HTRA1 inhibitors and their use

Abstract

Compounds that act as inhibitors of the serine protease HTRA1, compositions containing such compounds, and the use of such compounds in the treatment of HTRA1-related disorders, including age-related macular degeneration, are disclosed herein.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and interest in U.S. Provisional Patent Application No. 63 / 510,797, filed on 28 June 2023, which is incorporated herein by reference in its entirety.

[0002] Description of sequence listings The contents of the electronic sequence listing file titled STDU2_41633_601_SequenceListing.xml (size: 2,310 bytes, creation date: June 25, 2024) are incorporated herein by reference in their entirety.

[0003] This disclosure relates to compounds that act as inhibitors of the serine protease HTRA1, compositions comprising such compounds, and the use of such compounds in the treatment of HTRA1-related disorders, including, for example, age-related macular degeneration. [Background technology]

[0004] Age-related macular degeneration (AMD) is the leading cause of vision loss in people over 65 years of age and has two distinct disease forms: dry and wet. Currently, there are no effective treatments for dry AMD, which is the more common and earlier form of the disease.

[0005] Genome-wide association studies of AMD patients have identified genetic promoter mutations that lead to overexpression of the serine protease HTRA1, which increases the risk of the disease by up to eightfold (Klein et al. Science 2005, 308(5720), 385-389). Increased HTRA1 activity leads to abnormal proteolysis of thrombospondin-1, which activates the monocyte accumulation pathway and causes inflammation and retinal pigment epithelial degeneration characteristic of both hereditary and age-related dry AMD. Therefore, inhibition of HTRA1 may offer a treatment for AMD, including dry AMD, as well as other disorders associated with HTRA1. [Overview of the project]

[0006] In one aspect, a compound of formula (I)

Chemical formula

[0007] In some embodiments, R 1 R is selected from C3-C4 alkyl and C3-C5 cycloalkyl. In some embodiments, R 1 The following can be selected: [ka]

[0008] In some embodiments, R 1 The following can be selected: [ka]

[0009] In some embodiments, R 2a is hydrogen, and R 2b These are C1-C4 alkyl, -CH2-phenyl, -CH2-indolyl, and -(CH2)4NH-R 2c Selected from, here, R 2c R is selected from H and -COO(tBu), and phenyl is either unsubstituted or substituted with one substituent selected from hydroxy and C1-C4-alkoxy. In some embodiments, R 2a R consists of hydrogen and methyl, 2b The following can be selected: [ka]

[0010] In some embodiments, R 2a is hydrogen, R 2b The following is true: [ka]

[0011] In some embodiments, R a and R 2b These, together with the atoms to which they are bonded, form a optionally substituted five-membered saturated ring.

[0012] In some embodiments, R 3 R is selected from C1-C6 alkyl, -CH2-phenyl, -CH2-naphthyl, -CH2-indolly, -CH2-pyridyl, and -CH2-cyclohexyl, where phenyl is unsubstituted or substituted with one or two substituents independently selected from methyl, ethyl, fluoro, chloro, bromo, hydroxy, methoxy, cyano, fluoromethyl, difluoromethyl, and trifluoromethyl, and pyridyl is unsubstituted or substituted with one oxo group. In some embodiments, R 3 The following can be selected: [ka] [ka]

[0013] In some embodiments, R 3 The following can be selected: [ka]

[0014] In some embodiments, R 3 The following is true: [ka]

[0015] In some embodiments, R N R is selected from C3-C4 alkyl, phenyl, phenyl-C1-C3-alkyl, and heterocyclyl-C1-C3-alkyl, where phenyl is unsubstituted or substituted with one or two substituents independently selected from halo, methyl, and -COOH. In some embodiments, R N The following can be selected: [ka]

[0016] In some embodiments, Q N The following can be selected: [ka]

[0017] In some embodiments, Q C is -B(OR C1 )2, and each R C1 These are independently selected from hydrogen, C1-C4 alkyl, and phenyl, or two R C1However, together with the atoms to which they bond, they form a 5-6 member saturated ring which is optionally substituted. In some embodiments, each R C1 It is hydrogen.

[0018] In some embodiments, Q C is -C(O)R C2 And R C2 It is a C1-C4 haloalkyl group.

[0019] In some embodiments, the compound is selected from the compounds shown in Figure 1.

[0020] In another embodiment, a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier is disclosed herein.

[0021] In another embodiment, a method for treating an HTRA1-related disorder in a subject requiring treatment is disclosed herein, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof). In some embodiments, the disorder is selected from macular degeneration, Alzheimer's disease, arthritis, bladder cancer, intervertebral disc degeneration, Lyme disease, osteoarthritis, prodromal epilepsy, rheumatoid arthritis, and TGFBI-associated corneal dystrophy. In some embodiments, the disorder is age-related macular degeneration. In some embodiments, age-related macular degeneration is dry age-related macular degeneration.

[0022] In another embodiment, a method for inhibiting HTRA1 in a sample is disclosed herein, comprising contacting the sample with an effective amount of a compound disclosed herein (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof).

[0023] In another embodiment, the pharmaceutically acceptable use of the compounds disclosed herein (e.g., compounds of formula (I)) or pharmaceutically acceptable salts thereof is disclosed herein.

[0024] In another embodiment, the use of compounds disclosed herein (e.g., compounds of formula (I)) or pharmaceutically acceptable salts thereof for the treatment of disorders associated with HTRA1 is disclosed herein. In some embodiments, the disorder is selected from age-related macular degeneration, Alzheimer's disease, arthritis, bladder cancer, intervertebral disc degeneration, Lyme disease, osteoarthritis, prodromal epilepsy, rheumatoid arthritis, and TGFBI-associated corneal dystrophy. In some embodiments, the disorder is age-related macular degeneration. In some embodiments, age-related macular degeneration is dry age-related macular degeneration. [Brief explanation of the drawing]

[0025] [Figure 1] The structure of the compound disclosed herein is shown. [Figure 2] The structures of additional compounds included within the range of formula (I) are shown. [Modes for carrying out the invention]

[0026] This specification provides compounds that act as inhibitors of the serine protease HTRA1. This specification also provides compositions comprising such compounds, and the use of such compounds in the treatment of HTRA1-related diseases, including, for example, age-related macular degeneration.

[0027] definition Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure have meanings generally understood by those skilled in the art. For example, any nomenclature and techniques used in connection with cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization as described herein are well known and commonly used in the art. The meaning and scope of terms should be clear, but in the event of potential ambiguity, the definitions provided herein shall take precedence over dictionary or external definitions. Furthermore, unless otherwise required by context, singular terms shall include plurals and plural terms shall include singulars.

[0028] When used in this specification and the appended claims, the singular forms "a," "an," and "the" encompass multiple subjects unless otherwise explicitly indicated.

[0029] With reference to numerical ranges in this specification, each number intervening between them is explicitly assumed to be of a similar degree of precision. For example, in the range of 6 to 9, the numbers 7 and 8 are assumed in addition to 6 and 9, and in the range of 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly assumed.

[0030] Definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are as defined in Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Specified according to the Ed. (endpaper), specific functional groups are generally defined as described therein. Furthermore, for general principles of organic chemistry, as well as specific functional groups and reactivity, see Sorrell, Organic Chemistry, 2 ndedition,University Science Books,Sausalito,2006;Smith,March's Advanced Organic Chemistry:Reactions,Mechanism,and Structure,7 th Edition,John Wiley & Sons,Inc.,New York,2013;Larock,Comprehensive Organic Transformations,3 rd Edition, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd This information is contained in Edition, Cambridge University Press, Cambridge, 1987, and its entirety is incorporated herein by reference.

[0031] As used herein, the term "alkyl" refers to a radical of a linear or branched saturated hydrocarbon chain. An alkyl chain is, for example, a chain with 1 to 24 carbon atoms (C1-C1). 24 Alkyl), 1 to 16 carbon atoms (C1-C 16 Alkyl), 1 to 14 carbon atoms (C1-C 14 Alkyl), 1 to 12 carbon atoms (C1-C 12 Alkyl), 1 to 10 carbon atoms (C1-C 10Alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl.

[0032] As used herein, the term “aryl” refers to a monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms (“C6-C 14 In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl", i.e., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "aryl" (e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14 "Aryl" (e.g., anthracenyl and phenantrenyl).

[0033] As used herein, the term "arylalkyl" means an alkyl group as defined herein, wherein at least one hydrogen atom is replaced by an aryl group as defined herein. Representative examples of arylalkyls include, but are not limited to, benzyl, 2-phenylethyl, and 3-phenylpropyl.

