Compounds for the treatment of coronavirus disease

Abstract

The present invention generally relates to inhibitors of SARS-CoV-2-related 3C-like protease (Mpro) having formula (A), which are useful for the treatment of coronavirus disease. JPEG2025520539000618.jpg46170

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the priority and benefit of U.S. Provisional Patent Application No. 63 / 353,354, titled "Compound for the Treatment of Coronavirus Infection," filed on June 17, 2022, and U.S. Provisional Patent Application No. 63 / 414,287, titled "Compound for the Treatment of Coronavirus Infection," filed on October 7, 2022, the disclosures of which are hereby incorporated by reference in their entirety for all purposes.

[0002] (Field of the Invention) The present invention relates to inhibitors of the replication activity of coronaviruses. The inhibitors described herein may be useful for the treatment of diseases caused by coronavirus infections, including COVID - 19 caused by SARS - CoV - 2 infection. In particular, the present invention relates to compounds and pharmaceutical compositions that inhibit SARS - CoV - 2 - related 3C - like proteases, methods of treating coronavirus infections, and methods of synthesizing these compounds.

Background Art

[0003] (Background) Coronaviruses are a large family of viruses that typically cause mild to moderate upper respiratory tract diseases in humans. However, three coronaviruses have caused more severe and fatal illnesses in people: the Severe Acute Respiratory Syndrome Coronavirus (SARS - CoV) that emerged in November 2002 and caused Severe Acute Respiratory Syndrome (SARS); the Middle East Respiratory Syndrome Coronavirus (MERS - CoV) that emerged in 2012 and caused Middle East Respiratory Syndrome (MERS); and SARS - CoV - 2 that emerged in 2019 and caused Coronavirus Disease 2019 (COVID - 19).

[0004] Infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS - CoV - 2) causes Coronavirus Disease 2019 (COVID - 19).

[0005] The virus that causes COVID-19 spreads easily among people. According to data, the COVID-19 virus mainly spreads from person to person with close contact (within about 6 feet (2 meters)). The COVID-19 virus can also spread from people who are infected but have no symptoms. This is called asymptomatic infection. The COVID-19 virus can also spread from people who are infected but have not yet shown symptoms. This is called pre-symptomatic infection. There is a possibility of getting infected with COVID-19 when reinfected with SARS-CoV-2, and this can occur multiple times.

[0006] Whole genome sequence analysis revealed that SARS-CoV-2 has 79.6% sequence identity with SARS-CoV. SARS-CoV-2 seems to have a relatively high infection rate among humans, causing severe and fatal pneumonia and other disorders, threatening people of all ages, especially the elderly and those with pre-existing conditions such as immunodeficiency, lung diseases, and metabolic diseases. With the rapid increase in the number of infected and deceased, the development of therapeutic drugs for COVID-19 has become an urgent task.

[0007] SARS-CoV-2 is a complex virus consisting of three open reading frames that express polyproteins. The polyproteins undergo proteolytic processing to become their mature active forms. The spike glycoprotein is cleaved by cathepsin L and TMPRSS2, which are host proteases, while the remaining proteolytic processing steps are mediated by one of two virus-encoded proteases called main protease (Mpro or 3C-like protease (3CLpro)) and papain-like protease PLpro. Mpro plays an important role in the maturation of viral proteins required for RNA replication and is a suitable target for the development of direct-acting antiviral drugs that can inhibit SARS-CoV-2 infection. The Mpro enzyme of SARS-CoV-2 is approximately 96% similar to that of SARS-CoV.

[0008] Considering the ongoing spread of SARS-CoV-2, which is causing the COVID-19 pandemic worldwide, it is desirable to have a new method for inhibiting the replication of the SARS-CoV-2 virus and treating COVID-19 in patients.

[0009] (Summary) Generally, the present invention relates to a compound of formula (A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, or tautomer thereof, wherein, C is a heterocyclic ring selected from the following: [Chemical formula] m is an integer selected from 0, 1, 2; A is selected from CR 4 and N; B is selected from CR 6 and N; [Chemical formula] bond JPEG2025520539000005.jpg2142 is selected from a single bond and a double bond; p is an integer selected from 0, 1, and; E is selected from C(O) and N; provided that when the bond JPEG2025520539000006.jpg2142 is a single bond, p is 1 and E is C(O), and when the bond JPEG2025520539000007.jpg2142 is a double bond, p is 0 and E is N; m is an integer selected from 0, 1, 2; [Chemical formula] each bond JPEG2025520539000009.jpg2542 and JPEG2025520539000010.jpg2642 is a single bond or a double bond; When 2642 is a double bond, each bond JPEG2025520539000012.jpg2542 is a single bond; When 2642 is a single bond, each bond JPEG2025520539000014.jpg2542 is independently selected from a single bond or a double bond; each p is an integer independently selected from 0 and 1; provided that JPEG2025520539000015.jpgwhen 2542 is a single bond, p is 1, JPEG2025520539000016.jpgwhen 2542 is a double bond, p is 0; k is an integer selected from 0 and 1; provided that the bond

Chemical formula

Chemical formula

Chemical formula

[0010] A first aspect of the invention relates to a compound of formula (II):

