL) solution of compound (48) (400 mg, 0.60 mmol) at 25 °C. The resulting mixture was stirred at 60 °C for 18 hours, concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile, 20% to 50% gradient over 25 minutes; detector, UV 254 nm, to give compound (53) (350 mg) as a yellow solid.

[1324] LCMS: (ES, m / z): [M+H] + =598.4

[1325] Compound 54 (Example 20)

[1326] 4M HCl was added dropwise to a THF (10.00 mL) solution of compound (53) (300 mg, 0.50 mmol) stirred at 0 °C in 10.00 mL of 1,4-dioxane. The resulting mixture was stirred at 25 °C for 3 hours and neutralized to pH 7 with a saturated aqueous solution of NaHCO3. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC under the following conditions: column: Welch Ultimate C18 21.2 x 250 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: from 13% B to 16% B over 9 min; 254 nm; Rt: 6.33 min, yielding compound (54) (Example 20) (130 mg) as a yellow solid.

[1327] LCMS: (ES, m / z): [M+H] + =466.3

[1328] 1H NMR (300MHz, methanol-d4) δ7.80 (s, 1H), 7.66 (s, 1H), 4.70 (d, J=9.0Hz, 1H), 4.59 (dd, J=14.0, 2.9Hz, 1H), 4.25-4.11 (m, 2H), 3.92-3.80 (m , 5H), 3.45 (t, J=5.8Hz, 2H), 3.30 (s, 1H), 3.27 (d, J=4.5Hz, 1H), 3.21 (td, J=4.8, 2.0Hz, 2H), 3.03 (s, 6H), 2.52 (s, 3H), 2.43 (s, 3H).

[1329] Synthesis of Compound 56 (Example 21)

[1330] Example 21 was synthesized according to the following scheme.

[1331]

[1332] Compound 55

[1333] KMnO4 (854.79 mg, 5.41 mmol) in acetone (10 mL) was added dropwise to a solution of compound (47) (600 mg, 1.08 mmol) in acetone (10 mL) under stirring at 0 °C. The resulting mixture was stirred at 25 °C for 3 hours, then filtered and washed with water (3 x 5 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous ACN (0.1% NH3 aqueous solution) in a 10% to 50% gradient over 20 minutes; detector, UV 254 nm, yielding compound (55) (200 mg) as a yellow solid.

[1334] LCMS: (ES, m / z): [M+H] + =569.4

[1335] Compound 56 (Example 21)

[1336] Under an argon atmosphere, 4M HCl in 5.00 mL of 1,4-dioxane was added dropwise to a 10.00 mL H₂O solution of 200 mg of compound (55) stirred at 0 °C. The resulting mixture was stirred at 25 °C for 6 hours and then neutralized to pH 7 with a saturated aqueous NaHCO₃ solution. The resulting mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC under the following conditions: column: SunFire Prep C18 OBD column 19 × 150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 15% B to 15% B over 6 minutes; 254 / 220 nm; Rt: 4.50 min, yielding compound (56) (Example 21) (31.9 mg) as a yellow solid.

[1337] LCMS: (ES, m / z): [M+H] + =437.2

[1338] 1 ¹H NMR (300 MHz, methanol-d⁴) δ 8.07 (d, J = 10.8 Hz, 1H), 7.75 (d, J = 28.8 Hz, 2H), 4.81–4.75 (m, 1H), 4.62–4.46 (m, 2H), 4.28 (d, J = 9.2 Hz, 1H), 3.88–3.75 (m, 3H), 3.74–3.57 (m, 5H), 3.12 (s, 1H), 2.98 (s, 2H), 2.46 (d, J = 26.2 Hz, 6H).

[1339] Synthesis of Compound 59 (Example 22)

[1340] Example 22 was synthesized according to the following scheme.

[1341]

[1342] Compound 57

[1343] Compound (48) (350 mg, 0.55 mmol) and NaI (331.66 mg, 2.21 mmol) were mixed in acetone (20 mL) in a sealed tube. The resulting mixture was stirred at 70 °C for 18 hours. After cooling to 0 °C, the mixture was concentrated under reduced pressure. The residue was then purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous ACN solution (0.1% formic acid), 25% to 45% gradient over 20 minutes; detector, UV 254 nm, yielding a yellow oily compound (57) (280 mg).

[1344] LCMS: (ES, m / z): [M+H]+ =665.2

[1345] Compound 58

[1346] A mixture of compound (57) (280 mg, 0.42 mmol), TEA (85.02 mg, 0.84 mmol), and Pd / C (60 mg) in MeOH (20 mL) was stirred at 25 °C under a hydrogen atmosphere for 18 hours. The mixture was filtered and the residual solids were washed with MeOH (3 x 5 mL). The combined filtrates were concentrated under reduced pressure to give compound (58) (200 mg) as a yellow oil.

[1347] LCMS: (ES, m / z): [M+H] + =539.3

[1348] Compound 59 (Example 22)

[1349] Under a nitrogen atmosphere, 4M HCl in 1,4-dioxane (5 mL) was added dropwise to a 10 mL solution of MeOH (58) (300 mg, 0.56 mmol) of compound (58) stirred at 0 °C. The resulting mixture was stirred at 25 °C for 3 hours, then cooled to 0 °C and neutralized to pH 7 with a saturated aqueous NaHCO3 solution. The mixture was concentrated under reduced pressure and the residue was purified by reversed-phase rapid chromatography under the following conditions: column: XBridge C18 OBD Prep column. 5 μm, 19 mm x 250 mm; mobile phase A: water (10 mmol, NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 19% B to 27% B in 11 minutes; 254 nm; Rt: 9.32 minutes, yielding a yellow solid compound (59) (Example 22) (16.1 mg).

[1350] LCMS: (ES, m / z): [M+H] + =407.3

[1351] 1 H NMR (300MHz, methanol-d4) δ7.82 (s, 1H), 7.69 (s, 1H), 4.61 (s, 1H), 4.18 (t, J = 6.4Hz, 1H), 3.96 (t, J = 6.3Hz, 1H) , 3.69-3.58 (m, 4H), 2.65 (t, J=6.6Hz, 2H), 2.50 (s, 3H), 2.42 (s, 3H), 2.36 (s, 6H), 1.29 (d, J=6.3Hz, 3H).

[1352] Synthesis of Compound 61 (Example 23), Compound 63 (Example 24), and Compound 65 (Example 25)

[1353] Examples 23-25 ​​were synthesized according to the following scheme.

[1354]

[1355] Compound 60

[1356] PyBOP (400 mg, 0.77 mmol) was added fractionally to a stirred solution of compound (45) (300 mg, 0.41 mmol), 2-aminoethanol (240 mg, 3.93 mmol), and DIPEA (600 mg, 4.64 mmol) in DMF (10 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 3 h and then diluted with water (100 mL). The mixture was extracted with EtOAc (3 x 50 mL), and the combined organic layers were washed with water (3 x 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure and purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile (0.1% formic acid) in a 25% to 40% gradient over 20 min; detector, UV 254 nm, to give compound (60) (250 mg) as a yellow solid.

[1357] LCMS: (ES, m / z): [M+H] + =770.4

[1358] Compound 61 (Example 23)

[1359] 4M HCl in 1,4-dioxane (10 mL) was added dropwise to a 10 mL THF solution of compound (60) (360 mg, 0.45 mmol) at 0 °C, and the mixture was stirred at 25 °C for 3 hours. The mixture was then neutralized to pH 7 with a saturated aqueous NaHCO3 solution and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18OBD column, 5 μm, 19 x 150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: from 8% B to 25% B over 8 min; 220 nm; Rt: 7.9 min, yielding compound (61) (Example 23) (90 mg) as a yellow solid.

[1360] LCMS: (ES, m / z): [M+H] + =396.2

[1361] 1H NMR (300MHz, DMSO-d6) δ9.25 (t, J=5.5Hz, 1H), 7.65 (d, J=16.5Hz, 2H), 4.99 (d, J=3.9Hz, 1H), 4.88-4.79 (m, 2H), 4.65 (d d, J=25.2, 8.7Hz, 2H), 4.49 (t, J=5.3Hz, 1H), 4.28-4.07 (m, 2H), 3.67-3.49 (m, 6H), 3.35 (d, 2H), 2.37 (d, J=19.4Hz, 6H).

[1362] Compound 62

[1363] PyBOP (384.91 mg, 0.74 mmol) was added fractionally to a stirred solution of compound (45) (300 mg, 0.41 mmol), [2-(2-aminoethoxy)ethyl]dimethylamine (109.14 mg, 0.83 mmol), and DIPEA (192.42 mg, 1.48 mmol) in 10 mL of DMF at 0 °C. The resulting mixture was stirred at 25 °C for 3 hours, followed by dilution with 100 mL of water. The mixture was extracted with EtOAc (3 x 50 mL), and the combined organic layers were washed with water (3 x 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile (0.1% formic acid) in a 10% to 50% gradient over 20 minutes; detector, UV 254 nm, yielding a yellow solid compound (62) (200 mg).

[1364] LCMS: (ES, m / z): [M+H] + =841.5

[1365] Compound 63 (Example 24)

[1366] Under a nitrogen atmosphere, 4M HCl in 1,4-dioxane (10 mL) was added dropwise to a 10 mL THF solution of compound (62) (200 mg, 0.24 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 3 hours and neutralized to pH 7 with a saturated aqueous NaHCO3 solution. The mixture was concentrated under reduced pressure and purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 5 μm, 19 x 150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: from 12% B to 40% B over 8 min; 220 nm; Rt: 7.9 min, yielding compound (63) (Example 24) (70 mg) as a yellow solid.

[1367] LCMS: (ES, m / z): [M+H] + =467.2

[1368] 1 H NMR (300MHz, DMSO-d6) δ9.26 (d, J=5.8Hz, 1H), 7.64 (d, J=13.5Hz, 2H), 4.91 (d, J=48.1Hz, 2H ), 4.75-4.36 (m, 3H), 4.31-4.01 (m, 2H), 3.73-3.49 (m, 9H), 2.55-2.28 (m, 8H), 2.14 (s, 6H).