[0034] As used herein, the term "cycloalkyl" refers to a saturated carbocyclic radical containing 3 to 10 carbon atoms and 0 heteroatoms. Cycloalkyls may be monocyclic, bicyclic, bridging, condensed, or spirocyclic. Representative examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, and bicyclo[5.2.0]nonanyl.

[0035] As used herein, the term "cyano" refers to the -CN group.

[0036] As used herein, the terms "halogen" or "halo" refer to F, Cl, Br, or I.

[0037] As used herein, the term “haloalkyl” refers to an alkyl group as defined herein in which at least one hydrogen atom (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms) is replaced by a halogen. In some embodiments, each hydrogen atom of the alkyl group is replaced by a halogen (“perhaloalkyl”). Typical examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, and 3,3,3-trifluoropropyl.

[0038] As used herein, the term “heterocyclyl” refers to a radical of a 3- to 10-membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3- to 10-membered heterocyclyl”). In heterocyclyl groups containing one or more nitrogen atoms, the bond sites can be carbon atoms or nitrogen atoms, as long as the valence allows. Heterocyclyl groups can be monocyclic (“monocyclic heterocyclyl”), or condensed, bridging, or spirocyclic systems (e.g., bicyclic systems (“bicyclic heterocyclyl”)), and can be saturated or partially unsaturated. A heterocyclyl bicyclic ring system may contain one or more heteroatoms in one or both rings. "Heterocyclyl" includes ring systems in which the heterocyclyl ring defined above is fused with one or more cycloalkyl groups, with the bond site located on either the cycloalkyl ring or the heterocyclyl ring, or ring systems in which the heterocyclyl ring defined above is fused with one or more aryl or heteroaryl groups, with the bond site located on the heterocyclyl ring, in which case the ring member number continues to indicate the ring member number in the heterocyclyl ring system. A heterocyclyl group may be described, for example, as a 3- to 7-membered ring heterocyclyl, and the term "membered ring" refers to the ring atoms other than hydrogen within that part, namely carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Examples of 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azildinyl, oxyranyl, and thiorenyl. Examples of 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranil, dihydrofuranil, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinil, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanil, oxasulfuranil, disulfuranil, and oxazolidine-2-one.Examples of five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyridinonyl (e.g., 1-methylpyridine-2-onyl), and thianyl. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, pyridadinonyl (2-methylpyridazine-3-onyl), pyrimidinonyl (e.g., 1-methylpyrimidine-2-onyl, 3-methylpyrimidine-4-onyl), dithianyl, and dioxanyl. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinyl. Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanyl, oxekanyl, and thiokanyl. Examples of five-membered heterocyclyl groups condensed on a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinonyl. Examples of five-membered heterocyclyl groups condensed on a heterocyclyl ring (also referred to herein as 5,5-bicyclic heterocyclyl rings) include, but are not limited to, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl). Examples of six-membered heterocyclyl groups (also called 4,6-membered heterocyclyl rings) condensed on a heterocyclyl ring include, but are not limited to, diazaspirononanyl (e.g., 2,7-diazaspirononanyl).Examples of six-membered heterocyclyl groups condensed to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl rings) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl. Examples of six-membered heterocyclyl groups condensed to a cycloalkyl ring (also referred to herein as 6,7-bicyclic heterocyclyl rings) include, but are not limited to, azabicyclooctanyl (e.g., (1,5)-8-azabicyclo[3.2.1]octanyl). Examples of six-membered heterocyclyl groups condensed to a cycloalkyl ring (also referred to herein as 6,8-bicyclic heterocyclyl rings) include, but are not limited to, azabicyclononanyl (e.g., 9-azabicyclo[3.3.1]nonanyl).

[0039] As used herein, the term "nitro" refers to the -NO2 group.

[0040] Where a group or part can be substituted, the term “substituted” means that one or more hydrogens on the group indicated in the expression using “substituted” (e.g., 1, 2, 3, 4, 5, or 6; 1, 2, or 3 in some embodiments; 1 or 2 in other embodiments) can be replaced with a certain range of enumerated groups or preferred substituents known to those skilled in the art (e.g., one or more of the groups listed below), provided that the number of substituents does not exceed the normal valence of the specified atom. Substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkenyl, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, thiol, thion, or combinations thereof.

[0041] When used herein, the chemical structure contains [ka] The notation indicates a point where one part is bonded to another part (for example, a point where a substituent is bonded to the rest of the compound).

[0042] For the compounds described herein, the groups and substituents can be selected according to the allowable valencies of the atoms and substituents, and as a result, stable compounds that do not spontaneously undergo transformations such as rearrangement, cyclization, or elimination can be obtained through selection and substitution.

[0043] When substituents are denoted by standard chemical formulas and written from left to right, such notation also includes substituents that would be obtained by writing the structure from right to left. For example, if a divalent group is shown as -CH2O-, such notation also includes -OCH2-, and similarly, -OC(O)NH- includes -NHC(O)O-.

[0044] As used herein, the terms “administer,” “give,” or “give” mean to implant, absorb, ingest, inject, inhale, or otherwise introduce a compound or pharmaceutical composition.

[0045] As used herein, the terms “condition,” “disease,” and “disorder” are interchangeable.

[0046] The “effective amount” of a compound or composition refers to the amount sufficient to elicit a desired biological response (e.g., to treat a condition). As those skilled in the art will understand, the effective amount of a compound can vary depending on factors such as the desired biological outcome, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health status of the subject. Effective amounts encompass both therapeutic and prophylactic measures. For example, in the treatment of cancer, an effective amount of a compound or composition may reduce tumor burden or halt tumor growth or metastasis.

[0047] The “therapeutic dose” of a compound or composition is the amount sufficient to provide a therapeutic effect in the treatment of a condition, or to delay or minimize one or more symptoms associated with the condition. In some embodiments, the “therapeutic dose” is the amount sufficient to provide a therapeutic effect in the treatment of a condition, or to minimize one or more symptoms associated with the condition. The therapeutic dose of a compound means the amount of the therapeutic agent alone or in combination with other therapies that provide a therapeutic benefit in the treatment of a condition. The term “therapeutic dose” may include an amount that improves the overall therapy, reduces or avoids the symptoms or etiology of a condition, or enhances the therapeutic effect of another therapeutic agent.

[0048] The “targets” to which the administration is intended include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or other non-human animals, e.g., mammals (e.g., primates (e.g., crab-eating macaques, rhesus macaques); commercially available suitable mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs), and birds (e.g., commercially available suitable birds such as chickens, ducks, geese, quail, and / or turkeys).

[0049] As used herein, the terms “treatment,” “to treat,” and “to treat” refer to the reversal, alleviation, delay of onset, or inhibition of progression of a disease or condition, or one or more signs or symptoms thereof. In some embodiments, “treatment,” “to treat,” and “to treat” require that signs or symptoms of the disorder or condition of the disease have developed or been observed. In other embodiments, treatment may be administered even without signs or symptoms of the disease or condition. For example, treatment may be administered to an individual who is susceptible before the onset of symptoms (e.g., in light of the history of the symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after the symptoms have subsided, for example, to delay or prevent relapse.

[0050] compound Compound of formula (I): [ka] Or a pharmaceutically acceptable salt thereof is disclosed herein (wherein, Q N -XR N In the formula, X is selected from -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, and bonds, R N C1-C6 alkyl, aryl, and -(CR a R b ) p - Selected from Z; p is 1, 2, or 3, R a and R b Each is independently selected from hydrogen and C1-C4 alkyl, where one R a and one R b They optionally combine with the carbon atoms to which they are bonded to form 3- to 6-membered cycloalkyl groups; Z is selected from aryl and heterocyclyl groups, and each R N It is optionally substituted with one or two substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -OH, and -COOH; Q C is -B(OR C1 )2 and -C(O)R C2 Selected from, where each R C1 These are independently selected from hydrogen, 1-C6 alkyl, and aryl, or two R C1 They form a ring that is optionally substituted together with the atoms to which they are bonded, R C2 However, these are selected from C1-C4 alkyl and C1-C4 haloalkyl; R 1 These are selected from C3-C8 alkyl, hydroxy-C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl groups; R 2a is hydrogen or C1-C4-alkyl, and R 2bis C1-C8 alkyl, aryl-C1-C4-alkyl, heteroaryl-C1-C4-alkyl, hydroxy, and -(CH2) m NH-R 2c selected from, where m is 1, 2, 3, 4, 5, or 6, and R 2c is selected from H and -COO(C1-C6-alkyl), aryl is unsubstituted or substituted with 1 or 2 substituents independently selected from hydroxy and C1-C6-alkoxy, or R 2a and R 2b together with the atom to which they are attached form an optionally substituted ring, R 3 is selected from C1-C8 alkyl and -(CH2) n -Y, where n is 0, 1, 2, or 3, and Y is selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl, where alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are each independently unsubstituted or substituted with 1 or 2 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, halo, cyano, C1-C4 haloalkyl, hydroxy, amino, and 1-C4 alkoxy, where aryl or heteroaryl is optionally substituted with a group that together with R C2 forms an optionally substituted ring).