Chemical formula

[0011] A second aspect of the invention relates to a compound of formula (III): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, or tautomer thereof, wherein the bond JPEG2025520539000024.jpg2142 is selected from a single bond and a double bond; p is an integer selected from 0, 1; E is selected from C(O) and N; provided that when the bond JPEG2025520539000025.jpg2142 is a single bond, p is 1 and E is C(O), and when the bond JPEG2025520539000026.jpg2142 is a double bond, p is 0 and E is N; R N is selected from H, C1-C6 alkyl, cycloalkyl; R 1 is hydrogen, halogen, -OH, -CN, -NO2, -NR 14 R 15, selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 ; R 4 is hydrogen, halogen, -OH, -CN, -NO2, -NR 14 R 15 , selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 ; alternatively, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted with one or more R 16 ; R 7 , R 8 , R 9 and R 10 are each independently selected from H, C1-C6 alkyl, cycloalkyl; alternatively, R 8 and R 9 together with the atoms to which they are attached and any intervening atoms form a cycloalkyl optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; alternatively, R 9 and R 10 together with the atoms to which they are attached and any intervening atoms form a cycloalkyl optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; R 11 、R 12 、R 13 are each independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R 15 are each independently selected from H, C1-C6 alkyl; alternatively, R 14 and R 15 together with the atoms to which they are attached and any intervening atoms form a heterocyclyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl; R 16 is independently selected from halogen, -OH, -OH, -CN, -NO2, -NR 14 R 15 、C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C(O)OR 14 、-C(O)N-NR 14 R 15 、cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl; X is selected from hydrogen, halogen, OH, CN, NO2, CONH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and the alkyl is optionally substituted with cycloalkyl, heterocyclyl, aryl, and heteroaryl; Y is selected from C1-C6 alkyl-S(O) u -, C1-C6 alkyl-C(O)-, heteroaryl-C(O)-, and the alkyl or heteroaryl is optionally substituted with one or more halogens, -OH, -CN; m is an integer selected from 0, 1, 2; n is an integer selected from 0, 1, 2; u is an integer selected from 0, 1, 2; A cycloalkyl is a monocyclic or polycyclic saturated carbon ring containing 3 to 18 carbon atoms; An aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; A heterocyclyl is a saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused ring, bridged ring, or spiro ring), or 11- to 14-membered tricyclic ring system (fused ring, bridged ring, or spiro ring) having one or more heteroatoms selected from O, N, S, P, Se, or B; A heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, and having the remaining ring atoms as C.

[0012] A third aspect of the present invention relates to a compound of formula (IV):

Chemical formula

Chemical formula

Chemical formula

[0013] The fourth aspect of the present invention is a compound of formula (V):

Chemical formula

[0014] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can further comprise an excipient, a diluent, or a surfactant.

[0015] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can further comprise an excipient, a diluent, or a surfactant.

[0016] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can further comprise an excipient, a diluent, or a surfactant.

[0017] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can further comprise an excipient, a diluent, or a surfactant.

[0018] Another aspect of the present invention relates to a method for treating a coronavirus infection such as COVID-19. The method comprises administering to a patient in need of treatment for a coronavirus infection such as COVID-19 an effective amount of a compound of formula (II), formula (III), formula (IV), formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0019] Another aspect of the present invention relates to a method for inhibiting or preventing the replication of the SARS-CoV-2 virus. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (II), formula (III), formula (IV), formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0020] Another aspect of the present invention relates to a compound of formula (II), formula (III), formula (IV), formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for use in the manufacture of a medicament for inhibiting or preventing the replication of the SARS-CoV-2 virus.

[0021] Another aspect of the present invention relates to the use of a compound of formula (II), formula (III), formula (IV), formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof in the treatment of a disease or disorder associated with SARS-CoV-2 virus infection.

[0022] Another aspect of the present invention relates to a compound of formula (II), formula (III), formula (IV), formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for use in the manufacture of a medicament for treating or preventing a viral infection disclosed herein.

[0023] Another aspect of the present invention relates to a method of treating or preventing a coronavirus infection such as COVID-19 in a subject in need thereof. The method comprises administering to a patient in need of treatment an effective amount of a compound of formula (II), or a compound of formula (III), or a compound of formula (IV), or a compound of formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0024] Another aspect of the present invention relates to the use of a compound of formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof in the treatment of a coronavirus infection.

[0025] Another aspect of the present invention relates to the use of a compound of formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof in the treatment of a coronavirus infection.

[0026] Another aspect of the present invention relates to the use of a compound of formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof in the treatment of a coronavirus infection.

[0027] Another aspect of the present invention relates to the use of a compound of formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer thereof, or a pharmaceutical composition, in the treatment of coronavirus infection.

[0028] Another aspect of the present invention relates to the use of a compound of formula (II)-(V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer thereof, or a pharmaceutical composition, in the treatment of coronavirus infection.

[0029] The present invention further provides a method for treating coronavirus infection, which comprises administering to a patient suffering from coronavirus infection a compound of formula (II)-(V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer thereof, or a pharmaceutical composition.

[0030] The present invention provides an inhibitor of viral replication activity, which is a therapeutic agent in the treatment of coronavirus infection.

[0031] The present invention provides an inhibitor of SARS-CoV-2-related 3C-like protease, which is a therapeutic agent in the treatment of coronavirus infection.

[0032] The present invention provides an inhibitor of SARS-CoV-2-related Mpro protease, which is a therapeutic agent in the treatment of coronavirus infection.

[0033] The present invention further provides compounds and compositions having an improved efficacy and safety profile compared to known SARS-CoV-2-related 3C-like protease inhibitors.

[0034] The present invention further provides a method for treating a disease or disorder related to coronavirus infection, which comprises administering to a patient suffering from coronavirus infection a compound of formula (II)-(V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0035] The present invention provides a SARS-CoV-2 related 3C-like protease inhibitor which is a therapeutic agent for the treatment of coronavirus infection.

[0036] The present invention provides a SARS-CoV-2 related Mpro protease inhibitor which is a therapeutic agent for the treatment of coronavirus infection.

[0037] The present invention further provides compounds and compositions having an improved efficacy and safety profile compared to known SARS-CoV-2 related 3C-like protease inhibitors. The present invention also provides agents having a novel mechanism of action against SARS-CoV-2 related 3C-like protease in the treatment of coronavirus infection.