[1369] Compound 64

[1370] PyBOP (429.59 mg, 0.83 mmol) was added fractionally to a stirred solution of compound (45) (300 mg, 0.41 mmol), 2-(2-aminoethoxy)ethanol-1-ol (130.19 mg, 1.24 mmol), and DIPEA (214.56 mg, 1.65 mmol) in 10 mL of DMF at 0 °C. The resulting mixture was stirred at 25 °C for 3 hours, followed by dilution with 100 mL of water. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile (0.1% formic acid) in a 25% to 50% gradient over 20 minutes; detector, UV 254 nm, yielding a yellow solid compound (64) (200 mg).

[1371] LCMS: (ES, m / z): [M+H] + =814.4

[1372] Compound 65 (Example 25)

[1373] Under an argon atmosphere, 4M HCl in 1,4-dioxane (10 mL) was added dropwise to a 10 mL solution of compound (64) (200 mg, 0.18 mmol) in THF at 0 °C. The resulting mixture was stirred at 25 °C for 3 hours, and then neutralized to pH 7 with a saturated aqueous NaHCO3 solution. The resulting mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC under the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile (0.1% formic acid) in a 20% to 35% gradient over 20 minutes; detector, UV 254 nm, yielding compound (65) (Example 25) (50 mg) as a yellow solid.

[1374] LCMS: (ES, m / z): [M+H] + =440

[1375] 1 H NMR (300MHz, DMSO-d6) δ9.19 (t, J=5.5Hz, 1H), 7.64 (d, J=14.0Hz, 2H), 4.99 (d, J=4.5Hz, 1H), 4.83 (d, J=3.5 Hz, 1H), 4.71-4.56 (m, 3H), 4.48 (t, J=5.4Hz, 1H), 4.29-4.07 (m, 2H), 3.68-3.40 (m, 12H), 2.43-2.29 (m, 6H).

[1376] Synthesis of Compound 67 (Example 27) and Compound 69 (Example 26)

[1377] Examples 26 and 27 were prepared according to the following schemes:

[1378]

[1379] Compound (66) was obtained by replacing the OMs portion of compound (21) with ethylene glycol, or by replacing it with 2-dimethylaminoethyl-1-ol to obtain compound (68). The MOM protecting group on compound (66) was removed under acidic conditions to obtain compound (67) (Example 27), and the MOM protecting group on compound (68) was removed to obtain compound (69) (Example 26).

[1380] Synthesis of Compound 71 (Example 28) and Compound 73 (Example 29)

[1381] Examples 28 and 29 were synthesized according to the following scheme.

[1382]

[1383] Compound 70

[1384] DIPEA (160.04 mg, 1.24 mmol) and PyBOP (279.23 mg, 0.54 mmol) were added to a stirred solution of 1-methylpiperazine (82.69 mg, 0.83 mmol) and compound (45) (300 mg, 0.41 mmol) in DMF (5.00 mL) at 0 °C. The resulting mixture was stirred at 20 °C for 2 h. The mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, A: 0.05% aqueous NH4HCO3; B: acetonitrile; detector, UV 254 nm; 40% B, to give a yellow oily compound (70) (500 mg).

[1385] ESI-MS m / z = 809.8 [M+H] + 831.6 [M+Na] +

[1386] Compound 71 (Example 28)

[1387] 4M HCl in 1,4-dioxane (1.5 mL) was added dropwise to a 0°C solution of compound (70) (300 mg, 0.37 mmol). The resulting mixture was stirred at 20°C for 2 hours, followed by concentration under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: column: XBridge Prep Phenyl OBD column, 5 μm, 19 x 250 mm; mobile phase A: water (0.05% NH4OH), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: from 3% B to 3% B over 2 min; 254 / 220 nm; Rt: 8.50 min, yielding a pale yellow solid of compound (71) (Example 28) (90 mg).

[1388] LCMS: ESI-MS m / z=435.5[M+H] +

[1389] 1H-NMR (400MHz, methanol-d4): δ7.72-7.65 (d, 2H), 4.95-4.83 (dd, J=14.1, 9.7Hz, 1H), 4.45 (dd, J=14.1, 2.8Hz, 1H), 4.28 (ddd, J=9.7, 4.6, 2. 8Hz, 1H), 3.91-3.80 (m, 5H), 3.80-3.74 (m, 1H), 3.45 (dd, J=5.9, 4.2Hz, 2H), 2.60 (t, J=5.3Hz, 2H), 2.48 (s, 5H), 2.38 (d, J=16.8Hz, 6H).

[1390] Compound 72

[1391] DIPEA (160.04 mg, 1.24 mmol) and PyBOP (279.23 mg, 0.54 mmol) were added to a stirred solution of morpholine (71.92 mg, 0.83 mmol) and compound (45) (300 mg, 0.41 mmol) in DMF (3.00 mL) at 0 °C. The resulting mixture was stirred at 20 °C for 2 hours and then purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, A: 0.5% NH4HCO3 aqueous solution, B: acetonitrile, UV 254 nm, 40% B, to give compound (72) (300 mg) as a pale yellow solid.

[1392] ESI-MS m / z = 818.4 [M+Na] +

[1393] Compound 73 (Example 29)

[1394] 4M HCl in dioxane (3.00 mL) was added to a solution of compound (72) (300 mg, 0.38 mmol) and stirred at 20 °C for 6 hours. The mixture was neutralized to pH 7 at 0 °C with saturated NaHCO3 aqueous solution. The resulting mixture was concentrated under reduced pressure and purified by preparative HPLC under the following conditions (column: Welch Xtimate C18 21.2 x 250 mm, 5 μm; mobile phase A: 10 mmol NH4HCO3 water, mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: from 21% B to 26% B over 9 min; detector: 254 nm; Rt: 6.44 min) to give compound (73) (Example 29) (30.7 mg) as a yellow solid.

[1395] LCMS: ESI-MS m / z=422.2[M+H] +

[1396] 1 ¹H-NMR (300MHz, methanol-d⁴): δ 7.73–7.61 (d, 2H), 4.81–4.70 (m, 1H), 4.46 (dd, J = 14.0, 2.8 Hz, 1H), 4.28 (dt, J = 9.8, 3.2 Hz, 1H), 3.89–3.73 (m, 7H), 3.73–3.63 (m, 3H), 3.48–3.39 (m, 2H), 2.49 (s, 3H), 2.40 (s, 3H).

[1397] Synthesis of Compound 75 (Example 30) and Compound 78 (Example 32)

[1398] Examples 30 and 32 were synthesized according to the following scheme.

[1399]

[1400] Compound 74

[1401] Compound (4) (1 g, 1.92 mmol) was stirred at room temperature in a solution of DMF (8 mL) and CDI (800.63 mg, 4.94 mmol) was added. The resulting mixture was stirred at 30 °C for 16 h and ethyl (N-hydroxycarbamoyl)formate (800 mg, 6.06 mmol) was added. After holding at 80 °C for another 5 h, the mixture was cooled to room temperature. The mixture was then purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, A: 0.1% aqueous formic acid, B: ACN, 10% to 100% gradient over 30 min; detector, UV 254 nm, 70% B, to give a yellow semi-solid compound (74) (350 mg).

[1402] ESI-MS m / z = 617.5 [M+H] +

[1403] Compound 75 (Example 30)

[1404] LiBH4 (61.83 mg, 2.84 mmol) was added in portions to a stirred solution of compound (74) (350 mg, 0.57 mmol) in MeOH (20 mL) at 0 °C. The resulting mixture was stirred at 20 °C for 16 h. An aqueous solution of NH3 (5 mL) was added dropwise to the mixture at 20 °C and stirring was continued at 40 °C for another 2 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column 19 x 250 mm, 5 μm; mobile phase A: water (10 mmol NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 17% B to 21% B over 12 min; 254 / 220 nm; Rt: 8.13 min) to give compound (75) (Example 30) (66.6 mg) as a pale yellow solid.

[1405] LCMS ESI-MS m / z = 407.15 [M+H] +

[1406] 1 H NMR (300MHz, DMSO-d6) δ7.74 (s, 1H), 7.67 (s, 1H), 5.83 (t, J = 6.3Hz, 1H), 4.99 (d, J = 4.4Hz, 1H), 4.84 (s, 1H), 4.76 (d, J = 6.0Hz, 1H), 4.69 (d, J=6.3Hz, 2H), 4.48 (t, J=5.5Hz, 1H), 4.29 (d, J=14.0Hz, 1H), 4.16 (s, 1H), 3.62 (s, 3H), 2.43 (s, 3H), 2.35 (s, 3H).

[1407] Compound 76

[1408] LiBH4 (75.92 mg, 3.49 mmol) was added fractionally to a stirred solution of compound (74) (700 mg, 1.16 mmol) in MeOH (10 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h. The mixture was quenched at 0 °C by adding water (1 mL) and purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, A: 0.1% TFA aqueous solution, 0% to 100% gradient over 30 min; detector, UV 254 nm, 60% B, to give a yellow oily compound (76) (300 mg).

[1409] LCMS: ESI-MS m / z=575.3[M+H] +

[1410] Compound 77

[1411] DIPEA (202.45 mg, 1.57 mmol) and methanesulfonyl chloride (65.79 mg, 0.57 mmol) were added dropwise to a stirred solution of compound (76) (300 mg, 0.52 mmol) in DCM (10 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 2 hours and quenched with water. The organic layer was separated, washed with water (2 x 30 mL), and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give a yellow oily compound (77) (400 mg).

[1412] LCMS: ESI-MS m / z=653.4[M+H] + 675.5 [M+Na] +

[1413] Compound 78 (Example 32)

[1414] Compound (77) (400 mg) was stirred in 2 M dimethylamine / THF (30 mL) for 3 hours at 30 °C, and then concentrated under reduced pressure. Ammonia (10 mL) was added dropwise to the residue and the resulting mixture was stirred at 40 °C for another 16 hours. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column 19 x 250 mm, 5 μm; mobile phase A: water (0.05% ammonia), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 19% B to 25% B over 15 min; 220 / 254 nm; Rt: 11.72 min) to give compound (78) (Example 32) (25.5 mg) as a yellow solid.

[1415] LCMS: ESI-MS m / z=434.2[M+H] +

[1416] 1 ¹H NMR (300 MHz, methanol-d⁴): δ 7.79 (s, 1H), 7.74 (s, 1H), 4.80 (s, 1H), 4.53 (dd, J = 14.0, 2.8 Hz, 1H), 4.33 (dq, J = 9.7, 3.1 Hz, 1H), 3.90–3.79 (m, 5H), 3.75–3.68 (m, 1H), 2.52 (s, 3H), 2.43 (d, J = 1.6 Hz, 8H).