[0051] In some embodiments, R 1 is selected from C3-C8 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, and 5- to 6-membered monocyclic heteroaryl. In some embodiments, R 1 is selected from C3-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered monocyclic heterocyclyl having 1 heteroatom selected from O and N, and 5-membered heteroaryl having 1 heteroatom selected from O and N. In some embodiments, R 1R is selected from C3-C5 alkyl, C3-C5 cycloalkyl, 4-6 member monocyclic heterocyclyl having one oxygen atom, and 5 member heteroaryl having one oxygen atom. In some embodiments, R 1 The C3-C4 alkyl and C3-C5 cycloalkyl elements are selected from these.

[0052] In some embodiments, R 1 The following can be selected: [ka]

[0053] In some embodiments, R 1 The following can be selected: [ka]

[0054] In some embodiments, R 2a is hydrogen or C1-C4-alkyl, and R 2b These include C1-C8 alkyl, aryl-C1-C4-alkyl, heteroaryl-C1-C4-alkyl, hydroxy, and -(CH2) m NH-R 2c Selected from, where m is 1, 2, 3, 4, 5, or 6, R 2c R is selected from H and -COO(C1-C6-alkyl), and the aryl is either unsubstituted or substituted with one or two substituents independently selected from hydroxy and C1-C6-alkoxy. In some embodiments, R 2a is hydrogen or C1-C2-alkyl, and R 2b These include C1-C6 alkyl, aryl-C1-C2-alkyl, heteroaryl-C1-C2-alkyl, and -(CH2) m NH-R 2c Here, m is 2, 3, or 4, and R 2cR is selected from H and -COO(C1-C4-alkyl), and the aryl is either unsubstituted or substituted with one or two substituents independently selected from hydroxy and C1-C4-alkoxy. In some embodiments, R 2a is hydrogen, and R 2b These are C1-C4 alkyl, -CH2-phenyl, -CH2-indolyl, and -(CH2)4NH-R 2c Selected from, here, R 2c R is selected from H and -COO(tBu), and phenyl is either unsubstituted or substituted with one substituent selected from hydroxy and C1-C4-alkoxy. In some embodiments, R 2a R consists of hydrogen and methyl, 2b The following can be selected: [ka]

[0055] In some embodiments, R 2a is hydrogen, R 2b The following is true: [ka]

[0056] In some embodiments, R a and R 2b These, together with the atoms to which they are bonded, form an optionally substituted five-membered saturated ring. In some embodiments, R a and R 2b These, together with the atoms to which they are bonded, form an unsubstituted five-membered saturated ring. In some embodiments, R 2a and R 2b These, together with the atoms to which they are bonded, form a 5-membered saturated ring fused with a second 3- to 6-membered ring, which is further optionally substituted with one or two substituents selected from C1-C4 alkyl groups. In some embodiments, the group in formula (I) [ka] The following can be selected: [ka]

[0057] In some embodiments, R 3 C1-C8 alkyl and -(CH2) n -Selected from Y, where n is 0, 1, 2, or 3, and Y is selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl, where alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are each independently unsubstituted or substituted with one or two substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, halo, cyano, C1-C4 haloalkyl, hydroxy, amino, and 1-C4 alkoxy.

[0058] In some embodiments, R 3 C1-C6 alkyl and -(CH2) n -Selected from Y, where n is 1 or 2), Y is selected from monocyclic or bicyclic heteroaryls and C3-C6-cycloalkyls having one or two heteroatoms independently selected from aryl, N, O, and S, where alkyl, aryl, and heteroaryl are independently unsubstituted or substituted with one or two substituents independently selected from CC1-C4 alkyl, C3-C6 cycloalkyl, halo, cyano, C1-C4 haloalkyl, hydroxy, amino, and 1-C4 alkoxy. In some embodiments, R 3 The group is selected from C1-C6 alkyl, -CH2-phenyl, -CH2-naphthyl, -CH2-indolly, -CH2-pyridyl, and -CH2-cyclohexyl, where phenyl is unsubstituted or substituted with one or two substituents independently selected from methyl, ethyl, fluoro, chloro, bromo, hydroxy, methoxy, cyano, fluoromethyl, difluoromethyl, and trifluoromethyl, and pyridyl is unsubstituted or substituted with one oxo group.

[0059] In some embodiments, R 3 R C2 It is an aryl or heteroaryl group that forms a ring that is optionally substituted together with the other group.

[0060] In some embodiments, R 3 The following can be selected: [ka] [ka]

[0061] In some embodiments, R 3 The following can be selected: [ka]

[0062] In some embodiments, R 3 The following is true: [ka]

[0063] In some embodiments, X is -C(O)-. In some embodiments, X is -C(O)-. In some embodiments, X is -C(O)-NH-. In some embodiments, X is -S(O)-2-. In some embodiments, X is a bond.

[0064] In some embodiments, R N The substituent is selected from C3-C4 alkyl, phenyl, phenyl-C1-C3-alkyl, and heterocyclyl-C1-C3-alkyl, where phenyl is unsubstituted or substituted with one or two substituents independently selected from halo, methyl, and -COOH.

[0065] In some embodiments, R N The following can be selected: [ka]

[0066] In some embodiments, Q N The following can be selected: [ka]

[0067] In some embodiments, Q C is -B(OR C1 )2, and each R C1 These are independently selected from hydrogen, C1-C4 alkyl, and phenyl, or two R C1 However, together with the atoms to which they bond, they form a 5-6 member saturated ring which is optionally substituted. In some embodiments, each R C1 Q is hydrogen. In some embodiments, Q C is -C(O)R C2 And R C2 It is a C1-C4 haloalkyl group.

[0068] In some embodiments, the compound of formula (I) is the compound shown in Figure 1, or a pharmaceutically acceptable salt thereof.

[0069] Additional compounds of formula (I) are shown in Figure 2.

[0070] The compounds of this disclosure have at least one chiral center. Compounds having a chiral center give rise to enantiomers (optical isomers), diastereomers (configurational isomers), or both, and all conceivable enantiomers and diastereomers in mixtures and in pure or partially purified compounds are intended to be within the scope of this disclosure.

[0071] The independent synthesis of enantiomer or diastereomer-rich compounds, or their chromatographic separation, can be achieved as known in the art by appropriate modifications of the methods disclosed herein. The absolute stereochemistry of the compounds can be determined by using X-ray crystallography to determine, if necessary, the crystal structure of the crystalline product or crystalline intermediate derivatized with a reagent containing a chiral center of known absolute configuration.

[0072] If necessary, the racemic mixture of the compound can be separated, thereby isolating the individual enantiomers. This separation can be carried out by methods well known in the art, such as coupling the racemic mixture of the compound with a pure compound as an enantiomer to form a diastereomer mixture, and then separating the individual diastereomers by standard methods such as fractional crystallization or chromatography. The coupling reaction is often the formation of a salt using a pure acid or base as the enantiomer. The diastereomer derivative can then be converted back to the pure enantiomer by cleavage of the added chiral residue. The racemic mixture of the compound may also be separated directly by chromatography using a chiral stationary phase, a method well known in the art. Any enantiomer of the compound may be obtained as an alternative by stereoselective synthesis using optically pure starting materials or reagents of known configurations by methods well known in the art.

[0073] The compound (for example, the compound of formula (I)) may have a tautomer, and the tautomer also constitutes an embodiment of the present disclosure.

[0074] This disclosure also includes isotope-labeled compounds that are identical to those enumerated in formula (I), except that one or more atoms are replaced with atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes suitable for inclusion in the compounds of this disclosure are, respectively 2 H, 3 H, 13 C, 14 C,15 N, 18 O, 31 P, 35 S, 18 F, and 36 These include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine. Deuterium, i.e., 2 Substitution with heavier isotopes such as H may result in certain therapeutic benefits, such as increased half-life in vivo or reduced required dose, which may be preferable in some cases, as they lead to greater metabolic stability. Positron-emitting isotopes can be incorporated into compounds for medical imaging and positron emission tomography (PET) studies to determine receptor distribution. Suitable positron-emitting isotopes that can be incorporated into the compound of formula (I) are: 11 C, 13 N, 15 O, and 18 F is the isotope-labeled compound of formula (I). Generally, the isotope-labeled compound of formula (I) can be prepared by conventional methods known to those skilled in the art, or by processes similar to those described herein, using a suitable isotope-labeled reagent instead of a non-isotope-labeled reagent.