[0038] The present invention further provides compounds and compositions having an improved efficacy and safety profile compared to known SARS-CoV-2 related Mpro protease inhibitors. The present disclosure also provides agents having a novel mechanism of action against SARS-CoV-2 related Mpro protease in the treatment of coronavirus infection.

[0039] The present invention further provides a method for preventing, treating, or ameliorating coronavirus infection.

[0040] The present invention further provides a method for treating a disease, disorder, or symptom selected from the group consisting of cold; pneumonia (direct viral pneumonia or secondary bacterial pneumonia); bronchitis (direct viral bronchitis or secondary bacterial bronchitis); severe acute respiratory syndrome (SARS); Middle East respiratory syndrome (MERS); coronavirus disease 2019 (COVID-19); and coronavirus HuPn-2018, the method comprising administering to a patient suffering from at least one of the diseases or disorders a compound of formula (II)-(V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0041] In some embodiments, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound described herein (e.g., a method comprising one or more steps described in the general procedures).

[0042] In some embodiments, the present disclosure provides an intermediate described herein that is suitable for use in a method for preparing a compound described herein (e.g., the intermediate is selected from the intermediates described in Preparation Parts - P1 to P65).

[0043] In some embodiments, the present disclosure provides a method for preparing a compound of the present disclosure.

[0044] In some embodiments, the present disclosure provides a method for preparing a compound of the present disclosure, the method comprising one or more steps described herein.

[0045] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In this specification, unless the context clearly dictates otherwise, the singular forms also include the plural forms. Methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, but the appropriate methods and materials are described below. All publications, patent applications, patents, and other references mentioned in this specification are incorporated by reference. The references cited in this specification are not admitted to be prior art to the claimed invention. In case of conflict, the specification, including definitions, will control. Further, the materials, methods, and examples are illustrative only and not intended to be limiting. In case of conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

[0046] Other features and advantages of the present disclosure will become apparent from the following detailed description and the claims.

Best Mode for Carrying Out the Invention

[0047] (Detailed Description) The present disclosure provides a method for treating, preventing, or alleviating a viral infection associated with a coronavirus by administering a therapeutically effective amount of a compound disclosed herein to a subject in need thereof.

[0048] Details of the present disclosure are set forth in the following accompanying description. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods and materials are described herein. Other features, objects, and advantages of the present disclosure will become apparent from the specification and the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference in their entirety. Definitions

[0049] The articles "a" and "an" are used in the present disclosure to refer to one or more (i.e., at least one) of the grammatical objects of the article. By way of example, "an element" means one element or a plurality of elements.

[0050] In the present disclosure, the term "and / or" means either "and" or "or" unless otherwise specified.

[0051] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but need not) be bonded to another substituent (e.g., a heteroatom). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have one or more substituents different from hydrogen. For example, at any point along the chain, it can be bonded to a halogen atom, a hydroxyl group, or another substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the possibility of containing other functional groups, but does not necessarily have any additional functional groups. Suitable substituents for any substitution of the described groups include, but are not limited to, halogen, oxo, -OH, -CN, -NH2, -NO2, -COOH, -CH2CN, -O-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and -S(O)N((C1-C6)alkyl)2. Substituents can themselves be optionally substituted. As used herein, "optionally substituted" means substituted or unsubstituted, and its meaning is described below.

[0052] As used herein, the term "substituted" means that a particular group or moiety has one or more suitable substituents, and the substituents may be linked to the particular group or moiety at one or more positions. For example, an aryl substituted with cycloalkyl indicates whether the cycloalkyl is linked by bonding to one atom of the aryl or by condensing with the aryl to share two or more common atoms.

[0053] As used herein, the term "unsubstituted" means that a particular group has no substituents.

[0054] Unless otherwise defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When two aromatic rings (such as bicyclic) are included, the aromatic rings of the aryl group can be bonded at one point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group can be optionally substituted at any bonding point by one or more substituents, for example, 1 to 5 substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C1-C6)alkyl, (C1-C6)alkyl, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), N((C1-C6)alkyl)2, -S(O)2-(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and -S(O)N((C1-C6)alkyl)2. The substituents can be optionally substituted themselves. Further, when two fused rings are included, the aryl group as defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring. Examples of the ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, etc.

[0055] Unless otherwise defined, "heteroaryl" means a monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C. The polycyclic aromatic radical contains two or more fused rings and can further contain two or more spiro-fused rings, such as bicyclic, tricyclic, tetracyclic, etc. Unless otherwise specified, "fused" means two rings sharing two ring atoms. Unless otherwise specified, "spiro-fused" means two rings sharing one ring atom. Heteroaryl as defined herein also means a bicyclic heteroaromatic group where the heteroatom is selected from N, O, S, P, or B. Heteroaryl as defined herein also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl as defined herein also means a tetracyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. The aromatic radical may be independently substituted with one or more of the substituents described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]Pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b] including, but not limited to, pyrrolyl, 3H-indolyl, and derivatives thereof. Further, when containing two or more fused rings, the heteroaryl group as defined herein may have one or more saturated or partially unsaturated rings fused to one or more fully unsaturated aromatic rings. In a heteroaryl ring system containing more than two fused rings, the saturated or partially unsaturated ring may be further fused to the saturated or partially unsaturated ring described herein. Further, when containing three or more fused rings, the heteroaryl group as defined herein may spiro-fuse one or more saturated or partially unsaturated rings. Any saturated or partially unsaturated ring described herein is optionally substituted with one or more oxo. Exemplary ring systems of these heteroaryl groups are, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxyindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidine, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, or benzo[c][1,2]oxaborol-1(3H)-onyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-onyl, or 6a’,7’-dihydro-6’H,9’H-spiro[cyclopropane-1,8’-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-9’-onyl.

[0056] Halogen or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0057] "Alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon containing 1 to 12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0058] "Alkoxy" refers to a straight-chain or branched-chain saturated hydrocarbon containing 1 to 12 carbon atoms with a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy group, ethoxy group, propoxy group, butoxy group, tert-butoxy group, or pentyloxy group.