[1417] Synthesis of Compound 79 (Example 31)

[1418] Example 31 was synthesized according to the following scheme.

[1419]

[1420] Compound 78 (Example 32)

[1421] A MeOH (10 mL) solution of compound 77 (200 mg, 0.31 mmol) was treated in batches with sodium methoxide (200 mg, 3.70 mmol). The mixture was stirred at 0 °C for 3 hours and then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase A: 0.1% TFA aqueous solution, B: ACN; 10% to 70% gradient over 20 minutes; detector, UV 254 nm, yielding compound (79) (Example 31) (67 mg) as a yellow solid.

[1422] LCMS: ESI-MS m / z=421.20[M+H] +

[1423] 1 ¹H-NMR (300MHz, methanol-d⁴) δ 7.75 (d, J = 16.5 Hz, 2H), 4.82 (s, 1H), 4.73 (s, 2H), 4.51 (dd, J = 14.0, 2.7 Hz, 1H), 4.32 (ddd, J = 9.8, 4.4, 2.7 Hz, 1H), 3.91–3.76 (m, 3H), 3.71 (dd, J = 12.1, 6.2 Hz, 1H), 3.52 (s, 3H), 2.51 (s, 3H), 2.41 (s, 3H).

[1424] Synthesis of Compound 83 (Example 33)

[1425] Example 33 was synthesized according to the following scheme.

[1426]

[1427] Compound 80

[1428] Formic acid (10 mL) was added dropwise to a THF (10 mL) solution of compound (70) (2.0 g, 2.47 mmol) stirred at 0 °C. The resulting mixture was stirred at 25 °C for 18 h and then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN:water (0.1% FA), 10% to 50% ACN gradient over 20 min; detector, UV 254 nm, to give a yellow oily compound (80) (0.7 g).

[1429] LCMS: (ES, m / z): [M+H] + =567.4

[1430] Compound 81

[1431] Under an argon atmosphere, a DCM solution (30 mL) of MsCl (281.58 mg, 2.47 mmol) was added dropwise to a stirred solution of compound (80) (0.70 g, 1.24 mmol) and DIPEA (80 3.01 mg, 6.178 mmol) in DCM (30 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 1 hour under an argon atmosphere and then diluted with water (50 mL). The resulting mixture was extracted with DCM (3 x 20 mL), and the combined organic layers were washed with water (3 x 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography, eluting with (DCM / MeOH 10:1) to give compound (81) (500 mg) as a yellow solid.

[1432] LCMS: (ES, m / z): [M+H] + =645.3

[1433] Compound 82

[1434] Compound (81) (500 mg, 0.78 mmol) and 7 M NH3 (g) in MeOH (10 mL) were placed in a sealed tube and the mixture was stirred at 70 °C for 16 h. Subsequently, the mixture was concentrated under reduced pressure and the residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN: water (0.1% FA), 10% to 50% ACN gradient over 10 min; detector, UV 254 nm, to give a yellow oily compound (82) (350 mg).

[1435] LCMS: (ES, m / z): [M+H] + =566.4

[1436] Compound 83 (Example 33)

[1437] HCl (6M, in dioxane) (5 mL) was added dropwise to a mixture of compound (82) (200 mg, 0.35 mmol) stirred at 0 °C in MeOH (5 mL). The resulting mixture was stirred at 25 °C for 3 hours and then neutralized to pH 7 with a saturated aqueous solution of NaHCO3. The resulting mixture was concentrated under reduced pressure and the residue was purified by reversed-phase rapid chromatography under the following conditions: column: Gemini-NX C18 AXAI 21.2*150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 7% B to 15% B over 10 min; 254 / 220 nm; Rt: 7.09 min, yielding compound (83) (Example 33) (50 mg) as a yellow solid.

[1438] LCMS: (ES, m / z): [M+H] + =434.2

[1439] 1 H NMR (300MHz, methanol-d4) δ7.66 (s, 2H), 4.65 (d, J=8.9Hz, 1H), 4.55 (dd, J=14.0, 3.1Hz, 1H), 4.20-4.04 (m, 3 H), 3.77 (t, J=6.0Hz, 2H), 3.38-3.34 (m, 4H), 3.27-3.06 (m, 4H), 2.96 (s, 3H), 2.50 (s, 3H), 2.41 (s, 3H).

[1440] Synthesis of Compound 84 (Example 34)

[1441] Example 34 was synthesized according to the following scheme.

[1442]

[1443] Compound 84 (Example 34)

[1444] The solution of compound (74) (300 mg) in 7 M NH3 / MeOH (20 mL) was stirred for 16 hours at 20 °C and then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase A: 0.1% aqueous NH4HCO3; mobile phase B: ACN, 0% to 50% gradient over 30 minutes; detector, UV 254 nm, yielding compound (84) (Example 34) (85.9 mg) as a yellow solid.

[1445] LCMS: ESI-MS m / z=420.10[M+H] +

[1446] 1 H-NMR: (300MHz, DMSO-d6): δ8.48 (s, 1H), 8.22 (s, 1H), 7.75 (s, 1H), 7.69 (s, 1H), 5.01 (d, J=4.0Hz, 1H), 4.85 (s, 1H), 4.77 (d, J=5.9Hz, 1H) , 4.74-4.61 (m, 1H), 4.48 (d, J=5.5Hz, 1H), 4.30 (d, J=14.1Hz, 1H), 4.17 (s, 1H), 3.62 (s, 3H), 3.50-3.40 (m, 1H), 2.44 (s, 3H), 2.36 (s, 3H).

[1447] Synthesis of Compound 92 (Example 35)

[1448] Example 35 was synthesized according to the following scheme.

[1449]

[1450] Compound 85

[1451] CDI (6.69 g, 41.28 mmol) was added in portions to a stirred solution of compound (45) (10 g, 13.76 mmol) in DMF (50 mL) at 25 °C, followed by the addition of ethyl (N-hydroxycarbamoylimide) formate (6.54 g, 49.5 mmol). The mixture was irradiated with microwave at 50 °C for 18 h, followed by irradiation at 80 °C for 5 h. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (3 × 20 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN: water (0.1% FA), 60% to 85% gradient over 20 min; detector, UV 254 nm, to give compound (85) (4 g) as a yellow solid.

[1452] LCMS: (ES, m / z): [M+Na] + =845.5

[1453] Compound 86

[1454] LiBH4 (1.06 g, 48.66 mmol) was added fractionally to a stirred solution of compound (85) (4.0 g, 4.86 mmol) in MeOH (50 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h and then quenched with a saturated aqueous solution of NH4Cl (10 mL). The mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give a yellow oily compound (86) (3.5 g).

[1455] LCMS: (ES, m / z): [M+Na] + =803.5

[1456] Compound 87

[1457] MsCl (1466.96 mg, 12.81 mmol) was added dropwise to a 0°C stirred solution of compound (86) (2.0 g, 2.56 mmol) and DIPEA (3310.21 mg, 25.61 mmol) in DCM (20 mL) in DCM (1 mL) in 1 mL. The resulting mixture was stirred at 25°C for 1 hour and then concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN: water (0.1% FA), 10% to 70% gradient over 20 min; detector, UV 254 nm, to give a yellow oily compound (87) (2 g).

[1458] LCMS: (ES, m / z): [M+Na] + =881.5

[1459] Compound 88

[1460] A solution of compound (87) (2.0 g, 2 mmol) and dimethylamine (2 M, in MeOH) (5 mL) in THF (5 mL) was stirred at 80 °C for 16 h, and then concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN: water (0.1% FA), 10% to 50% gradient over 20 min; detector, UV 254 nm, to give a yellow oily compound (88) (1.6 g).

[1461] LCMS: (ES, m / z): [M+H] + =808.6

[1462] Compound 89

[1463] Formic acid (20 mL, 0.44 mmol) was added dropwise to a THF (20 mL) solution of compound (88) (1.60 g, 1.98 mmol) stirred at 0 °C. The resulting mixture was stirred at 25 °C for 16 h and then concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN: water (0.1% FA), 10% to 50% gradient over 10 min; detector, UV 254 nm, to give a yellow oily compound (89) (700 mg).

[1464] LCMS: (ES, m / z): [M+H] + =566.4

[1465] Compound 90

[1466] MsCl (708.83 mg, 6.19 mmol) was added dropwise to a 0°C stirred solution of compound (89) (700 mg, 1.24 mmol) and DIPEA (1599.48 mg, 12.38 mmol) in DCM. The resulting mixture was stirred at 25°C for 1 hour and then concentrated under vacuum. The residue was purified by preparative thin-layer chromatography, eluting with (DCM / MeOH 10:1) to give compound (90) (500 mg) as a yellow oil.

[1467] LCMS: (ES, m / z): [M+H] + =644.5

[1468] Compound 91

[1469] Compound (90) (550 mg, 0.85 mmol) and NH3(g) / MeOH (12 mL, 422.77 mmol) were stirred in a sealed tube at 70 °C for 16 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN: water (0.1% FA), 10% to 50% gradient over 20 min; detector, UV 254 nm, to give a yellow oily compound (91) (260 mg).

[1470] LCMS: (ES, m / z): [M+H] + =565.5

[1471] Compound 92 (Example 35)

[1472] 4M HCl (g) was added dropwise to a MeOH (4 mL, 98.8 mmol) solution of compound (91) (240 mg, 0.43 mmol) stirred at 0 °C in 4 mL of 1,4-dioxane (4 mL, 131.65 mmol). The resulting mixture was stirred at 25 °C for 3 hours and then concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography under the following conditions: column: SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 8% B to 15% B over 12 minutes; 254 / 220 nm, yielding compound (92) (Example 35) (40 mg) as a yellow solid.

[1473] LCMS: (ES, m / z): [M+H] + =433.2

[1474] 1 H NMR (400MHz, methanol-d4) δ7.82 (s, 1H), 7.72 (s, 1H), 4.73 (s, 3H), 4.64 (dd, J=14.1, 2.9Hz, 1H), 4.22 (ddd, J=9.2, 6.2, 2.8Hz, 1H), 4.10 (ddd, J=8 .2, 5.8, 3.6Hz, 1H), 3.81 (t, J=6.0Hz, 1H), 3.24 (dd, J=12.9, 3.7Hz, 1H), 3.17-3.11 (m, 1H), 3.07 (s, 6H), 2.54 (s, 3H), 2.45 (d, J=0.9Hz, 3H).