[0075] The compounds can be synthesized according to a variety of methods, including those shown in the examples. The compounds and intermediates can be isolated and purified by methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds include, but are not limited to, recrystallization at high or low temperatures with any activated carbon pretreatment, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups by grinding, as described, for example, in “Vogel's Textbook of Practical Organic Chemistry”, 5th edition (1989), pub. Longman Scientific & Technical, Essex CM20 2JE, England, by Furniss, Hannaford, Smith, and Tatchell.

[0076] The reaction conditions and reaction times for each individual step may vary depending on the specific reactants used and the substituents present in them. The reactants may be work-up in a conventional manner (e.g., by removing the solvent from the residue) and may be further purified according to methodologies commonly known in the art, including but not limited to crystallization, distillation, extraction, tritulation, and chromatography. Unless otherwise stated, the starting materials and reagents are commercially available or may be prepared by those skilled in the art from commercially available materials using methods described in the chemical literature.

[0077] Standard experiments, including the proper handling of reaction conditions, reagents, and the order of the synthetic pathway, the protection of any chemical functionalities that cannot be adapted to the reaction conditions, and the appropriate time step in the reaction sequence of the method, are included in the scope of this disclosure. Suitable protecting groups and methods for protecting and deprotecting various substituents using such suitable protecting groups are well known to those skilled in the art, for example, Protective Groups in Organic Synthesis (4 th This can be found in the book by Greene titled "PGM Wuts and TW Greene" (ed.), John Wiley & Sons, NY (2006).

[0078] If an optically active form of the disclosed compound is required, it can be obtained by performing one of the procedures described herein using an optically active starting material (e.g., prepared by asymmetric induction of an appropriate reaction step), or by separating a mixture of stereoisomers of the compound or intermediate using a standard procedure (such as chromatographic separation, recrystallization, or enzymatic degradation).

[0079] Similarly, if a pure geometric isomer of a compound is required, it can be obtained by using the pure geometric isomer as a starting material and performing one of the procedures described herein, or by separating a mixture of geometric isomers of the compound or intermediate using standard procedures such as chromatographic separation.

[0080] The synthesis schemes and specific examples described herein are illustrative and should not be construed as limiting the scope of this disclosure or the claims. Substitutions, modifications, and equivalents of the synthesis methods and specific examples are intended.

[0081] The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to a salt or amphoteric ion of a compound that is water-soluble or oil-soluble or dispersible, suitable for treating disorders without excessive toxicity, irritation, or allergic response, commensurate with a reasonable benefit / risk ratio, and effective for the intended use. The salt may be prepared during the final isolation and purification of the compound, or separately by reacting the amino group of the compound with a suitable acid. For example, the compound may be dissolved in a suitable solvent (e.g., methanol and water, but not limited to) and treated with an acid such as at least one equivalent of hydrochloric acid. The resulting salt may be precipitated, isolated by filtration, and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide the salt. Typical salts include acetate, adipine, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, p-toluenesulfonate, undecanoate, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. The amino group of the compound can also be quaternized with alkyl chlorides, alkyl bromides, and alkyl iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, and stearyl. In one embodiment, the compound is in the form of a trifluoroacetate.

[0082] Base addition salts can be prepared during the final isolation and purification of the disclosed compounds by the reaction of a carboxyl group of a metal cation (e.g., lithium, sodium, potassium, calcium, magnesium, or aluminum) with a suitable base (e.g., hydroxide, carbonate, or bicarbonate) or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-efenamine, and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, etc.

[0083] The compounds disclosed herein may exist in solvated forms, including non-solvated and hydrated forms. Generally, the solvated forms are equivalent to the non-solvated forms and are included within the scope of this disclosure. Certain compounds of this disclosure may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent with respect to the uses envisioned by this disclosure and are intended to be included within the scope of this disclosure.

[0084] Pharmaceutical composition The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (e.g., a patient, which may be human or non-human). The pharmaceutical composition may contain a “therapeutic effective dose” or a “prophylactic effective dose” of the agent. “Therapeutic effective dose” refers to the amount effective in the dosage and duration required to achieve a desired therapeutic outcome. The therapeutic effective dose of a composition may be determined by those skilled in the art and may vary depending on factors such as the individual’s condition, age, sex, and weight, as well as the composition’s ability to induce a desired response in the individual. The therapeutic effective dose is also the amount in which the therapeutically beneficial effect outweighs any toxic or adverse effects of any of the compounds of the present invention. “Prophylactic effective dose” refers to the amount effective in the dosage and duration required to achieve a desired preventive outcome. Since prophylactic doses are typically administered to a subject before or during the initial stages of a disease or condition, the prophylactic effective dose will be less than the therapeutic effective dose.

[0085] Pharmaceutical compositions may contain pharmaceutically acceptable carriers. As used herein, the term “pharmaceutically acceptable carrier” means a non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or any type of formulation aid. Some examples of substances that can function as pharmaceutically acceptable carriers are: sugars (e.g., lactose, glucose, and sucrose); starches (e.g., corn starch and potato starch); cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate); tragacanth powder; malt; gelatin; talc; excipients (e.g., cocoa butter and suppository wax); oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil); Recall (e.g., propylene glycol, but not limited); esters (e.g., ethyl oleate and ethyl laurate, but not limited); agar; buffers (e.g., magnesium hydroxide and aluminum hydroxide, but not limited); alginic acid; pyrogenic substances without water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer. Other non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate, but not limited), as well as colorants, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives, and antioxidants may also be present in the composition at the discretion of the formulation.

[0086] Therefore, compounds and their pharmaceutically acceptable salts can be formulated for administration, for example, in solid doses, eye drops, topical oily preparations, injection, inhalation (either orally or nasally), implantation, or by oral, buccal, parenteral, or rectal administration. Techniques and formulations can generally be found in "Remington's Pharmaceutical Sciences" (Meade Publishing Co., Easton, Pa.). Therapeutic compositions typically must be sterile and stable under manufacturing and storage conditions.

[0087] The type of carrier to be used will be determined by the route through which the disclosed compound is administered and the form of the composition. The composition may be in various forms suitable for systemic administration (e.g., oral, rectal, nasal, sublingual, oral, implant, or parenteral) or topical administration (e.g., transdermal, transpulmonary, transnasal, ocular, intraocular, liposome delivery system, or iontophoresis). In some embodiments, the composition is in a form suitable for parenteral administration, such as intravenous, intramuscular, or subcutaneous administration. In some embodiments, the composition is in a form suitable for implants, such as ocular implants.

[0088] In some embodiments, the composition is in a form suitable for administration to the eye, such as in ophthalmic formulations. Such compositions may contain components such as surfactants, isotonic agents, buffers, preservatives, cosolvents, and viscosity enhancers.

[0089] In some embodiments, ophthalmic formulations comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier are disclosed herein. Such compositions may be suitable for topical administration to subjects requiring topical instillation.

[0090] Ophthalmic formulations that can be administered topically, around the eye, or intraocularly contain an effective amount of one or more compounds of formula (I), or pharmaceutically acceptable salts thereof. In some embodiments, for formulations intended for topical administration to the eye in the form of eye drops or ophthalmic ointments, the amount of compound of formula (I) is 0.001 to 1.0% (w / w). When applied as eye drops, in some embodiments, one to two drops of such a formulation are administered once or several times a day.

[0091] The compounds of this disclosure may be administered as solutions, suspensions, or emulsions (dispersions) in an ophthalmologically acceptable vehicle. As used herein, “ophthalmologically acceptable” means a component that does not cause any serious eye damage or eye discomfort at the intended concentration and over the intended duration of use. Solubilizers and stabilizers should be non-reactive. “Ophthalmologically acceptable vehicle” means any substance or combination of substances that is non-reactive with the compound and suitable for administration to a patient. Suitable vehicles may be non-aqueous liquid media containing silicone oil, USP mineral oil, white oil, polyethylene glycol, polyethoxylated castor oil, and physiologically acceptable vegetable oils such as corn oil and peanut oil. Other suitable vehicles may be aqueous or oil-in-water solutions suitable for topical application to the eye. These vehicles may be preferred based on their ease of formulation and their ability to facilitate administration of such formulations by infusing drops of the composition into the affected eye. The formulation may also be a suspension, a viscous or semi-viscous gel, or another type of solid or semi-solid formulation. In some embodiments, the formulation comprises one or more fatty bases, e.g., natural waxes, e.g., white beeswax, carnauba wax, wool wax (wool fat), refined lanolin, anhydrous lanolin; petroleum waxes, e.g., solid paraffin, microcrystalline wax; hydrocarbons, e.g., liquid paraffin, white petrolatum, yellow petrolatum; or a combination thereof. The formulation may be applied by hand or using an applicator, e.g., a wipe, contact lens, dropper, or spray.