[0059] "Alkenyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. The "alkenyl" group contains at least one double bond in the chain. The double bond of the alkenyl group may be non-conjugated or conjugated with another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. The alkenyl group may be unsubstituted or substituted. The alkenyl defined herein may be straight-chain or branched.

[0060] "Alkynyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. The "alkynyl" group contains at least one triple bond in the chain. Examples of alkynyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl or hexynyl. The alkynyl group may be unsubstituted or substituted.

[0061] The term "alkylene" or "alkylenyl" refers to a divalent alkyl radical. Any of the above monovalent alkyl groups can be alkylene by extraction of a second hydrogen atom from the alkyl. As defined herein, alkylene can be C1-C6 alkylene. Alkylene can further be C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-.

[0062] "Cycloalkyl" means a monocyclic or polycyclic saturated carbon ring containing 3 to 18 carbon atoms. The polycyclic cycloalkyl may be a fused bicyclic cycloalkyl, a bridged bicyclic cycloalkyl, or a spiro fused bicyclic cycloalkyl. The polycyclic cycloalkyl contains at least one non-aromatic ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norbornenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, spiro[3.5]nonyl, spiro[5.5]undecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

[0063] "Heterocyclyl", "heterocyclic", or "heterocycloalkyl" containing 3 - 24 atoms including carbon and one or more heteroatoms selected from N, O, S, P, or B is monocyclic or polycyclic, where the ring is not aromatic. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents may themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S - oxide, thiomorpholinyl S - dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.

[0064] The term "aromatic" means a planar ring having 4n + 2 electrons in a conjugated system. As used herein, "conjugated system" means a system in which p - orbitals having delocalized electrons are connected, and this system can include lone electron pairs.

[0065] The term "haloalkyl" as used herein refers to an alkyl group as defined herein that is substituted by one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0066] The term "haloalkoxy" as used herein refers to an alkoxy group as defined herein that is substituted by one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0067] As used herein, the term "cyano" means a substituent having a carbon atom bonded to a nitrogen atom by a triple bond, i.e., C≡N.

[0068] "Spirocycloalkyl" or "spirocyclic" means a bicyclic carbon-based ring system in which the two rings are linked through a single atom. The rings may be of different sizes and nature, or of the same size and nature. Examples include spiropentane, spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, spirodecane. One or both of the spiro rings may be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more carbon atoms in the spiro ring may be substituted with a heteroatom (e.g., O, N, S, or P). (C3-C 12 ) Spirocycloalkyl is a spiro ring containing from 3 to 12 carbon atoms. One or more carbon atoms may be substituted with a heteroatom.

[0069] The terms "spiroheterocycloalkyl", "spiroheterocyclic" or "spiroheterocyclic" are understood to mean a spiro ring in which at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl or piperidinyl).

[0070] The term "solvate" refers to various stoichiometric complexes formed by a solute and a solvent. Such solvents for the purposes of the present disclosure should not be ones that can interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are usually called hydrates. Hydrates include compositions containing a stoichiometric amount of water, as well as compositions containing a variable amount of water.

[0071] The term "isomer" refers to compounds that have the same composition and molecular weight but different physical and / or chemical properties. The structural differences can be in the constitution (geometric isomers) or the ability to rotate the plane of polarization (stereoisomers). With respect to stereoisomers, the compounds of formula (A) may have one or more asymmetric carbon atoms and can occur as racemates, racemic mixtures, and individual enantiomers or diastereomers.

[0072] This disclosure also contemplates isotopically labeled compounds of formula (A) (e.g., 2 labeled with 14 H and 2 C). Deuterium (i.e., 14 H or D) isotopes and carbon-14 (i.e.,

[0073] C) isotopes are particularly preferred in view of ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or decreased required dosage) and thus may be preferred in some circumstances. Isotopically labeled compounds of formula (A) can generally be prepared by following procedures similar to those disclosed in the following schemes and / or examples by replacing the appropriate unlabeled reagent with an appropriately labeled reagent.The present disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compounds and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, basic acetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, theocurate, tosylate, triethiodide, and valerate.

[0074] "Patient" or "subject" is a mammal such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate such as a monkey, chimpanzee, baboon, or macaque.

[0075] "Effective amount", when used in connection with a compound, is an amount effective to treat or prevent a disease in a subject as described herein.

[0076] As used herein, the term "carrier" includes carriers, excipients, and diluents, and refers to a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, composition, or vehicle that is involved in the transport or conveyance of a pharmaceutical from one organ or part of the body to another organ or part of the body.

[0077] As used herein, the term "treating" with respect to a subject refers to ameliorating at least one symptom of a disorder in the subject. Treating includes curing, ameliorating, or at least partially ameliorating the disorder.

[0078] As used herein, the term "disorder" is used to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise specified.

[0079] As used herein, the terms "administer", "administering", or "administration" refer to either directly administering to a subject the disclosed compound or a pharmaceutically acceptable salt or composition of the disclosed compound, or administering to a subject a prodrug derivative or analog of the compound or a pharmaceutically acceptable salt or composition of the compound, which can form an equivalent amount of the active compound in the subject's body.

[0080] As used herein, the term "prodrug" refers to a compound that is convertible in vivo to the disclosed compound by metabolic means (e.g., hydrolysis).

[0081] The term "salt" means a pharmaceutically acceptable salt.

[0082] The term "pharmaceutically acceptable salt" also refers to salts of the compositions of the present disclosure having acidic functional groups such as carboxylic acid functional groups and bases.

[0083] As used herein, the term "SARS-CoV-2 related 3C-like protease inhibitor" refers to a compound of formula (II), formula (III), formula (IV), or formula (V) that inhibits SARS-CoV-2 related 3C-like protease, and / or a composition comprising a compound of formula (II), formula (III), formula (IV), or formula (V).