[1475] Synthesis of Compound 97 (Example 36)

[1476] Example 36 was synthesized according to the following scheme.

[1477]

[1478] Compound 93

[1479] Triisopropylchlorosilane (370.35 mg, 1.92 mmol) was added dropwise to a stirred solution of compound (86) (1.00 g, 1.28 mmol) and imidazole (261.54 mg, 3.84 mmol) in DCM (40 mL) at 0 °C. The resulting mixture was stirred at 30 °C for 16 h, then diluted with water (200 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give a yellow oily compound (93) (1.1 g).

[1480] LCMS: (ES, m / z): [M+Na] + =959.8

[1481] Compound 94

[1482] Formic acid (20 mL, 0.44 mmol) was added dropwise to a THF (20 mL, 0.28 mmol) solution of compound (93) (1.1 g, 1.17 mmol) stirred at 0 °C. The resulting mixture was stirred at 25 °C for 16 h. The resulting mixture was concentrated under vacuum, and the residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH:water, 10% to 50% gradient over 10 min; detector, UV 254 nm, to give a yellow oily compound (94) (220 mg).

[1483] LCMS: (ES, m / z): [M+Na] + =717.6

[1484] Compound 95

[1485] MsCl (181.33 mg, 1.58 mmol) in DCM was added dropwise to a stirred solution of compound (94) (220 mg, 0.32 mmol) and DIPEA (409.18 mg, 3.17 mmol) in DCM (5 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give compound (95) (230 mg) as a yellow solid.

[1486] LCMS: (ES, m / z): [M+Na] + =881.5

[1487] Compound 96

[1488] Compound (95) (230 mg, 0.3 mmol) and 7 M NH3 (g) / MeOH (10 mL, 0.59 mmol) were stirred in a sealed tube at 70 °C for 18 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH:water, 10% to 50% gradient over 10 min; detector, UV 254 nm, to give a yellow oily compound (96) (170 mg).

[1489] LCMS: (ES, m / z): [M+H] + =694.6

[1490] Compound 97 (Example 36)

[1491] 4M HCl (g) was added dropwise to a THF (4 mL, 0.055 mmol) solution of compound (96) (170 mg, 0.25 mmol) stirred at 0 °C in 4 mL of 1,4-dioxane (0.11 mmol). The resulting mixture was stirred at 25 °C for 4 hours and then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: Gemini-NX C18 AXAI packed column, 21.2 x 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 7% B to 28% B over 12 min; 254 / 220 nm, yielding compound (97) (Example 36) (60 mg) as a yellow solid.

[1492] LCMS: (ES, m / z): [M+H] + =406.3

[1493] 1 H NMR (300MHz, methanol-d4) δ8.55 (s, 1H), 7.75 (d, J = 34.8Hz, 2H), 4.83 (s, 2H), 4.65 (s, 2H), 4.15 ( d, J=32.7Hz, 2H), 3.79 (s, 1H), 3.21 (s, 1H), 3.12 (d, J=9.5Hz, 1H), 2.48 (d, J=27.7Hz, 6H).

[1494] Synthesis of Compound 99 (Example 37)

[1495] Example 37 was synthesized according to the following scheme.

[1496]

[1497] Compound 98

[1498] The mixture of compound (4) (2 g, 3.84 mmol) in SOCl2 (10 mL) was stirred at 50 °C for 5 h, and then concentrated under reduced pressure. The residue was diluted with DCM (10 mL), and a solution of ethyl (hydrazine carbonyl) formate (0.51 g, 3.86 mmol) and DIPEA (1.49 g, 11.53 mmol) in DCM (10 mL) was added dropwise while stirring at 0 °C. After 30 min, the mixture was diluted with DCM (50 mL) and washed with water (3 × 50 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase A: 0.5% NH4HCO3, mobile phase B: ACN, 0% to 50% gradient over 3 min; detector, UV 254 nm, to give a yellow solid intermediate. The intermediate was then stirred overnight at 70 °C in POCl3 (10 mL), and then concentrated under vacuum. The residue was diluted with DCM (50 mL) and washed with water (3 x 50 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase A: 0.1% TFA, mobile phase B: ACN, 0% to 70% gradient over 30 min; detector, UV 254 nm, to give a yellow solid compound (98).

[1499] Compound 99 (Example 37)

[1500] A solution of LiOH·H₂O (27.22 mg, 0.65 mmol) in water (2 mL) was added dropwise to a MeOH (5 mL) solution of compound (98) (200 mg, 0.32 mmol) under stirring at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour and then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase A: 0.1% TFA aqueous solution, mobile phase B: ACN, 0% to 50% gradient over 50 minutes; detector, UV 254 nm, yielding a yellow solid of compound (99) (Example 37) (41.8 mg).

[1501] LCMS: ESI-MS m / z=377.25[M+H] +

[1502] 1H-NMR: (300MHz, DMSO-d6): δ9.47 (s, 1H), 7.73-7.68 (d, 2H), 5.02-5.00 (m, 1H), 4.86-4.84 (m, 1H), 4.66-4.63 (m, 1H), 4.63-4.51 (m, 1H), 4.48-4.29 (m, 1H), 4.25-4.16 (m, 1H), 4.22-4.01 (m, 1H), 3.73-3.61 (s, 3H), 3.51-3.43 (s, 1H), 2.42 (s, 3H), 2.34 (s, 3H).

[1503] Synthesis of Compound 104 (Example 38) and Compound 105 (Example 39)

[1504] Examples 38 and 39 were synthesized according to the following scheme.

[1505]

[1506] Compound 100

[1507] PyBOP (6 g, 11.53 mmol) was added fractionally to a stirred solution of compound (4) (3 g, 5.76 mmol), DIPEA (3.72 g, 28.82 mmol), and N-(2-aminoethyl)-N-methylcarbamate tert-butyl ester (1.21 g, 6.94 mmol) in DMF (50 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 1 h, then diluted with water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography, eluting with (EtOAc / PE = 1:1) to give compound (100) (2.8 g) as a yellow solid.

[1508] LCMS: (ES, m / z): [M+H] + =677.2

[1509] Compound 101

[1510] TFA (15 mL) was added dropwise to a DCM (30 mL) solution of compound (100) (2.8 g, 4.14 mmol) stirred at 0 °C. The resulting mixture was stirred at 25 °C for 2 hours and then concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography, eluting with (EtOAc / PE = 1:1) to give compound (101) (2 g) as a yellow solid.

[1511] LCMS: (ES, m / z): [M+H]+ =577.2

[1512] Compound 102

[1513] POCl3 (1.06 g, 6.91 mmol) was added dropwise to a DCE (30 mL) solution of compound (101) (2 g, 3.47 mmol) stirred at 0 °C. The resulting mixture was stirred at 70 °C for 4 h and then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH:water, 10% to 50% gradient over 10 min; detector, UV 254 nm, yielding compound (102) (1.2 g) as a yellow solid.

[1514] LCMS: (ES, m / z): [M+H] + =382.3

[1515] Compound 103

[1516] KMnO4 (509.25 mg, 3.22 mmol) was added dropwise to a 30 mL solution of compound (102) (600 mg, 1.07 mmol) in acetone (5 mL) under stirring at 0 °C. The resulting mixture was stirred at 25 °C for 16 h and then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH:water, 10% to 50% gradient over 10 min; detector, UV 254 nm, yielding compound (103) (200 mg) as a yellow solid.

[1517] LCMS: (ES, m / z): [M+H] + =557.1

[1518] Compound 104 (Example 38)

[1519] To a MeOH (5 mL) solution of compound (103) (300 mg, 0.54 mmol) stirred at 0 °C, 4 M HCl (g) in MeOH (21.41 mL, 704.64 mmol) was added dropwise. The resulting mixture was stirred at 25 °C for 4 hours and then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH:water, 10% to 50% gradient over 10 minutes; detector, UV 254 nm, yielding compound (104) (Example 38) (30 mg) as a yellow solid.

[1520] LCMS: (ES, m / z): [M+H] + =389.2

[1521] 1 H NMR: (400MHz, methanol-d4) δ7.79 (d, J=18.3Hz, 2H), 7.73-7.69 (m, 1H), 7.59-7.55 (m, 1H), 4.88-4.84 (m, 1H), 4.55 (dd, J=1 4.0, 2.7Hz, 1H), 4.35 (d, J=10.0Hz, 1H), 4.30 (s, 3H), 3.87-3.80 (m, 3H), 3.74-3.68 (m, 1H), 2.53 (s, 3H), 2.44 (s, 3H).

[1522] Compound 105 (Example 39)

[1523] Compound (102) (400 mg, 0.72 mmol) was stirred in 7 M NH3 (g) / MeOH (8 mL) at room temperature and then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18OBD column, 5 μm, 19 × 150 mm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 31% B to 54% B over 10 min; 254 nm) to give compound (105) (Example 39) (60 mg) as a yellow solid.

[1524] LCMS: (ES, m / z): [M+H]=391.2

[1525] 1 ¹H NMR: (400MHz, methanol-d⁴) δ = 8.55 (s, 1H), 7.79 (s, 2H), 4.88–4.82 (m, 1H), 4.53–4.49 (m, 1H), 4.32–4.21 (m, 1H), 4.20–4.06 (m, 4H), 3.89–3.79 (m, 3H), 3.73–3.68 (m, 1H), 3.57 (s, 2H), 2.54 (s, 3H), 2.41 (s, 3H).

[1526] Synthesis of Compound 110 (Example 40)

[1527] Example 40 was synthesized according to the following scheme.

[1528]

[1529] Compound 106

[1530] DiPEA (24.83 g, 192.12 mmol) and PyBOP (20 g, 38.43 mmol) were added fractionally to a mixture of compound (4) (10 g, 19.21 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.52 g, 57.63 mmol) in DMF (150 mL) at 0 °C with stirring. The resulting mixture was stirred at room temperature for 1 h, then quenched with 1 M HCl (200 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with saturated aqueous NaCl solution (3 × 200 mL), dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure after filtration. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:3) to give compound (106) (8.5 g) as a yellow solid.