[0092] Various isotonic agents may be used to adjust the tonicity of the composition to, for example, the tonicity of natural tears. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, dextrose, and / or mannitol can be added to the composition to bring it closer to physiological tonicity. The amount of such isotonic agent may vary depending on the specific agent added. In some embodiments, the formulation contains a sufficient amount of isotonic agent so that the final composition has an ophthalmologically acceptable volume molar concentration (e.g., about 200-400 mOsm / kg).

[0093] A suitable buffer system (e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate, or boric acid) can be added to the formulation to prevent pH drift under storage conditions. The specific concentration will vary depending on the drug used. In some embodiments, the buffer is selected to maintain a target pH within the range of pH 6 to 7.5.

[0094] Topical ophthalmic formulations may also include aqueous carriers. Such carriers may be formulated as phospholipid carriers, artificial tear carriers, or mixtures of both. As used herein, “phospholipid carrier” and “artificial tear carrier” mean an aqueous formulation that (i) comprises one or more phospholipids (in the case of phospholipid carriers) or other compounds to assist in the consistency of endogenous tears, natural tear accumulation, or otherwise temporarily relieve symptoms and conditions of dry eye at the time of ocular administration; (ii) is safe; and (iii) provides a suitable delivery vehicle for topical administration of an effective amount of one or more compounds disclosed herein.

[0095] Other compounds designed to lubricate, approximate the consistency of endogenous tears, aid in natural tear accumulation, or otherwise temporarily alleviate the symptoms and conditions of dry eye upon ocular administration are known in the art. Such compounds may increase the viscosity of a composition and include, but are not limited to, monomeric polyols such as glycerol, propylene glycol, and ethylene glycol; polymeric polyols such as polyethylene glycol, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and hydroxypropylcellulose; dextran such as dextran 70; water-soluble proteins such as gelatin; and vinyl polymers, such as polyvinyl alcohol, polyvinylpyrrolidone, povidone, and carbomer; and the like.

[0096] Other compounds may also be added to the ophthalmic formulations of this disclosure to increase the viscosity of the composition. Examples of viscosity improvers include, but are not limited to, hyaluronic acid and its salts, chondroitin sulfate and its salts, dextran, polysaccharides such as various cellulose polymers, vinyl polymers, and acrylic acid polymers. Generally, phospholipid carrier compositions or artificial tear carrier compositions exhibit a viscosity of 1 to 400 centipoise.

[0097] Preservatives may be required to prevent microbial contamination during use. Suitable preservatives include benzalkonium chloride, chlorobutanol, benzododecinium bromide, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, polyquaternium-1, or other agents known to those skilled in the art. Such preservatives are typically used at levels of 0.001–1.0% w / v. Compositions of the present invention may be sterile but not preserved, and such compositions generally do not contain preservatives.

[0098] In other embodiments, the compound of formula (I) is formulated for systemic administration. The carrier for systemic administration typically comprises at least one of the following: diluents, lubricants, binders, disintegrants, colorants, flavorings, sweeteners, antioxidants, preservatives, flow enhancers, solvents, suspending agents, wetting agents, surfactants, or combinations thereof.

[0099] Suitable diluents include sugars (e.g., glucose, lactose, dextrose, and sucrose); diols (e.g., propylene glycol), calcium carbonate, sodium carbonate, and sugar alcohols (e.g., glycerin, mannitol, and sorbitol). The amount of diluent(s) in a systemic or topical composition is usually about 50 to about 90% by weight of the composition.

[0100] Suitable lubricants include silica, talc, stearic acid and its magnesium and calcium salts, calcium sulfate, and liquid lubricants (e.g., polyethylene glycol, and vegetable oils (e.g., peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil)). The amount of lubricant(s) in a systemic or topical composition is usually about 5 to about 10% by weight of the composition.

[0101] Suitable binders include polyvinylpyrrolidone, aluminum magnesium silicate, starch (e.g., corn starch and potato starch), gelatin, tragacanth, and cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose). The amount of binder(s) in the whole composition is usually about 5 to about 50% by weight of the composition.

[0102] Suitable disintegrants include agar, alginic acid and its sodium salts, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clay, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is usually about 0.1 to about 10% by weight of the composition.

[0103] Suitable colorants include FD&C dyes. When used, the amount of colorant in a whole-body or topical composition is usually about 0.005 to about 0.1% by weight of the composition.

[0104] Suitable flavorings include menthol, peppermint, and fruit flavors. The amount of flavoring(s) used in a systemic or topical composition is typically about 0.1% to 1.0%.

[0105] Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s) in a systemic or topical composition is usually about 0.001% to about 1% by weight of the composition.

[0106] Suitable antioxidants include butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5% by weight of the composition.

[0107] Suitable preservatives include benzalkonium chloride, methylparaben, and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is usually about 0.01 to about 5% by weight of the composition.

[0108] A suitable flow promoter is silicon dioxide. The amount of the flow promoter(s) in a whole-body or topical composition is typically about 1 to about 5% by weight of the composition.

[0109] Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, hydroxylated castor oil, alcohol (e.g., ethanol), and aqueous buffers (e.g., phosphate buffer solution). In some embodiments, the solvent is an aqueous buffer such as phosphate buffer solution. The amount of solvent(s) in a whole-body or topical composition is typically about 0 to about 100% by weight of the composition.

[0110] Suitable suspensions include AVICEL RC-591 (manufactured by FMC Corporation in Philadelphia, Pennsylvania) and sodium alginate. The amount of suspension(s) in a systemic or topical composition is typically about 1 to about 8% by weight of the composition.

[0111] Suitable surfactants include lecithin, polysorbate 80, sodium lauryl sulfate, and TWEENS (manufactured by Atlas Powder Company, Wilmington, Delaware). Suitable surfactants are disclosed below: CTFA Cosmetic Ingredient Handbook, 1992, pp. 587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant(s) in a systemic or topical composition is typically about 0.1% to about 5% by weight of the composition.

[0112] The amounts of components in a whole-body composition may vary depending on the type of whole-body composition being prepared, but generally, a whole-body composition contains 0.01% to 50% by weight of an active compound and 50% to 99.99% by weight of one or more carriers. Compositions for parenteral administration typically contain 0.1% to 10% by weight of an active ingredient and 90% to 99.9% by weight of a carrier (e.g., a diluent and a solvent).

[0113] Compositions for oral administration may have various dosage forms. For example, solids include tablets, capsules, granules, and bulk powders. These oral dosage forms contain a safe and effective amount of the active ingredient, usually at least about 5% by weight, more specifically about 25% to about 50% by weight. Oral drug compositions contain about 50% to about 95% by weight, more specifically about 50% to about 75% by weight of a carrier.

[0114] Tablets may be compressed tablets, powder tablets, enteric-coated tablets, sugar-coated tablets, film-coated tablets, or multi-compressed tablets. Tablets typically contain an active ingredient and a carrier (e.g., an ingredient selected from diluents, lubricants, binders, disintegrants, colorants, flavorings, sweeteners, flow enhancers, and combinations thereof). Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are FD&C dyes that can be added for appearance. Chewable tablets preferably contain sweeteners (e.g., aspartame and saccharin) or flavorings (e.g., menthol, peppermint, fruit flavors), or combinations thereof.

[0115] Capsules (e.g., implants, sustained-release formulations, and sustained-release formulations) typically contain an active compound and a carrier containing one or more of the diluents disclosed above, within a gelatin-containing capsule. Granules typically contain the disclosed compounds, preferably a flow enhancer (e.g., silicon dioxide) to improve flow properties. Implants may be of a biodegradable or non-biodegradable type.

[0116] The selection of components for carriers of oral compositions is determined by secondary considerations such as taste, cost, and storability, but these are not important to the purposes of this disclosure.

[0117] The solid composition can typically be coated in a conventional manner using pH-dependent or time-dependent coatings, and the disclosed compounds are released in the gastrointestinal tract near the desired application, or at various points in time to extend the desired effect. The coatings typically comprise one or more components selected from the group consisting of cellulose phthalate acetate, polyvinyl phthalate acetate, hydroxypropyl methylcellulose phthalate, ethylcellulose, EUDRAGIT® coating (available from Evonik Industries of Essen, Germany), wax, and shellac.

[0118] Oral administration compositions may take the form of a liquid. For example, preferred liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-foaming granules, suspensions reconstituted from non-foaming granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, and syrups. Liquid oral administration compositions typically contain the disclosed compounds and a carrier (i.e., a carrier selected from diluents, colorants, flavorings, sweeteners, preservatives, solvents, suspending agents, and surfactants). Oral liquid compositions preferably contain one or more components selected from colorants, flavorings, and sweeteners.