[0084] As used herein, the term "SARS-CoV-2 virus replication inhibitor" refers to a compound of formula (II), formula (III), formula (IV), or formula (V) that inhibits the replication of SARS-CoV-2 virus and / or a composition comprising a compound of formula (II), formula (III), formula (IV), or formula (V).

[0085] The term "SARS-CoV-2 inhibitor" means a SARS-CoV-2 related coronavirus 3C-like protease inhibitor compound described herein, or a pharmaceutically acceptable salt, hydrate, prodrug, active metabolite, or solvate thereof, or a compound that inhibits the replication of SARS-CoV-2 in some way.

[0086] The amount of the compound of the composition described herein required to achieve a therapeutic effect can be determined empirically according to conventional procedures for a particular purpose. Generally, when administering a therapeutic agent (e.g., a compound or composition of formula (II), formula (III), formula (IV), or formula (V) described herein (and / or an additional agent)) for a therapeutic purpose, the therapeutic agent is administered at a pharmacologically effective dose.

[0087] "Pharmacologically effective amount", "pharmacologically effective dosage", "therapeutically effective amount", or "effective amount" means an amount sufficient to produce a desired physiological effect, or an amount capable of achieving a desired result, particularly for treating coronavirus infections. The effective amount as used herein includes, for example, an amount sufficient to delay the onset of symptoms of a disorder or disease, alter the course of symptoms of a disorder or disease (e.g., slow the progression of the symptoms of the disease), reduce or eliminate one or more symptoms or signs of a disorder or disease, and reverse the symptoms of a disorder or disease. Therapeutic benefit also includes arresting or slowing the progression of the underlying disease or disorder, whether or not improvement is obtained. The compounds of the present disclosure

[0088] In one aspect, the present disclosure provides compounds of formula (II) and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotope derivatives, and tautomers thereof.

Chemical formula

[0089] For the compounds of formula (II), R N , R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , A, B, X, Y, m, and n can each be selected from the groups described herein, where applicable, and R N , R 1, R 2 , R 3 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , for any one of A, B, X, Y, m and n, any group described herein, if applicable, is R N , R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , it is understood that it can be combined with any group described herein for one or more of the remaining A, B, X, Y, m and n.

[0090] In some embodiments, A is selected from CR 4 and N; B is selected from CR 6 and N; R N is selected from H, C1-C6 alkyl, cycloalkyl; R 1 is hydrogen, halogen, -OH, -CN, -NO2, -NR 14 R 15 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 ; R 2 is hydrogen, halogen, -OH, -CN, -NO2, -NR 14 R 15, selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 ; alternatively, R 1 and R 2 are both oxo; R 3 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 ; R 4 is selected from hydrogen, halogen, -OH, -CN, -NO2, -NR 14 R 15 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 ; alternatively, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted with one or more R 16 ; alternatively, R 3 and R 4 are both oxo; R 6 is selected from H, C1-C6 alkyl, cycloalkyl, halogen, -CN, -OH; R 7 、R 8 、R 9 and R 10 are each independently selected from H, C1-C6 alkyl, cycloalkyl; alternatively R 8 and R 9 together with the atoms to which they are attached and any intervening atoms form a cycloalkyl optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; alternatively R 9 and R 10 together with the atoms to which they are attached and any intervening atoms form a cycloalkyl optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; R 11 、R 12 、R 13 are each independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R 15 are each independently selected from H, C1-C6 alkyl; alternatively R 14 and R 15 together with the atoms to which they are attached and any intervening atoms form a heterocyclyl optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; R 16 is independently selected from halogen, -OH, -OH, -CN, -NO2, -NR 14 R 15 、C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C(O)OR 14 、-C(O)N-NR 14 R 15 、cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl; X is selected from hydrogen, halogen, OH, CN, NO2, CONH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and the alkyl is optionally substituted with cycloalkyl, heterocyclyl, aryl, and heteroaryl; Y is C1-C6 alkyl-S(O) u -, C1-C6 alkyl-C(O)-, heteroaryl-C(O)-, and the alkyl or heteroaryl is optionally substituted with one or more halogens, -OH, -CN; m is an integer selected from 0, 1, 2; n is an integer selected from 0, 1, 2; u is an integer selected from 0, 1, 2.

[0091] In some embodiments, A is CR 4 is.

[0092] In some embodiments, A is CH.

[0093] In some embodiments, A is CCH3.

[0094] In some embodiments, A is N.

[0095] In some embodiments, B is CR 6 is.

[0096] In some embodiments, B is CH.

[0097] In some embodiments, B is N.

[0098] In some embodiments, R N is selected from H, C1-C6 alkyl, cycloalkyl.

[0099] In some embodiments, RN is H.

[0100] In some embodiments, R N is C1-C6 alkyl.

[0101] In some embodiments, R N is methyl.

[0102] In some embodiments, R N is ethyl.

[0103] In some embodiments, R N is cycloalkyl.

[0104] In some embodiments, R N is cyclopropyl.

[0105] In some embodiments, R N is cyclobutyl.

[0106] In some embodiments, R N is cyclopentyl.

[0107] In some embodiments, R N is cyclohexyl.

[0108] In some embodiments, R 1 is hydrogen, halogen, -OH, -CN, -NO2, -NR 14 R 15 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 .

[0109] In some embodiments, R 1 is hydrogen.

[0110] In some embodiments, R 1 is deuterium.

[0111] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, and the cycloalkyl, aryl, heterocycle or heteroaryl is optionally substituted with one or more R 16 .

[0112] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl, which is optionally substituted with one or more R 16 .

[0113] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 6-membered unsubstituted aryl.

[0114] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl, which is substituted with one or more halogens.

[0115] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl, which is substituted with one or more F.

[0116] In some embodiments, R 1 and R 4Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one F.