[1531] LCMS: (ES, m / z): [M+H] + =564.4

[1532] Compound 107

[1533] Compound (106) (8 g, 14.2 mmol) was stirred at -10 °C under an argon atmosphere and methyl magnesium bromide (56.78 mL, 56.78 mmol) was added dropwise to a mixture in THF (200 mL). The mixture was quenched at 0 °C with NH4Cl (200 mL) and then extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with saturated aqueous NaCl solution (3 x 150 mL), dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure after filtration. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give a yellow oily compound (107) (1.6 g).

[1534] LCMS: (ES, m / z): [M+H] + =519.4

[1535] Compound 108

[1536] CuBr2 (1033.81 mg, 4.63 mmol) was added fractionally to a stirred solution of compound (107) (2 g, 3.86 mmol) in EtOAc (200 mL) at 0 °C. The resulting mixture was stirred at room temperature for 3 h. Subsequently, the mixture was diluted with 1 M HCl (2 x 100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL), dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure after filtration. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN: water, 10% to 100% gradient over 30 min; detector, UV 254 nm, to give a yellow oily compound (108) (800 mg).

[1537] LCMS: (ES, m / z): [M+H] + =597.1

[1538] Compound 109

[1539] N-carbamoyliminoacetamide (67.7 mg, 0.67 mmol) was added fractionally to an ACN solution of compound (108) (200 mg, 0.34 mmol) under stirring at room temperature. The resulting mixture was stirred at 50 °C for 16 h and then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN:water (0.1% FA), 10% to 50% gradient over 10 min; detector, UV 254 nm, to give a yellow oily compound (109) (120 mg).

[1540] LCMS: (ES, m / z): [M+H] + =558.1

[1541] Compound 110 (Example 40)

[1542] At 25°C, 7 MNH3 (g) in MeOH (3 mL) was added dropwise to a stirred MeOH solution of compound (109) (200 mg). The resulting mixture was stirred at 25°C for 3 hours and then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN: water, 10% to 50% gradient over 20 minutes; detector, UV 254 nm, yielding compound (110) (Example 40) (70 mg) as a yellow solid.

[1543] LCMS: (ES, m / z): [M+H]+=390.2

[1544] 1¹H NMR: (400 MHz, methanol-d⁴) δ 8.48 (s, 1H), 7.91 (s, 1H), 7.64 (d, J = 4.1 Hz, 2H), 4.88–4.90 (m, 1H), 4.46 (dd, J = 14.1, 2.7 Hz, 1H), 4.31 (ddd, J = 9.6, 4.7, 2.5 Hz, 1H), 3.88–3.78 (m, 3H), 3.74–3.68 (m, 1H), 2.46 (s, 3H), 2.39 (s, 3H).

[1545] Synthesis of Compound 113 (Example 41)

[1546] Example 41 was synthesized according to the following scheme.

[1547]

[1548] Compound 111

[1549] A solution of compound (4) (2056 mg, 3.95 mmol) in SOCl2 (15.00 mL) was stirred at 50 °C for 5 hours, and then concentrated under reduced pressure. The residue was dissolved in DCM (20 mL) and added dropwise to a solution of DIPEA (1531.12 mg, 11.85 mmol) and (2-aminoethyl)dimethylamine (1044.35 mg, 11.85 mmol) in THF (20 mL) at 0 °C with stirring. The resulting mixture was stirred at 20 °C for 1 hour, then diluted with DCM (50 mL) and washed with water (2 x 50 mL). After filtration, the organic layer was dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure to give compound (111), which could be used in the next step without further purification.

[1550] ESI-MS m / z = 591.4 [M+H] +

[1551] Compound 112

[1552] PCl5 (705.08 mg, 3.39 mmol) was added dropwise to a stirred solution of compound (111) (500 mg, 0.85 mmol) in a DCE (10 mL) at 0 °C. The mixture was cooled to -5 °C, and trimethylsilyl azidophosphate (487.66 mg, 4.23 mmol) was added dropwise. The resulting mixture was then stirred at 80 °C for 16 h, diluted with DCM (20 mL), and quenched at room temperature with a saturated aqueous solution of NH4CO3 (30 mL). The mixture was washed with water (2 × 50 mL) and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase A: 0.1% aqueous solution of NH4HCO3, mobile phase B: ACN; 0% to 100% gradient over 30 min; detector, UV 254 nm, yielding compound (112) (200 mg) as a yellow solid.

[1553] ESI-MS m / z = 616.4 [M+H] +

[1554] Compound 113 (Example 41)

[1555] 7 M NH3·H2O (8 mL) was added dropwise to a 10 mL MeOH solution of compound (112) (200 mg, 0.33 mmol) under stirring at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase A: water (10 mmol NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 5% B to 38% B over 8 minutes; 254 / 220 nm) to give compound (113) (Example 41) (60 mg) as a yellow solid.

[1556] LCMS: ESI-MS m / z=448.2[M+H] +

[1557] 1H-NMR: (400MHz, DMSO-d6): δ7.70 (d, J=8.5Hz, 2H), 5.01 (d, J=4.0Hz, 1H), 4 .90-4.84(m, 1H), 4.76(d, J=6.2Hz, 1H), 4.73-4.60(m, 3H), 4.50(t, J=5.4Hz , 1H), 4.28 (dd, J=13.8, 2.5Hz, 1H), 4.17 (s, 1H), 3.62 (d, J=4.6Hz, 3H), 3.49 -3.42(m, 1H), 2.62(t, J=6.1Hz, 2H), 2.43(s, 3H), 2.35(s, 3H), 1.94(s, 6H).

[1558] Synthesis of Compound 116 (Example 42)

[1559] Example 42 was synthesized according to the following scheme.

[1560]

[1561] Compound 114

[1562] Compound (4) (4 g, 7.69 mmol) was stirred in SOCl2 (30 mL) at 50 °C for 5 h, then cooled to room temperature and concentrated under reduced pressure. The residue (3.5 g) was diluted with DCM (20 mL) and stirred at room temperature while NH3 (g) / 1,4-dioxane (0.4 M) (200 mL) was added dropwise over 20 min. The resulting mixture was stirred at 0 °C for another 1 h, then diluted with water (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with water (2 × 300 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in POCl3 (40 mL) and stirred at 80 °C for 16 h. The mixture was concentrated under reduced pressure, diluted with water (100 mL), and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water (3 x 100 mL), dried over anhydrous Na₂SO₄, and the filtrate was concentrated under reduced pressure after filtration. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1), to give a yellow solid compound (114) (2.2 g).

[1563] ESI-MS m / z = 502.3 [M+H] +

[1564] Compound 115

[1565] A mixture of AgNO3 (328.23 mg, 1.93 mmol) and NaN3 (440.75 mg, 6.78 mmol) in DMF (15 mL) was stirred at room temperature for 10 min. Then, a DMF solution of compound (114) (1.70 g, 3.39 mmol) was added dropwise at room temperature, and the resulting mixture was stirred at 110 °C for 16 h. The mixture was acidified to pH 5 with 1 M HCl and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (2 × 100 mL), dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure after filtration. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, A: 0.1% FA aqueous solution, B: CAN, 10% to 50% gradient over 30 min; detector, UV 254 nm, 35%, yielding compound (115) (1 g) as a yellow solid.

[1566] ESI-MS m / z = 545.3 [M+H] +

[1567] Compound 116 (Example 42)

[1568] 1-Bromo-3-methylbutane (300 mg, 1.99 mmol) was added in portions to a stirred solution of compound (115) (500 mg, 0.81 mmol) and K2CO3 (448.24 mg, 3.24 mmol) in DMF (10 mL) at 0 °C. The resulting mixture was stirred at 20 °C for 16 h and then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase A: water (10 mmol NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 5% B to 38% B over 8 min; 254 / 220 nm) to give compound (116) (Example 42) (48.9 mg) as a pale yellow solid.

[1569] LCMS: ESI-MS m / z=448.2[M+H] +

[1570] 1H-NMR: (400MHz, DMSO-d6): δ7.69 (s, 1H), 7.64 (s, 1H), 4.99 (d, J=4.3Hz, 1H), 4.89 ( t, J=6.2Hz, 2H), 4.84 (d, J=3.9Hz, 1H), 4.75 (d, J=6.2Hz, 1H), 4.66 (dd, J=13.8, 10.0 Hz, 1H), 4.48 (t, J=5.5Hz, 1H), 4.27 (dd, J=13.8, 2.6Hz, 1H), 4.16 (s, 1H), 3.62 (s, 3 H), 3.49-3.42 (m, 1H), 2.89 (t, J=6.2Hz, 2H), 2.41 (s, 3H), 2.34 (s, 3H), 2.19 (s, 6H).

[1571] Synthesis of Compound 117 (Example 43)

[1572] Example 43 was synthesized according to the following scheme.

[1573]

[1574] Compound 117 (Example 43)

[1575] Methyl iodine (391.00 mg, 2.76 mmol) was added dropwise to a mixture of compound (115) (500 mg, 0.92 mmol) and K2CO3 (380.72 mg, 2.76 mmol) in ACN (15 mL) at 50 °C with stirring. The resulting mixture was stirred at 50 °C for 2 hours. After cooling to room temperature, ammonium hydroxide (10 mL) was added dropwise to the mixture and stirring was continued at room temperature for another 16 hours. After concentration under reduced pressure, the residue was purified by preparative HPLC under the following conditions (column: Welch XB-C18, 21.2 x 250 mm, 5 μm; mobile phase A: water (10 mmol NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 20% B, 254 / 220 nm) to give compound (117) (Example 43) (55.1 mg) as a pale yellow solid.

[1576] ESI-MS m / z = 391.15 [M+H] +

[1577] 1¹H-NMR: (400MHz, DMSO-d6): δ 7.66 (d, J = 13.7Hz, 2H), 4.98 (d, J = 4.5Hz, 1H), 4.83 (d, J = 4.4Hz, 1H), 4.74–4.65 (m, 2H), 4.49 (s, 4H), 4.27 (d, J = 13.7Hz, 1H), 4.16 (s, 1H), 3.62 (d, J = 5.0Hz, 3H), 3.50–3.40 (m, 1H), 2.41 (s, 3H), 2.34 (s, 3H). Synthesis of Compound 121 (Example 44)

[1578] Example 44 was synthesized according to the following scheme.