[0119] Other compositions useful for achieving systemic delivery of the target compound include sublingual, buccal, and nasal dosage forms. Such compositions typically contain one or more soluble fillers (e.g., diluents including sucrose, sorbitol, and mannitol) and binders (e.g., acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropyl methylcellulose). Such compositions may further contain lubricants, colorants, flavorings, sweeteners, antioxidants, and flow enhancers.

[0120] The disclosed compounds can be administered topically. Topical compositions that can be applied topically to the skin may take any form, including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-in and rinse-off hair conditioners, emulsions, cleansers, moisturizers, sprays, skin patches, etc. A topical composition comprises the disclosed compounds (e.g., the compounds disclosed herein or their pharmaceutically acceptable salts) and a carrier. The carrier of the topical composition preferably helps the compound to penetrate the skin. The carrier may further comprise one or more optional components.

[0121] The amount of carrier used in combination with the disclosed compound is sufficient to provide a practical amount of composition for administration per unit dose of the compound. Methods and compositions for producing dosage forms useful for the methods disclosed herein are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979), Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981), and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0122] The carrier may consist of a single component or a combination of two or more components. In topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more components selected from phosphate-buffered saline, isotonic water, deionized water, monofunctional alcohol, symmetrical alcohol, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristylpropionate, dimethyl isosorbide, castor oil, and combinations thereof. More specifically, carriers for skin application include propylene glycol, dimethyl isosorbide, and water, and even more specifically, phosphate-buffered saline, isotonic water, deionized water, monofunctional alcohol, and symmetrical alcohol.

[0123] The carrier of the topical composition may further contain one or more components selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.

[0124] Suitable emollients include: stearyl alcohol, glyceryl monostearate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate. Di-n-butyl sebacate, isopropyl myristart, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petroleum, mineral oil, butyl myristart, isostearic acid, palmitic acid, isopropyl linolate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristart, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95% by weight of the composition.

[0125] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically about 0% to 95% by weight of the composition.

[0126] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Specific examples of solvents include ethyl alcohol and homotopic alcohol. The amount of solvent(s) in a topical composition is typically about 0% to 95% by weight of the composition.

[0127] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutylphthalate, gelatin, and combinations thereof. A specific example of a humectant is glycerin. The amount of humectant(s) in a topical composition is usually 0% to 95% by weight of the composition.

[0128] The amount of thickener(s) in a topical composition is typically about 0% to 95% by weight of the composition.

[0129] Suitable powders include beta-cyclodextrin, hydroxypropyl cyclodextrin, chalk, talc, fuller's earth, kaolin, starch, gum, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is usually 0% to 95% by weight of the composition.

[0130] The amount of fragrance in a topical composition is usually about 0% to 0.5% by weight of the composition, and in particular, about 0.001% to 0.1% by weight.

[0131] Suitable pH-adjusting additives include HCl or NaOH in amounts sufficient to adjust the pH of the topical pharmaceutical composition.

[0132] How to use Compounds of formula (I) can be used to treat a variety of disorders associated with HTRA1. Accordingly, a method for treating an HTRA1-related disorder in a subject requiring treatment is disclosed herein, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof).

[0133] HTRA1 is associated with many disorders. Examples include, but are not limited to, macular degeneration (e.g., Yang et al. (2006) Science 314(5801), 992-993; Lin et al. (2018) Aging Cell, 17(4), e12710; Jones et al. (2011) Proc. Natl. Acad. Sci. USA, 108(35), 14578-14583; Vierkotten et al. (2011) PloS One, 6(8), e22959); Alzheimer's Disease (see, e.g., Grau et al. (2005) Proc. Natl. Acad. Sci. USA, 102(17), 6021-6026; Tennstaedt et al. (2012) J. Biol. Chem. 287(25) 20931-20941;Xiao et al. (2021) CNS Neurosci. Ther. 27(12), 1531-1539), bladder cancer (see, eg, Lorenzi et al. (2013) Int. J. Cancer 133(11), 2650-2661);intervertebral disc degeneration (see, eg, Tiaden, et al. (2012) J. Biol. Chem. 287(25), 21335-21345;Akhatib et al. (2013) J. Biol. Chem. 288(26), 19280-19287);Lyme disease (see, eg, Russell et al. (2016) Mol. Microbiol. 99(3), 586-596;Russell et al. (2013) Mol. Microbiol. 90(2), 241-251; Russell et al. (2013) Mol. Microbiol. 90(2), 228-240; and Ye et al. (2016) Infect. Immun. 84(8), 2372-2381); osteoarthritis (see, eg, Holt et al.(2012) Osteoarthr. Cartilage, 20(5), 430-439;Chen et al. (2019) Am. J. Pathol. 189(7), 1423-1434;Bhutada et al. (2022) Osteoarthr. Cartilage, 30(8), 1091-1102;Tossetta et al. (2022) Bone, 157(116350), 116350;Tsuchiya et al. (2005) Bone, 37(3), 323-336;Polur et al. (2010) Histol. Histopathol. 25(5), 599-608);preeclampsia (see, eg, Gesuita et al. (2019) Pregnancy Hypertens. 18, 58-62;Liu et al. (2018) Mol. Med. Rep. 18(3), 2937-2944;Teoh et al. (2015), Placenta (2016). 990-995;Ajayi et al (2008) Am J. Obstet Gynecol 199(5), 557.e1-10);rheumatoid arthritis (see, eg, Grau et al. (2006) J. Biol. Chem. 281(10-2020); corneal dystrophies (see, eg, Venkatraman et al. (2017) J. Proteome Res. 16(8), 2899-2913;Poulsen et al. (2019) J. Biol. Chem. 294(31), 11817-11828.

[0134] Accordingly, a method for treating a disorder in a subject requiring treatment of the disorder is disclosed herein, wherein the disorder is selected from macular degeneration, Alzheimer's disease, arthritis, bladder cancer, intervertebral disc degeneration, Lyme disease, osteoarthritis, pre-eclampsia, rheumatoid arthritis, and TGFBI-associated corneal dystrophy, and the method comprises administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof). In some embodiments, the disorder is macular degeneration. In some embodiments, the disorder is age-related macular degeneration. In some embodiments, the disorder is dry age-related macular degeneration. [Examples]

[0135] The abbreviations used in these examples include: CBz is carboxybenzyl, DCM is dichloromethane, DIPEA is N,N-diisopropylethylamine, DMF is N,N-dimethylformamide, DMSO is dimethyl sulfoxide, and HBTU is 3-[bis(dimethylamino)methylium]-3H-benzotriazole-1-oxidehexafluorophosphate.

[0136] Example 1: R 1 Synthesis of α-borylated amines [ka] For example, see Buesking et al. J. Org. Chem. 2014, 79 (8), 3671-3677.

[0137] Step A. Tetraethoxytitanium was added to a solution of aldehyde 1 and (R)-2-methylpropane-2-sulfinamide 2 in tetrahydrofuran. The reaction mixture was stirred at ambient temperature for 12 to 48 hours. The reaction mixture was then added to a mixture of saturated sodium chloride aqueous solution and ethyl acetate. The resulting suspension was filtered through a Celite pad and washed with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the desired compound as a colorless oil, which was used without further purification (yield 50-85%).

[0138] Step B. Tricyclohexylphosphine tetrafluoroborate (1.2 mol%) was stirred in toluene, and then an aqueous solution of copper II sulfate (1.2 mol%) was added. Next, benzylamine (5 mol%) was added dropwise, and the blue two-phase solution became a pale blue emulsion. After stirring for 10-30 minutes, a solution of (R)-N-sulfinamide 3 was added as a toluene solution. Then, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan was added as a single solid portion, and the reaction mixture was stirred for 12-36 hours. The reaction mixture was filtered through a Celite pad and concentrated under reduced pressure. It was purified by column chromatography to obtain α-borylated sulfinamide 4 in yield of 20-60%, typically as a white solid.

[0139] Step C. α-Borylated sulfinamide 4 was dissolved in 1,4-dioxane, and then 4M HCl was added to the 1,4-dioxane. After 3 to 12 hours, the formed precipitate was filtered and washed with a hexane:diethyl ether mixture to obtain α-Borylated amine 5 as an HCl salt, typically in a white solid with a yield of 20 to 60%.

[0140] Table 1 below shows the structure and characterization data of compounds prepared according to the general method described above.

[0141] [Table 1-1] [Table 1-2]

[0142] Example 2: Synthesis of boronic acid ester compounds Method 1 [ka] Step A. To a stirred solution of Fmoc-amino acid 6 in dichloromethane, the HCl salt of α-borylated amine 5 was added. The mixture was cooled to 0°C, and HBTU was added followed by DIPEA. The reaction mixture was stirred at ambient temperature for 12–36 hours. The mixture was diluted with saturated sodium chloride aqueous solution and ethyl acetate. The layers were separated, and the aqueous phase was extracted three times with ethyl acetate. The combined ethyl acetate extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by chromatography to obtain compound 7 in 80–95% yield, typically as a white solid.