[0117] In some embodiments, R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one or more Cls.

[0118] In some embodiments, R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one Cl.

[0119] In some embodiments, R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is optionally substituted with one or more C1-C6 alkyls.

[0120] In some embodiments, R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one or more methyls.

[0121] In some embodiments, R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one methyl.

[0122] In some embodiments, R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is optionally substituted with one or more C1-C6 alkoxys.

[0123] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl which is substituted with one or more methoxys.

[0124] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl which is substituted with one methoxy.

[0125] In some embodiments, R 2 is selected from hydrogen, halogen, -OH, -CN, -NO2, -NR 14 R 15 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 .

[0126] In some embodiments, R 2 is H.

[0127] In some embodiments, R 2 and R 3 form a double bond together.

[0128] In some embodiments, R 3 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 .

[0129] In some embodiments, R 3and R 2 together form a double bond.

[0130] In some embodiments, R 3 is H.

[0131] In some embodiments, R 4 is selected from hydrogen, halogen, -OH, -CN, -NO2, -NR 13 R 14 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 .

[0132] In some embodiments, R 4 is H.

[0133] In some embodiments, R 4 and R 1 , together with the atoms to which they are attached and any intervening atoms, form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted with one or more R 16 .

[0134] In some embodiments, R 4 and R 1 , together with the atoms to which they are attached and any intervening atoms, form a 6-membered aryl, which is optionally substituted with one or more R 16 .

[0135] In some embodiments, R 4 and R 1 , together with the atoms to which they are attached and any intervening atoms, form an unsubstituted 6-membered aryl.

[0136] In some embodiments, R 4 and R 1 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl which is substituted with one or more halogens.

[0137] In some embodiments, R 4 and R 1 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl which is substituted with one or more Fs.

[0138] In some embodiments, R 4 and R 1 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl which is substituted with one F.

[0139] In some embodiments, R 4 and R 1 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl which is substituted with one or more Cls.

[0140] In some embodiments, R 4 and R 1 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl which is substituted with one Cl.

[0141] In some embodiments, R 4 and R 1 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl which is optionally substituted with one or more C1-C6 alkyls.

[0142] In some embodiments, R 4 and R 1Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one or more methyls.

[0143] In some embodiments, R 4 and R 1 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one methyl.

[0144] In some embodiments, R 4 and R 1 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is optionally substituted with one or more C1-C6 alkoxys.

[0145] In some embodiments, R 4 and R 1 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one or more methoxys.

[0146] In some embodiments, R 4 and R 1 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one methoxy.

[0147] In some embodiments, m is an integer selected from 0, 1, 2.

[0148] In some embodiments, m is 0.

[0149] In some embodiments, m is 1.

[0150] In some embodiments, m is 2.

[0151] In some embodiments, n is an integer selected from 0, 1, 2.

[0152] In some embodiments, n is 2.

[0153] In some embodiments, n is 1.

[0154] In some embodiments, n is 0.

[0155] In some embodiments, R 7 , R 8 , R 9 and R 10 are each independently selected from H, C1-C6 alkyl.

[0156] In some embodiments, R 8 and R 9 together with the atom to which they are attached and any intervening atoms form a cycloalkyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0157] In some embodiments, R 8 and R 9 together with the atom to which they are attached and any intervening atoms form a cyclopropane ring optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0158] In some embodiments, R 9 and R 10 together with the atom to which they are attached and any intervening atoms form a cycloalkyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0159] In some embodiments, R 7 and R 8 are each H, and R 9 and R 10 are each C1-C6 alkyl.

[0160] In some embodiments, R7 and R 8 are each H, and R 9 and R 10 are each CH3.

[0161] In some embodiments, n is 2, and R 7 and R 8 are each H, and R 9 and R 10 are each C1-C6 alkyl.

[0162] In some embodiments, n is 2, and R 7 and R 8 are each H, and R 9 and R 10 are each CH3.

[0163] In some embodiments, n is 2, and R 9 and R 10 together with the atoms to which they are attached and any intervening atoms form one or more halogens, -OH, -CN, a cycloalkyl optionally substituted with C1-C6 alkyl.

[0164] In some embodiments, n is 2, and R 9 and R 10 together with the atoms to which they are attached and any intervening atoms form one or more halogens, -OH, -CN, a cyclopropane ring optionally substituted with C1-C6 alkyl.

[0165] In some embodiments, n is 1, and R 8 and R 9 together with the atoms to which they are attached and any intervening atoms form one or more halogens, -OH, -CN, a cycloalkyl optionally substituted with C1-C6 alkyl.

[0166] In some embodiments, n is 1, and R 8 and R 9Together with the atoms to which they are attached and any intervening atoms, they form a cyclopropane ring optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0167] In some embodiments, n is 1, and R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, they form a cyclopropane ring optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0168] In some embodiments, n is 1, and R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, they form a cyclopropane ring optionally substituted with one or more C1-C6 alkyl.

[0169] In some embodiments, n is 1, and R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, they form a cyclopropane ring optionally substituted with two C1-C6 alkyl.

[0170] In some embodiments, n is 1, and R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, they form a cyclopropane ring optionally geminally substituted with two C1-C6 alkyl.

[0171] In some embodiments, n is 1, and R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, they form a cyclopropane ring optionally geminally substituted with two methyls.

[0172] In some embodiments, R 11 , R12 , R 13 is independently selected from H, C1-C6 alkyl, cycloalkyl, halogen, -CN respectively.

[0173] In some embodiments, R 11 , R 12 , R 13 are each C1-C6 alkyl.

[0174] In some embodiments, R 11 , R 12 , R 13 are each methyl.

[0175] In some embodiments, R 11 , R 12 , R 13 are each halogen.

[0176] In some embodiments, R 11 , R 12 , R 13 are each F.