[1579]

[1580] Compound 118

[1581] The mixture of compound (4) (3 g, 5.76 mmol) in SOCl2 (20 mL) was stirred at 50 °C for 5 hours, and then concentrated under vacuum. The residue was diluted with DCM (10 mL), cooled to 0 °C, and a solution of ethanolamine (1056.23 mg, 17.29 mmol) and DIPEA (2.23 g) in THF (10 mL) was added dropwise with stirring. The resulting mixture was stirred at room temperature for 30 minutes, then diluted with DCM (50 mL) and washed with water (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue of compound (118) was used directly in the next step without further purification.

[1582] Compound 119

[1583] The mixture of compound (118) (3.5 g, 6.21 mmol) and Ac2O (6.34 g, 62.10 mmol) in pyridine (15 mL) was stirred at room temperature for 16 hours. The resulting mixture was concentrated under vacuum, and the residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase A: 0.1% FA aqueous solution, mobile phase B: ACN; 0% to 100% gradient over 30 minutes; detector, UV 254 nm, yielding compound (119) (3.1 g) as a yellow solid.

[1584] Compound 120

[1585] Phosphorus pentachloride (1375.30 mg, 6.61 mmol) was added dropwise to a DCE (20 mL) solution of compound (119) (1 g, 1.65 mmol) stirred at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. After cooling to -5 °C, trimethylsilyl azide (951.22 mg, 8.26 mmol) was added dropwise to the mixture. The mixture was stirred at 50 °C for another 16 h, then diluted with DCM (100 mL) and quenched at 0 °C by adding saturated ammonium bicarbonate (100 mL). The resulting mixture was washed with water (2 × 100 mL), and the organic layer was dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase A: 0.1% FA aqueous solution, mobile phase B: ACN; 0% to 100% B gradient over 30 minutes; detector, UV 254 nm, yielding a yellow solid compound (120) (330 mg).

[1586] Compound 121 (Example 44)

[1587] The mixture of compound (120) (330 mg, 0.523 mmol) in 7 M NH3 / MeOH (5 mL) was stirred at room temperature for 5 hours. After concentration under reduced pressure, the residue was purified by preparative HPLC under the following conditions (column: XBridge PrepOBD C18 column, 19 x 250 mm, 5 μm; mobile phase A: water (10 mmol NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 16% B to 24% B over 12 minutes; 254 / 220 nm) to give compound (121) (Example 44) (91.8 mg) as a yellow solid.

[1588] ESI-MS m / z = 421.15 [M+H] +

[1589] 1 H-NMR: (400MHz, DMSO-d6): δ7.70 (d, J=10.6Hz, 2H), 5.01 (d, J=3.9Hz, 1H), 4 .94 (t, J=5.4Hz, 1H), 4.86 (d, J=3.9Hz, 1H), 4.80 (d, J=6.0Hz, 1H), 4.68-4.62 (m, 3H), 4.50 (t, J=5.4Hz, 1H), 4.28 (dd, J=13.6, 2.6Hz, 1H), 4.17 (s, 1H), 3.7 3(q, J=5.5Hz, 2H), 3.62(s, 3H), 3.49-3.41(m, 1H), 2.43(s, 3H), 2.36(s, 3H).

[1590] Synthesis of Compound 129 (Example 45)

[1591] Example 45 was synthesized according to the following scheme.

[1592]

[1593] Compound 122

[1594] Trt-Cl (17.14 g, 61.48 mmol) was added fractionally to a pyridine (200 mL) solution of compound (40) (8 g, 20.49 mmol) stirred at 0 °C. The resulting mixture was stirred at 70 °C for 16 h, then diluted with water (600 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water (3 x 100 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give compound (122) (10 g) as a yellow solid.

[1595] LCMS: (ES, m / z): [M+Na] + =655.4

[1596] Compound 123

[1597] Compound (122) (3 g, 4.74 mmol) and DIPEA (18.39 g, 142.29 mmol) were added dropwise to a stirred solution of DMF (300 mL) at 0 °C, containing MOM-Cl (30.28 g, 455.43 mmol) in DMF (50 mL). The resulting mixture was stirred at 70 °C for 18 hours, then diluted with water (600 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water (3 x 200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (2:1) to give compound (123) (2 g) as a yellow solid.

[1598] LCMS: (ES, m / z): [M+Na] + =787.5

[1599] Compound 124

[1600] Formic acid (10 mL, 217.26 mmol) was added dropwise to a THF (10 mL) solution of compound (123) (2 g, 2.62 mmol) stirred at 0 °C. The resulting mixture was stirred at 25 °C for 4 h and then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH:water, 10% to 50% gradient over 10 min; detector, UV 254 nm, to give a yellow oily compound (124) (750 mg).

[1601] LCMS: (ES, m / z): [M+H] + =523.5

[1602] Compound 125

[1603] Ms-Cl (2.55 g, 22.26 mmol) in DCM (10 mL) was added dropwise to a stirred solution of compound (124) (2.30 g, 4.45 mmol) in DCM (100 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 0.5 h and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give a yellow oily compound (125) (2 g).

[1604] LCMS: (ES, m / z): [M+H] + =601.5

[1605] Compound 126

[1606] NaI (374.34 mg, 2.5 mmol) was added in portions to a 20 mL solution of compound (125) (300 mg, 0.5 mmol) in acetone, which was being stirred at 25 °C. The resulting mixture was stirred at 70 °C for 18 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give compound (126) (290 mg) as a yellow solid.

[1607] LCMS: (ES, m / z): [M+H] + =633.3

[1608] Compound 127

[1609] Compound (126) (290 mg, 0.46 mmol) was stirred at 25 °C in DMF (5 mL) and NaN3 (59.62 mg, 0.92 mmol) was added in portions. The resulting mixture was stirred at 50 °C for 18 hours, then diluted with water (50 mL) and the solid was filtered off. The solid was washed with EtOAc (3 × 10 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give compound (127) (270 mg) as a yellow solid.

[1610] LCMS: (ES, m / z): [M+H] + =548.4

[1611] Compound 128

[1612] Triphenylphosphine (718.49 mg, 2.74 mmol) was added in portions to a stirred solution of compound (127) (270 mg, 0.49 mmol) in water (1 mL) and THF (5 mL) at 25 °C. The resulting mixture was stirred for 16 hours and then concentrated under reduced pressure. The remaining compound (128) was used directly in the next step without further purification.

[1613] LCMS-PH-AVR-FTE0056-5: (ES, m / z): [M+H] + =522.4

[1614] Compound 129 (Example 45)

[1615] 6M HCl (5 mL) was added dropwise to a THF (10 mL) solution of the stirred compound (128) (230 mg, 0.44 mmol) to maintain the temperature below 0 °C. The resulting mixture was then stirred at 25 °C for 4 hours and neutralized to pH 7 with a saturated aqueous solution of NaHCO3. The resulting mixture was concentrated under reduced pressure and the residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH:water, 10% to 50% gradient over 10 minutes; detector, UV 254 nm, yielding a yellow solid compound (129) (Example 45) (70 mg).

[1616] LCMS: (ES, m / z): [M+H] + =390.3

[1617] 1H NMR: (400MHz, DMSO-d6) δ7.71 (d, J=23.9Hz, 2H), 5.14-4.73 (m, 2H), 4.61 (dd, J=13.8, 9.7Hz, 2H), 4.33 (dd, J=13.9, 2.7Hz, 2H), 4. 16 (s, 4H), 3.62 (dq, J=11.6, 6.4, 5.0Hz, 3H), 2.85 (dd, J=12.8, 3.7Hz, 1H), 2.69 (dd, J=12.8, 6.1Hz, 1H), 2.44 (s, 3H), 2.36 (s, 3H).

[1618] Synthesis of Compound 132 (Example 46)

[1619] Example 46 was synthesized according to the following scheme.

[1620]

[1621] Compound 130

[1622] HATU (5.84 g, 15.37 mmol) was added fractionally to a stirred solution of compound (4) (4 g, 7.69 mmol), glycine ethyl ester (1.19 g, 11.54 mmol), and DIPEA (2.98 g, 23.06 mmol) in DMF (50 mL) at 0 °C. The resulting mixture was stirred at 0–20 °C for 2 h, then diluted with water (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with water (3 × 300 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give compound (130) (5 g) as a yellow solid.

[1623] Compound 131

[1624] Silicon tetrachloride (2.15 g, 12.66 mmol) and trimethylsilyl azidophosphate (2.43 g, 21.09 mmol) were added dropwise to a DCE (20 mL) solution of compound (130) (2.5 g, 4.23 mmol) stirred at 0 °C. The resulting mixture was stirred at 70 °C for 16 h, then cooled to room temperature, diluted with DCM (100 mL), and washed with water (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase A: 0.1% aqueous FA solution; mobile phase B: ACN; gradient from 0% to 70% over 30 min; detector, UV 254 nm, yielding compound (131) (1.6 g) as a yellow solid.

[1625] Compound 132 (Example 46)

[1626] An aqueous solution of lithium hydroxide (58.26 mg, 2.433 mmol) was added dropwise to a MeOH (5 mL) solution of compound (131) (300 mg, 0.49 mmol) stirred at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour, then neutralized to pH 6 with 1 M HCl and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase A: 0.1% TFA aqueous solution, mobile phase B: ACN, 0% to 30% gradient over 30 minutes; detector, UV 254 nm, yielding compound (132) (Example 46) (65 mg) as a yellow solid.

[1627] ESI-MS m / z = 435.20 [M+H] +

[1628] 1 H-NMR: (400MHz, MeOD-d4): δ7.76-7.71 (d, 2H), 5.68 (s, 2H), 4.83 (dd, J=14.1, 9.7Hz, 1H), 4.53 (dd, J=14.1, 2.8 Hz, 1H), 4.31 (ddd, J=9.7, 4.7, 2.8Hz, 1H), 3.89-3.80 (m, 3H), 3.75-3.66 (m, 1H), 2.51 (s, 3H), 2.47-2.39 (m, 3H).

[1629] Synthesis of Compound 135 (Example 47)

[1630] Example 47 was synthesized according to the following scheme.