[0143] Step B. Compound 7 was treated with a 20% solution of piperidine in DMF for 15 minutes, and the mixture was evaporated to dryness. This residue was then incorporated into DCM, and the CBz-protected amino acid was added. The solution was cooled to 0°C, and HBTU, followed by DIPEA, was added sequentially. The reaction mixture was stirred at room temperature for 12–36 hours. The mixture was diluted with saturated aqueous sodium chloride and ethyl acetate. The layers were separated, and the aqueous phase was extracted three times with ethyl acetate. The combined ethyl acetate extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 8, which was used in subsequent chemical reactions without further purification.

[0144] Method 2 [ka] Step A. The HCl salt / methyl ester of amino acid 9 and the Z-amino acid were added together under a nitrogen atmosphere, followed by the addition of DCM (0.1-0.3 M). The solution was cooled to 0°C, and HBTU, followed by DIPEA, was added sequentially. The reaction mixture was stirred at room temperature for 12-36 hours. The mixture was diluted with saturated sodium chloride aqueous solution and ethyl acetate. The layers were separated, and the aqueous phase was extracted three times with ethyl acetate. The combined ethyl acetate extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude final pre-compound 8, which was used in subsequent chemical reactions without further purification.

[0145] Step B. The methyl ester was dissolved in a mixture of THF and water, then LiOH was added and the mixture was stirred overnight at ambient temperature. The mixture was pH=1 with 1M HCl and extracted three times with ethyl acetate. The combined organic fraction was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by reverse-phase chromatography to obtain free acid 10 in 40-99% yield.

[0146] Step C. The HCl salts of boronic acids were mixed under a nitrogen atmosphere, and then DCM (0.1-0.3 M) was added. The solution was cooled to 0°C, and HBTU, followed by DIPEA, was added sequentially. The reaction mixture was stirred at room temperature for 12-36 hours. The mixture was diluted with saturated aqueous sodium chloride solution and ethyl acetate. The layers were separated, and the aqueous phase was extracted three times with ethyl acetate. The combined ethyl acetate extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain crude boronic acid ester 8, which was used in subsequent chemical reactions without further purification.

[0147] Example 3: Synthesis of the boronic acid compound of formula (I) [ka] To a stirred solution of boronic acid ester (1.0 equivalent) in acetone and water (0.1 M total), methylboronic acid (10 equivalents) and 1 M hydrochloric acid aqueous solution were added. The reaction mixture was stirred at ambient temperature for 12 to 48 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by chromatography using a Biotage Sfa C18 D column with a water / acetonitrile gradient (100% to 0% water in 40 column volume). After drying by lyophilization, boronic acid was obtained as a white solid (17-90% yield).

[0148] Example 4: Synthesis of Trifluoroamino Alcohol [ka] Step A: (3S)-3-(dibenzylamino)-1,1,1-trifluoro-4-methylpentan-2-ol A catalytic amount of TBAF was added at 0°C to a solution mixture of aldehydes (1 equivalent) in THF and stirred for 5 minutes. Then, TMSCF3 (2 equivalents) was added and stirring continued for 15 minutes. Next, another catalytic amount of TBAF was added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated under vacuum, the crude product was diluted with ethyl acetate and washed with water, the organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography to obtain dibenzylamino alcohol.

[0149] Step B: (3S)-3-amino-1,1,1-trifluoro-4-methylpentan-2-ol To a mixed solution of dibenzylamino alcohol (1 equivalent) in MeOH, the catalyst Pd(OH)2 was added at room temperature under an H2- gas atmosphere, and the mixture was allowed to stand at room temperature for 16 hours. The reaction mixture was filtered through a Celite bed, and the organic layer was concentrated under vacuum. The crude product was purified by column chromatography to obtain trifluoroamino alcohol.

[0150] Trifluoroamino alcohols were coupled using the same method as in either Method 1 or Method 2. Trifluoroketones were revealed after amide formation using standard Dess-Martin oxidation according to the procedure described in WO2016 / 135070.

[0151] Example 5: Synthesis of the compound of formula (I) compound 1 [ka] To a stirred solution of benzyl N-[(1S)-1-benzyl-2-[[(1S)-1-[[(R)-cyclobutyl-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]carbamoyl]-3-methyl-butyl]amino]-2-oxo-ethyl]carbamate 11 (264 mg, 0.44 mmol, 1.0 equivalent) in acetone (2.4 mL), methylboronic acid (261 mg, 4.4 mmol, 10 equivalents) and 0.2 M aqueous hydrochloric acid (2.4 mL) were added. The reaction mixture was stirred at room temperature for 3 days. This mixture was concentrated under reduced pressure and purified on a Biotage Sfa C18 D column by a water / MeOH gradient (100% water to 0% water at 40 column volume) to obtain 122 mg (0.23 mmol, 70%) of the desired product as a white solid. 1H NMR (500 MHz, MeOD) δ 7.38-7.20 (m,10H), 5.03 (s, 2H), 4.59 (dd, J = 9.9, 4.4 Hz, 1H), 4.37 (dd, J = 9.4, 5.2 Hz, 1H), 3.10 (dd, J = 14.0, 5.3 Hz, 1H), 2.87 (dd, J = 14.1, 9.2 Hz, 1H), 2.56 (d, J = 9.1 Hz, 1H), 2.43 (p, J = 8.1 Hz, 1H), 2.09-2.0 (m, 2H), 1.87 (h, J = 8.9 Hz, 1H), 1.82-1.70 (m, 4H), 1.62-1.55 (m, 2H), 0.94 (d, J = 5.9 Hz, 3H), 0.90 (d, J = 5.8 Hz, 3H), 0.19 (s, 1H). C 28 H 38 BN3O6[M-OH] + Theoretical value: 506.3; Measured value: 506.3. Additional compound and characterization data The additional compounds were prepared using appropriate starting materials and following the general procedure described above. Their structure and characterization data are shown in Table 2.

[0152] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 Table 2-24 Table 2-25 Table 2-26 Table 2-27 Table 2-28 Table 2-29 Table 2-30 Table 2-31 Table 2-32 Table 2-33 Table 2-34 Table 2-35 Table 2-36 Table 2-37 Table 2-38 Table 2-39 Table 2-40 Table 2-41 [Table 2-42] [Table 2-43] [Table 2-44] [Table 2-45] [Table 2-46] [Table 2-47] [Table 2-48] [Table 2-49] [Table 2-50] [Table 2-51] [Table 2-52]

[0153] Example 6: RBC Protease Assay Reaction buffer: 50 mM Tris (pH 8.0), 200 mM NaCl, 0.25% SHAPS, 0.75% DMSO (final). HTRA1 enzyme: R&D Systems catalog number 2916-SE-020, human HTRA1 / PRSS11 protein Gly156-Pro480 derived from E. coli, with N-terminal Met and C-terminal 6-His tags, MW=36kDa. Substrate: H2 optimal substrate, Ex / Em=320 / 405 nm, McA-IRRVSYSF(K-Dnp)K (SEQ ID NO: 1). Control compound: Compound 18. Reaction conditions: Final substrate concentration in assay = 2.5 μM, HTRA1, 6.5 nM.

[0154] Reaction Procedure: Enzyme and substrate solutions were prepared in fresh reaction buffer. The enzyme solution was supplied to the reaction well, and then the compound in DMSO was supplied to the reaction mixture in nanoliter ranges using ACOUSTIC Technology (Echo 550, LabCyte Inc., Sunnyvale, CA). After a 20-minute incubation, the substrate solution was added to the reaction well to initiate the reaction. Enzyme activity was monitored every 5 minutes for 120 minutes at room temperature as a time-dependent measurement of the increase in fluorescence signal from the fluorescently labeled peptide substrate. The data was analyzed by taking the slope (signal / time) of the linear portion of the measurement. (Note: The measurement period varies for each protease, with some being linear from 0 to 120 minutes, others from 0 to 30 minutes, etc.). The slope was calculated using Excel, and curve fitting was performed using GraphPad Prism software.

[0155] IC obtained from this assay 50 The values ​​are shown in Table 2.

[0156] Example 7: Cytotoxicity assay ARPE19 cells were grown to 95% confluence and placed in lanes 2-12 of a 96-well plate, with 20,000 cells per well (2 x 10⁶ cells per well). 4Cells were seeded at a final volume of 100 μL per well, and incubated at 37°C for 24 hours. The cell medium was carefully aspirated, taking care not to touch the cells at the bottom of the plate, and the cells were immediately washed by adding 100 μL of PBS per well. The PBS was aspirated, followed by the addition of 50 μL of serum-free medium to each well.