[0177] In some embodiments, R 11 is methyl, and R 12 and R 13 are each F.

[0178] In some embodiments, R 14 and R 15 are independently selected from H, C1-C6 alkyl respectively.

[0179] In some embodiments, R 14 and R 15 are each H.

[0180] In some embodiments, R 14 and R 15 are each methyl.

[0181] In some embodiments, R 14 and R 15Together with the atoms to which they are attached and any intervening atoms, they form a heterocyclyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0182] In some embodiments, R 16 is independently selected from halogen, -OH, -OH, -CN, -NO2, -NR 13 R 14 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C(O)OR 13 , -C(O)N-NR 13 R 14 , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl.

[0183] In some embodiments, X is selected from hydrogen, halogen, OH, CN, NO2, CONR 13 R 14 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl is optionally substituted with cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0184] In some embodiments, X is -CN.

[0185] In some embodiments, X is CONR 13 R 14 .

[0186] In some embodiments, X is CONH2.

[0187] In some embodiments, X is selected from C1-C6 alkyl optionally substituted with cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0188] In some embodiments, X is selected from C1-C6 alkyl substituted with heterocyclyl.

[0189] In some embodiments, X is

Chemical formula

[0190] In some embodiments, X is

Chemical formula

[0191] In some embodiments, Y is C1-C6 alkyl-S(O) u -, C1-C6 alkyl-C(O)-, heteroaryl-C(O)-, and the alkyl or heteroaryl is optionally substituted with one or more halogens, -OH, -CN.

[0192] In some embodiments, u is an integer selected from 0, 1, 2.

[0193] In some embodiments, u is 0.

[0194] In some embodiments, u is 1.

[0195] In some embodiments, u is 2.

[0196] In some embodiments, Y is CF3C(O)-.

[0197] In some embodiments, Y is CH3S(O)2-.

[0198] In some embodiments, Y is CF3S(O)2-.

[0199] In some embodiments, Y is CF3CH2S(O)2-.

[0200] In some embodiments, Y is

Chemical formula

[0201] In another aspect, the present disclosure provides compounds of formula (III) and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotope derivatives, and tautomers thereof.

Chemical formula

[0202] For the compounds of formula (III), R N , R 1 , R 4 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , E, X, Y, m, n and p can each independently be selected from the groups described herein, where applicable, and for any of R N , R 1 , R 4 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , E, X, Y, m, n and p, any of the groups described herein can, where applicable, be N , R 1 , R 4 , R 7 , R 8, R 9 , R 10 , R 11 , R 12 , R 13 It is understood that it can be combined with any of the groups described herein for one or more of the remaining ones of E, X, Y, m, n, and p.

[0203] In some embodiments, bond JPEG2025520539000046.jpg2142 is selected from single bonds and double bonds; p is an integer selected from 0 and 1; E is selected from C(O) and N; However, when the bond JPEG2025520539000047.jpg2142 is a single bond, p is 1, and when the bond JPEG2025520539000048.jpg2142 is a double bond, p is 0; However, when the bond JPEG2025520539000049.jpg2142 is a double bond, E is N, and when the bond JPEG2025520539000050.jpg2142 is a single bond, E is C(O); R N is selected from H, C1-C6 alkyl, cycloalkyl; R 1 is hydrogen, halogen, -OH, -CN, -NO2, -NR 14 R 15 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 ; R 4 is hydrogen, halogen, -OH, -CN, -NO2, -NR 14 R 15, selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 ; alternatively, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted with one or more R 16 ; R 7 , R 8 , R 9 and R 10 are each independently selected from H, C1-C6 alkyl, cycloalkyl; alternatively, R 8 and R 9 together with the atoms to which they are attached and any intervening atoms form a cycloalkyl optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; alternatively, R 9 and R 10 together with the atoms to which they are attached and any intervening atoms form a cycloalkyl optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; R 11 , R 12 , R 13 are each independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R 15 are each independently selected from H, C1-C6 alkyl; alternatively, R 14 and R 15combine with the atoms to which they are attached and any intervening atoms to form one or more heterocyclyls optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl; R 16 are independently selected from halogen, -OH, -OH, -CN, -NO2, -NR 14 R 15 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C(O)OR 14 , -C(O)N-NR 14 R 15 , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl; X is selected from hydrogen, halogen, OH, CN, NO2, CONH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and the alkyl is optionally substituted with cycloalkyl, heterocyclyl, aryl, and heteroaryl; Y is selected from C1-C6 alkyl-S(O) u -, C1-C6 alkyl-C(O)-, and the alkyl is optionally substituted with one or more halogens, -OH, -CN; m is an integer selected from 0, 1, 2; n is an integer selected from 0, 1, 2; u is an integer selected from 0, 1, 2.

[0204] In some embodiments, the bond JPEG2025520539000051.jpg2142 is a single bond, p is 1, and E is C=O.

[0205] In some embodiments, the bond JPEG2025520539000052.jpg2142 is a double bond, p is 0, and E is N.

[0206] In some embodiments, m is an integer selected from 0, 1, and 2.

[0207] In some embodiments, m is 0.

[0208] In some embodiments, m is 1.

[0209] In some embodiments, m is 2.

[0210] In some embodiments, R N is selected from H, C1-C6 alkyl, and cycloalkyl.

[0211] In some embodiments, R N is selected from H.

[0212] In some embodiments, R N is selected from C1-C6 alkyl.

[0213] In some embodiments, R N is selected from methyl.

[0214] In some embodiments, R N is selected from cycloalkyl.

[0215] In some embodiments, R N is selected from cyclopropyl.

[0216] In some embodiments, R 1 is selected from hydrogen, halogen, -OH, -CN, -NO2, -NR 14 R 15 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 .

[0217] In some embodiments, R 1 is H.

[0218] In some embodiments, R 1 is C1-C6 alkyl.