[1631]

[1632] Compound 133

[1633] HATU (474.84 mg, 1.25 mmol) was added fractionally to a stirred solution of compound (4) (500 mg, 0.96 mmol), β-alanine ethyl ester (168.80 mg, 1.44 mmol), and DIPEA (620.78 mg, 4.80 mmol) in DMF (5 mL) at 0 °C. The resulting mixture was stirred at 0–20 °C for 2 h, then diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography, eluting with (EtOAc) to give compound (133) (530 mg) as a yellow solid.

[1634] Compound 134

[1635] SiCl4 (481.21 mg, 2.83 mmol) and trimethylsilyl azidoide (543.87 mg, 4.72 mmol) were added in portions to a stirred mixture of compound (133) (585 mg, 0.94 mmol) in DCE (10 mL) at 0 °C. The resulting mixture was stirred at 70 °C for 16 h, then diluted with DCM (20 mL), washed with water (3 × 20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography, eluting with (PE / EtOAc 2:3) to give compound (134) (500 mg) as a yellow solid.

[1636] Compound 135 (Example 47)

[1637] Trimethyltin hydroxide (673.2 mg, 3.72 mmol) was added in portions to a DCE (10 mL) solution of compound (134) (200 mg, 0.31 mmol) stirred at 0 °C. The resulting mixture was stirred at 80 °C for 16 h, then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with MeOH (5 mL), acidified to pH 6 with HCl (aqueous solution), and purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase A: 0.1% FA aqueous solution, mobile phase B: ACN, 0% to 30% gradient over 20 min; detector, UV 254 nm, yielding compound (135) (Example 47) (56 mg) as a yellow solid.

[1638] ESI-MS m / z = 449.15 [M+H] +

[1639] 1¹H-NMR: (400MHz, MeOD-d⁴): δ 7.76 (d, J = 4.7Hz, 2H), 4.95 (s, 2H), 4.81 (s, 1H), 4.53 (dd, J = 14.1, 2.8Hz, 1H), 4.33 (ddd, J = 9.7, 4.6, 2.8Hz, 1H), 3.89–3.77 (m, 3H), 3.70 (dd, J = 12.2, 6.4Hz, 1H), 3.08 (t, J = 6.7Hz, 2H), 2.52 (s, 3H), 2.42 (s, 3H). Synthesis of Compound 137 (Example 48).

[1640] Example 48 was synthesized according to the following scheme.

[1641]

[1642] Compound 136

[1643] Lawson's reagent (682.28 mg, 1.69 mmol) was added dropwise to a mixture of compound (38) (900 mg, 1.69 mmol) in toluene (30 mL) under stirring at 25 °C. The resulting mixture was stirred at 120 °C for 4 h and then concentrated under reduced pressure. The residue was dissolved in THF (10 mL), and methyl iodine (2394.32 mg, 16.87 mmol) was added dropwise to the stirred mixture at 25 °C. The mixture was stirred at 25 °C for 18 h and then concentrated under reduced pressure. N-formylhydrazine (202.61 mg, 3.37 mmol) was added to the residue at 25 °C, and the resulting mixture was stirred at 70 °C for 18 h and then concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography, eluting with (PE / EtOAc 1:1) to give compound (136) (300 mg) as a yellow solid.

[1644] LCMS: (ES, m / z): [M+H] + =558.3

[1645] Compound 137 (Example 48)

[1646] The mixture of compound (136) (300 mg, 0.54 mmol) and NH3 (g) / MeOH (10 mL) was stirred at 25 °C for 2 hours and then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH:water, 10% to 50% gradient over 10 minutes; detector, UV 254 nm, to give compound (137) (Example 48) (100 mg) as a yellow solid.

[1647] LCMS: (ES, m / z): [M+H] + =390.2

[1648] 1 H NMR: (400MHz, DMSO-d6) δ8.63 (s, 1H), 7.67 (d, J=12.1Hz, 2H), 5.01 (d, J=3.7Hz , 1H), 4.88-4.84 (m, 1H), 4.80 (d, J=6.1Hz, 1H), 4.67 (dd, J=13.8, 10.0Hz, 1H), 4.50 (t, J=5.3Hz, 1H), 4.25 (dd, J=13.8, 2.6Hz, 1H), 4.16 (td, J=6.8, 3.4Hz, 1H ), 3.70 (s, 3H), 3.65-3.57 (m, 3H), 3.47-3.43 (m, 1H), 2.42 (s, 3H), 2.35 (s, 3H).

[1649] Synthesis of Compound 141 (Example 49)

[1650] Example 49 was synthesized according to the following scheme.

[1651]

[1652] Compound 138

[1653] Allylamine (164.54 mg, 2.88 mmol) and HATU (1095.78 mg, 2.88 mmol) were added dropwise to a solution of compound (4) (1 g, 1.92 mmol) and DIPEA (744.93 mg, 5.76 mmol) in DMF (10 mL) at 0 °C. The resulting mixture was stirred at 0–20 °C for 2 h, then diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (2 × 100 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give compound (138) (1 g) as a yellow solid.

[1654] Compound 139

[1655] Silicon tetrachloride (728.66 mg, 4.29 mmol) and trimethylsilyl azidophosphate (823.57 mg, 7.15 mmol) were added dropwise to a stirred mixture of compound (138) (800 mg, 1.43 mmol) in DCE (10 mL) at 0 °C. The resulting mixture was stirred at 70 °C for 16 hours and then cooled to room temperature. DCM (50 mL) was added, the mixture was washed with water (3 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography, eluting with (PE / EtOAc 1:2) to give compound (139) (500 mg) as a yellow solid.

[1656] Compound 140

[1657] K₂CO₃ (141.85 mg, 1.03 mmol), K₂O₄·2H₂O (1.26 mg, 0.003 mmol), K₃Fe(CN)₆ (11.26 mg, 0.034 mmol), and AD-mix-β(dhqd)₂phal (26.65 mg, 0.034 mmol) were added in portions to a stirred mixture of compound (139) (200 mg, 0.34 mmol) in H₂O / t-BuOH (10 mL) at 0 °C. The resulting mixture was stirred at 0–20 °C for 16 h and then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase A: 0.1% FA aqueous solution, mobile phase B: ACN; 10% to 50% gradient over 20 min; detector, UV 254 nm, yielding compound (140) (120 mg) as a yellow solid.

[1658] Compound 141 (Example 49)

[1659] NH3·H2O (2 mL) was added dropwise to a MeOH (4 mL) solution of compound (140) (200 mg) stirred at 0 °C. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase A: 0.1% FA aqueous solution, mobile phase B: ACN; 0% to 30% gradient over 20 minutes; detector, UV 254 nm, yielding compound (141) (Example 49) (56 mg) as a yellow solid.

[1660] ESI-MS m / z = 451.20 [M+H] +

[1661] 1H-NMR: (400MHz, DMSO-d6): δ7.70 (d, J=10.6Hz, 2H), 5.03 (dd, J=8.9, 4.7Hz, 2 H), 4.87 (d, J=3.7Hz, 1H), 4.79 (t, J=5.4Hz, 2H), 4.77-4.62 (m, 2H), 4.49 (dt, J =17.7, 6.9Hz, 2H), 4.27 (d, J = 13.8Hz, 1H), 4.16 (s, 1H), 3.79 (s, 1H), 3.62 (d, J =4.5Hz, 3H), 3.45(m, 1H), 3.32(m, 1H), 3.21(m, 1H), 2.43(s, 3H), 2.35(s, 3H).

[1662] Synthesis of Compound 143 (Example 50)

[1663] Example 50 was synthesized according to the following scheme.

[1664]

[1665] Compound 142

[1666] POCl3 (176.06 mg, 1.148 mmol) was added dropwise to a stirred solution of compound (124) (200 mg, 0.38 mmol) and pyridine (151.37 mg, 1.91 mmol) in THF at 0 °C. The resulting mixture was stirred at 20 °C for 3 hours and then concentrated under reduced pressure. The remaining compound (142) was used directly in the next step without further purification.

[1667] LCMS: (ES, m / z): [M+H] + =603.2

[1668] Compound 143 (Example 50)