[0157] The drug solution was prepared in four separate batches at the desired final concentrations of 0.0005 μM, 0.005 μM, 0.5 μM, 5 μM, and 50 μM. The required intermediate concentration was determined to be twice the desired final concentration when 5 μL of the drug was added to 245 μL of serum-free medium. For example, for cells treated with 50 μM of the drug, 5 μL of 5 mM drug stock needed to be added to 245 μL of serum-free medium for a 100 μM intermediate dilution. First, the drug was diluted in DMSO, then 5 μL of each drug was added to 245 μL of serum-free medium according to the above calculations, and then serum-free medium dilutions containing 2% DMSO were prepared for 8 wells of control cells.

[0158] To perform a drug treatment assay in ARPE19 cells, 50 μL of intermediate drug dilution was added to four designated wells, and the plate was incubated at 37°C for 5 hours. The drug treatment medium was aspirated from the cells, and the tip was replaced every half of the plate. Cells were replenished with 150 μL of complete medium per well, and the plate was subsequently incubated at 37°C for 72 hours.

[0159] To perform CCK8 readings, 10 mL of 10% CCK8 solution was prepared per plate by diluting the CCK8 reagent with serum-free medium (Dojindo, CK04). The medium was aspirated from the cells, and then 100 μL of 10% CCK8 solution was added per well, including lane 1 (which served as a blank) and no cells. The plates were incubated at 37°C for 1 hour. All significant bubbles were removed with a hypodermic needle. Absorbance values ​​were obtained at 450 nM using a Tecan plate reader.

[0160] CC from absorbance readings 50To determine the values, the blank / baseline signal was calculated by averaging the values ​​from the blank wells. The blank was subtracted from all other data points. The maximum signal was calculated by averaging the values ​​from the control wells. All values ​​were divided by the maximum signal and multiplied by 100 to calculate the metabolic activity percentage. Prism was used to fit the data points to a nonlinear regression curve, where each drug corresponds to the cytotoxic concentration (CC) that causes 50% cell death. 50 The decision was made. The data is shown in Table 3.

[0161] [Table 3]

Claims

1. Compound of formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (In the formula, Q N is -X-R N where X is selected from -C(O)-, -C(O)O-, -C(O)NH-, -S(O) 2 -, and a bond, and R N is C 1 -C 6 alkyl, aryl, and -(CR a [[ID=十四]]R b ) p -Z, p is 1, 2, or 3, R a and R b are each independently hydrogen and C 1 -C 4 alkyl, where one R a and one R b together with the carbon atom to which they are attached optionally together form a 3- to 6-membered cycloalkyl, Z is selected from aryl and heterocyclyl, and each R N is optionally substituted with one or two substituents independently selected from halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -OH, and -COOH; Q C is -B(OR C1 ) 2 and -C(O)R C2 Selected from, where each R C1 These are, independently, hydrogen and C 1 -C 6 Selected from alkyl and aryl, or two R C1 They form a ring that can be optionally substituted together with the atoms to which they are bonded, R C2 However, C 1 -C 4 Alkyl and C 1 -C 4 Selected from haloalkyls; R 1 C 3 -C 8 Alkyl, hydroxy-C 1 -C 6 Alkyl, C 3 -C 6 Selected from cycloalkyls, 3- to 6-membered heterocyclines, and monocyclic heteroaryls; R 2a is hydrogen or C 1 -C 4 It is alkyl, R 2b C 1 -C 8 Alkyl, aryl-C 1 -C 4 Alkyl, heteroaryl-C 1 -C 4 Alkyl, hydroxy, and - (CH 2 ) m NH-R 2c Selected from, where m is 1, 2, 3, 4, 5, or 6, R 2c H and -COO(C 1 -C 6 Selected from alkyl, the aryl is unsubstituted or hydroxy and C 1 -C 6 Substituted with one or two substituents independently selected from the alkoxy, or R 2a and R 2b However, together with the atoms to which they are bonded, they form a ring that can be optionally substituted; R 3 C 1 -C 8 Alkyl and -(CH 2 ) n - Selected from Y, where n is 0, 1, 2, or 3, and Y is selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl, where each alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is independently unsubstituted or C 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl, halo, cyano, C 1 -C 4 Haloalkyl, hydroxy, amino, and 1 -C 4 Substituted with one or two substituents independently selected from the alkoxy, where the aryl or heteroaryl is R C2 (It is arbitrarily substituted with a group that forms a ring together with it.)

2. R 1 However, C 3 -C 4 Alkyl and C 3 -C 5 A compound according to claim 1, selected from cycloalkyl groups, or a pharmaceutically acceptable salt thereof.

3. R 1 However, the compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, selected from the following: 【Chemistry 2】

4. R 1 However, the compound according to any one of claims 1 to 3, selected from the following, or a pharmaceutically acceptable salt thereof: 【Transformation 3】

5. R 2a is hydrogen, and R 2b is C 1 -C 4 alkyl, -CH 2 -phenyl, -CH 2 -indolyl, and -(CH 2 ) 4 NH-R 2c selected from, where R 2c is selected from H and -COO(tBu), and the phenyl is unsubstituted or substituted with one substituent selected from hydroxy and C 1 -C 4 alkoxy, the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. R 2a is hydrogen or methyl, and R 2b is selected from the following, the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof: 【Chemistry 4】

7. R 2a However, it is hydrogen, R 2b but 【Transformation 5】 The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. R 2a and R 2b The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein these atoms, together with the atoms to which they are bonded, form an optionally substituted five-membered saturated ring.

9. R 3 However, C 1 -C 6 Alkyl, -CH 2 -phenyl, -CH 2 -Naphthyl, -CH 2 -Indolyl, -CH 2 -Pyridyl, and -CH 2 - A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, selected from cyclohexyl, wherein the phenyl is unsubstituted or substituted with one or two substituents independently selected from methyl, ethyl, fluoro, chloro, bromo, hydroxy, methoxy, cyano, fluoromethyl, difluoromethyl, and trifluoromethyl, and the pyridyl is unsubstituted or substituted with one oxo group.

10. R 3 However, a compound according to any one of claims 1 to 9, selected from the following, or a pharmaceutically acceptable salt thereof: 【Chemistry 6-1】 【Chemistry 6-2】

11. R 3 However, a compound according to any one of claims 1 to 10, selected from the following, or a pharmaceutically acceptable salt thereof: 【Transformation 7】

12. R 3 but 【Transformation 8】 The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

13. R N However, C 3 -C 4 Alkyl, phenyl, phenyl-C 1 -C 3 Alkyl and heterocyclyl-C 1 -C 3 A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, selected from alkyl, wherein the phenyl is unsubstituted or substituted with one or two substituents independently selected from halo, methyl, trifluoromethyl, methoxy, and -COOH.

14. R N However, a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, selected from the following: 【Chemistry 9】

15. Q N However, the compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, selected from the following: 【Chemistry 10】

16. Q C However, -B(OR C1 ) 2 And each R C1 However, independently, hydrogen, C 1 -C 4 Selected from alkyl and phenyl, or two R C1 The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein these atoms, together with the atoms to which they are bonded, form an optionally substituted 5-6 member saturated ring.

17. Each R C1 A compound according to any one of claims 1 to 16, wherein the compound is hydrogen, or a pharmaceutically acceptable salt thereof.

18. Q C However, -C(O)R C2 And R C2 However, C 1 -C 4 A compound according to any one of claims 1 to 15, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof.

19. A compound according to claim 1, selected from the compounds shown in Figure 1, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. A method for treating an HTRA1-related disorder in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20.

22. The method according to claim 21, wherein the disorder is selected from macular degeneration, Alzheimer's disease, arthritis, bladder cancer, intervertebral disc degeneration, Lyme disease, osteoarthritis, prodromal epilepsy, rheumatoid arthritis, and TGFBI-associated corneal dystrophy.

23. The method according to claim 21, wherein the disorder is age-related macular degeneration.

24. The method according to claim 23, wherein the age-related macular degeneration is dry age-related macular degeneration.

25. A method for inhibiting HTRA1 in a sample, comprising contacting the sample with an effective amount of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20.

26. Use as a pharmaceutical product of the compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 19.

27. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for treating a disorder related to HTRA1.

28. The use according to claim 27, wherein the disorder is selected from age-related macular degeneration, Alzheimer's disease, arthritis, bladder cancer, intervertebral disc degeneration, Lyme disease, osteoarthritis, prodromal epilepsy, rheumatoid arthritis, and TGFBI-associated corneal dystrophy.

29. The use according to claim 27, wherein the disorder is age-related macular degeneration.

30. The use according to claim 29, wherein the age-related macular degeneration is dry age-related macular degeneration.

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