[1669] 4M HCl (gas) was added dropwise to a THF (5 mL) solution of compound (142) (200 mg, 0.33 mmol) stirred at 20 °C in 5 mL of 1,4-dioxane (5.00 mL, 0.14 mmol). The resulting mixture was stir...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof; in: X is selected from H, NR 4X R 5X and optionally 1-3 R a Substituted C1-C6 alkyl; Y is selected from the following group: (i)CO2R 6Y ; (ii)C(O)NR 4Y R 5Y ; (iii) a heteroaryl group containing 5-6 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from N, N(H), 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 Replacement; and (iv) a heterocycloalkenyl group containing 5-6 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S, and wherein one or more heterocycloalkenyl ring carbon atoms are optionally replaced by 1-2 independently selected R b replace; Z is selected from the following group: (i) H, (ii)C 1-6 alkyl, (iii)NR 4Z R 5Z , (iv)OR 6Z , (v)OC(O)R 7Z , (vi)OP(O)OR 8Z OR 9z and (vii) a heterocyclic group containing 4 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R h replace; Each Z x is H; or each Z x Together with the carbon to which they are attached, they form C=O; R 1 , R 2 and R 3 Each independently selected from R 6A 、C(O)R 7A and P(O)OR 8A OR 9A ; R4 X and R5 X Each independently selected from the following group: 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; R 4Y and R 5Y Each independently selected from the following group: (i) H; (ii)C 1-12 Alkyl, which is optionally substituted by 1 to 6 R a replace; (iii) a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S, and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R h replace; (iv)-(W 1 -W 2 ) n -W 3 ,in: Each time it appears, W 1 Independently for C 1-3 Alkylene, which is optionally substituted by 1 to 4 R a replace; Each time it appears, W 2 are independently -N(H)-, -N(Rd)-, -O- or -S-; ·W 3 Is H or C 1-7 Alkyl, which is optionally substituted by 1-4 R a Replacement; and n is 2-4; or (v)R 4Y and R 5Y Together with the nitrogen atom to which they are attached, they form a ring containing 3-8 ring atoms, wherein the ring contains: (a) 1-7 ring carbon atoms, each of which is replaced by 1-2 ring carbon atoms independently selected from H and C 1-3 (b) 0-3 ring heteroatoms (except R 4Y and R 5Y The ring heteroatoms other than the nitrogen atom to which the ring is attached are each independently selected from N(H), N(R d ), O and S; R 4z and R 5Z Each independently selected from the following group: (i) H; (ii)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace; (iii)C 3-6 Cycloalkyl; (iv)-C(O)(C 1-4 alkyl); (v) -C(O)O(C 1-4 alkyl); (vi) -CON(R')(R'); (vii)-S(O) 1-2 (NR'R”); (viii)-S(O) 1-2 (C 1-4 alkyl); (ix) -OH; (x)C 1-4 Alkoxy; and (xi)-(Q 1 -Q 2 ) q -Q 3 ,in: · Every time it appears, Q 1 Independently for C 1-3 Alkylene, which is optionally substituted by 1 to 4 R a replace; · Every time it appears, Q 2 are independently -N(H)-, -N(R d )-, -O-, or -S-; Q 3 Is H or C 1-7 Alkyl, which is optionally substituted by 1-4 R a Replacement; and q is 2-4; Each time it appears, R 6A Independently selected from the group consisting of: (i) H; and (ii)C 1-10 Alkyl, optionally with 1-6 independently selected R a replace; R 6Z Independently selected from the following group: (i) H; (ii)C 1-10 Alkyl, optionally with 1-6 independently selected R a replace; (iii)-(C 0-2 Alkylene)-(C 6-10 Aryl), wherein C 6-10 Aryl is optionally substituted with 1-2 independently selected R h replace; (iv)-(C 0-2 alkylene)-(heteroaryl), wherein the heteroaryl group contains 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(C 1-3 alkyl), O and S, and wherein one or more heteroaryl ring carbon atoms are optionally substituted with 1-4 independently selected Rh; (v)-(C 1-2 Alkylene)-C(=O)NH-(C 1-3 Alkylene)-R 6Z’ ,and (vi)-(T 1 -T 2 ) t -T 3 ,in: Each time it appears, T 1 Independently for C 1-3 Alkylene, which is optionally substituted by 1 to 4 R a replace; Each time it appears, T 2 are independently -N(H)-, -N(R d )-, -O-, or -S-; ·T 3 Is H or C 1-7 Alkyl, which is optionally substituted by 1-4 R a Replacement; and t is 2-4; R 6Z’ Select from the following group: C(=O)OH,N(C 1-4 alkyl)2, NH2, NH(C 1-4 alkyl), and a heterocyclic group containing 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected C 1-3 Alkyl substitution; Every time R appears 6Y Independently selected from the group consisting of: (i) H; (ii)-(Y 1 ) m -Y 2 ,in: m is 0 or 1; ·Y 1 It is C 1-6 Alkylene, which is optionally substituted by 1 to 6 R a Replacement; and ·Y 2 yes: (a)C 3-10 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace, (b)C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace; (c) a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from N, N(H), 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, or (d) a heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace; (iii)C 1-12 Alkyl, optionally with 1-6 independently selected R a Replacement; and (iv)-(Z 1 -Z 2 ) p -Z 3 ,in: · Every time it appears, Z 1 Independently for C 1-3 Alkylene, which is optionally substituted by 1 to 4 R a replace; · Every time it appears, Z 2 are independently -N(H)-, -N(R d )-, -O-, or -S-; ·Z 3 Is H or C 1-7 Alkyl, which is optionally substituted by 1-4 R a Replacement; and p is 2-4; Each time it appears, R 7Z and R7 A Each independently selected from the following group: (i) H; (ii)C 1-10 Alkyl, optionally with 1-6 independently selected R a replace; (iii)C 6-10 Aryl, which is optionally substituted by 1 to 4 R c Replacement; and (iv)C 3-6 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace; Each time it appears, R 8A , R 8Z , R 9A and R 9Z Each independently (i) H; or (ii)C 1-10 Alkyl, optionally with 1-6 independently selected R a replace; Each occurrence of R a Independently selected from the group consisting of: -OH; -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); C(═NH)N(R′)(R″); cyano; and C 3-6 Cycloalkyl, which is optionally substituted by 1-4 independently selected C 1-4 Alkyl substitution; Each occurrence of R b Independently selected from the following group: C 1-6 Alkyl; C 1-4 Haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f ; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)(C 1-4 alkyl); -C(=O)O(C 1-4 alkyl); -C(=O)OH; -C(=O)N(R')(R"); -S(O) 1-2 (NR'R");-S(O) 1-2 (C 1-4 alkyl); cyano; and C 3-6 Cycloalkyl, which is optionally substituted by 1-4 independently selected C 1-4 Alkyl substitution; Each occurrence of R c Independently selected from the group consisting of: (i) halogen; (ii) cyano; (iii)C 1-10 alkyl; (iv) 1-6 independently selected R a Substituted C 1-10 alkyl; (v) C optionally substituted with 1-3 independently selected Rb 3-6 Cycloalkyl; (vi)C 2-6 alkenyl; (vii)C 2-6 Alkynyl; (viii)C 1-4 Alkoxy; (ix)C 1-4 Haloalkoxy; (x) optionally 1-4 independently selected C 1-4 Alkyl-substituted-(C 0-3 Alkylene)-C 3-6 Cycloalkyl; (xi)-S(O) 1-2 (C 1-4 alkyl); (xii)-NR e R f 4 (xiii) -OH; (xiv)-S(O) 1-2 (NR’R”); (xv)-C 1-4 Thioalkoxy; (xvi) -NO2; (xvii)-C(=O)(C 1-4 alkyl); (xviii) -C(=O)O(C 1-4 alkyl); (xix) -C(=O)OH; and (xx)-C(=O)N(R′)(R″); R d Selected from the group consisting of: optionally 1-3 independently selected R g Substituted 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; 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; Or, R e and R f Together with the nitrogen atom to which they are attached, they form a ring containing 3-8 ring atoms, wherein the ring contains: (a) 1-7 ring carbon atoms, each of which is replaced by 1-2 ring carbon atoms independently selected from H and C 1-3 and (b) 0 to 3 ring heteroatoms (excluding those with R e and R f The ring heteroatoms other than the nitrogen atom to which the ring is attached are each independently selected from N(H), N(R d ), O and S; Each occurrence of R g Independently selected from the group consisting of -OH, -F, NR'R", C 1-3 Alkoxy, -CON(R')(R"), -CONHS(O)2(C 1-4 alkyl) and -C(O)OH; Each occurrence of R h Independently selected from the following group: C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy and halogen; as well as 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 of which is replaced by 1-2 independently selected from H and C 1-3 and (b) 0-3 ring heteroatoms (excluding the nitrogen atoms connected to R' and R "), each independently selected from N (H), N (R d ), O and S; Provided that the compound is not:

2. The compound according to claim 1, wherein The compound has formula (Ia): or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein The compound is selected from: or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

5. The pharmaceutical composition according to claim 4, wherein The pharmaceutical composition is in the form of liquid, suspension or solid.

6. The pharmaceutical composition according to claim 4, wherein The pharmaceutical composition is in the form of topical administration.

7. The pharmaceutical composition according to any one of claims 4 to 6, wherein The pharmaceutical composition is administered using an applicator.

8. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, or a pharmaceutical composition according to any one of claims 4 to 7, in the preparation of a medicament for treating the cornea, wherein electromagnetic radiation is applied to the cornea to produce crosslinks in the cornea.

9. Use of a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 3, or a pharmaceutical composition as described in any one of claims 4 to 7, in the preparation of a medicament for treating a disease in which pathology and / or symptoms and / or progression of the disease are caused by abnormal corneal shape.

10. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, or the pharmaceutical composition according to any one of claims 4 to 7, in the preparation of a medicament for treating corneal ectasia diseases.

11. The use according to any one of claims 5 to 10, wherein The drug is used in combination with one or more selected from the group consisting of a delivery agent, a preparation applicable to the corneal epithelium, an enhancement preparation, a post-treatment preparation, an additional cross-linking agent, an additive other than a cross-linking agent, an additional ophthalmic therapeutic agent, and an ophthalmic surgery.

12. The use according to any one of claims 5 to 11, wherein The drug is used in combination with an ocular oxygen concentration, wherein the concentration is selected to be greater than the oxygen concentration in the atmosphere.

13. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: Treatment of compound i with a base followed by neutralization with an acid: and Compound ii is converted to compound iii using a coupling reagent and A: Where A is an alcohol, X and R 6Y As defined in claim 1.

14. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: Convert compound ii to compound iv: wherein B is a hydroxy protecting group reagent, each P is a hydroxy protecting group, and optionally a base is used; Compound iv is converted to compound vi using an amine: wherein each C is a coupling agent, and optionally a base is used; and Compound vi is converted to compound vii using an amine: Where D is a reagent capable of removing the protecting group P, and X, R 4Y and R 5Y As defined in claim 1.

15. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: Use E to convert compound viii into compound ix: E is an anhydride, optionally with a base; and Use F to transform compound ix into compound x: wherein F is a reagent capable of selectively removing allyl ester protecting groups, such as Pd(PPh3)4 or Pd(OAc)2, and X and R 7Z As defined in claim 1.

16. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: Use G to transform compound xi into compound xii: Where G is a protecting group reagent capable of reacting selectively on primary hydroxyl groups, P 1 is a primary hydroxyl protecting group, optionally using a base; Use B to transform compound xii into compound xiii: wherein B is a hydroxy protecting group reagent, each P is a hydroxy protecting group, and optionally a base is used; Compound xiii is converted to compound xix using H: wherein H is a reagent capable of hydrolyzing methyl esters, such as NaOH, LiOH or NH4OH; Use C to convert compound iv into compound vi: wherein each C is a coupling agent, optionally with a base; and Use D to transform compound xx into compound xxi: Where D is a reagent capable of removing the protecting group P, X, R 4Y and R 5Y As defined in claim 1.

17. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: Use J to transform compound xx into compound xxii: wherein J is a reagent capable of selectively removing a trityl or 2-chlorotrityl protecting group, optionally using a base; Compound xxii was converted to compound xxiii using K: K is a reagent capable of converting a hydroxyl group into a leaving group, and LG is a leaving group; Compound xxiii is converted to compound xxv using an amine: as well as Compound xxv was converted to compound xxvi using D: Where D is a reagent capable of removing the protecting group P, X, R 4Y , R 5Y , R 4Z and R 5z As defined in claim 1.

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