[0219] In some embodiments, R 1 is methyl.

[0220] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, and the cycloalkyl, aryl, heterocycle or heteroaryl is optionally substituted with one or more R 16 .

[0221] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl, which is optionally substituted with one or more R 16 .

[0222] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 6-membered unsubstituted aryl.

[0223] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl, which is substituted with one or more halogens.

[0224] In some embodiments, R 1 and R 4Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one or more Fs.

[0225] In some embodiments, R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one F.

[0226] In some embodiments, R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one or more Cls.

[0227] In some embodiments, R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one Cl.

[0228] In some embodiments, R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is optionally substituted with one or more C1-C6 alkyls.

[0229] In some embodiments, R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one or more methyls.

[0230] In some embodiments, R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one methyl.

[0231] In some embodiments, R1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl which is optionally substituted with one or more C1-C6 alkoxys.

[0232] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl which is substituted with one or more methoxys.

[0233] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl which is substituted with one methoxy.

[0234] In some embodiments, R 2 is selected from hydrogen, halogen, -OH, -CN, -NO2, -NR 14 R 15 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 .

[0235] In some embodiments, R 4 is selected from hydrogen, halogen, -OH, -CN, -NO2, -NR 14 R 15 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 .

[0236] In some embodiments, R 4 is H.

[0237] In some embodiments, R 4 is C1-C6 alkyl.

[0238] In some embodiments, R 4 is methyl.

[0239] In some embodiments, R 4 and R 1 together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, and the cycloalkyl, aryl, heterocycle or heteroaryl is optionally substituted with one or more R 16 .

[0240] In some embodiments, R 4 and R 1 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl, which is optionally substituted with one or more R 16 .

[0241] In some embodiments, R 4 and R 1 together with the atoms to which they are attached and any intervening atoms form a 6-membered unsubstituted aryl.

[0242] In some embodiments, R 4 and R 1 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl, which is substituted with one or more halogens.

[0243] In some embodiments, R 4 and R 1Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one or more Fs.

[0244] In some embodiments, R 4 and R 1 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one F.

[0245] In some embodiments, R 4 and R 1 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one or more Cls.

[0246] In some embodiments, R 4 and R 1 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one Cl.

[0247] In some embodiments, R 4 and R 1 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is optionally substituted with one or more C1-C6 alkyls.

[0248] In some embodiments, R 4 and R 1 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one or more methyls.

[0249] In some embodiments, R 4 and R 1 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one methyl.

[0250] In some embodiments, R4 and R 1 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl which is optionally substituted with one or more C1-C6 alkoxys.

[0251] In some embodiments, R 4 and R 1 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl which is substituted with one or more methoxys.

[0252] In some embodiments, R 4 and R 1 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl which is substituted with one methoxy.

[0253] In some embodiments, n is an integer selected from 0, 1, 2.

[0254] In some embodiments, n is 2.

[0255] In some embodiments, n is 1.

[0256] In some embodiments, n is 0.

[0257] In some embodiments, R 7 , R 8 , R 9 and R 10 are each independently selected from H, C1-C6 alkyl, cycloalkyl.

[0258] In some embodiments, R 8 and R 9 together with the atoms to which they are attached and any intervening atoms form a cycloalkyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0259] In some embodiments, R 8 and R 9 together with the atoms to which they are attached and any intervening atoms form a cyclopropane ring optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0260] In some embodiments, R 9 and R 10 together with the atoms to which they are attached and any intervening atoms form a cycloalkyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0261] In some embodiments, R 7 and R 8 are each H, and R 9 and R 10 are each C1-C6 alkyl.

[0262] In some embodiments, R 7 and R 8 are each H, and R 9 and R 10 are each CH3.

[0263] In some embodiments, n is 2, and R 7 and R 8 are each H, and R 9 and R 10 are each C1-C6 alkyl.

[0264] In some embodiments, n is 2, and R 7 and R 8 are each H, and R 9 and R 10 are each CH3.

[0265] In some embodiments, n is 2, and R 9 and R 10Together with the atoms to which they are attached and any intervening atoms, they form a cycloalkyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0266] In some embodiments, n is 2, and R 9 and R 10 Together with the atoms to which they are attached and any intervening atoms, form a cyclopropane ring optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0267] In some embodiments, n is 1, and R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, form a cycloalkyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0268] In some embodiments, n is 1, and R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, form a cyclopropane ring optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0269] In some embodiments, n is 1, and R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, form a cyclopropane ring optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0270] In some embodiments, n is 1, and R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, form a cyclopropane ring optionally substituted with one or more C1-C6 alkyl.

[0271] In some embodiments, n is 1, and R 8 and R 9 together with the atoms to which they are attached and any intervening atoms form a cyclopropane ring optionally substituted with two C1-C6 alkyls.

[0272] In some embodiments, n is 1, and R 8 and R 9 together with the atoms to which they are attached and any intervening atoms form a cyclopropane ring optionally geminally substituted with two C1-C6 alkyls.

[0273] In some embodiments, n is 1, and R 8 and R 9 together with the atoms to which they are attached and any intervening atoms form a cyclopropane ring optionally geminally substituted with two methyls.

[0274] In some embodiments, R 11 , R 12 , R 13 are each independently selected from H, C1-C6 alkyl, cycloalkyl, halogen, -CN.

[0275] In some embodiments, R 11 , R 12 , R 13 are each C1-C6 alkyl.

[0276] In some embodiments, R 11 , R 12 , R 13 are each methyl.

[0277] In some embodiments, R 11 , R 12 , R 13 are each halogen.

[0278] In some embodiments, R 11, R 12 , R 13 are each F.

[0279] In some embodiments, R 11 is methyl and R 12 and R 13 are each F.

[0280] In some embodiments, R 14 and R 15 are each independently selected from H, C1-C6 alkyl.

[0281] In some embodiments, R 14 and R 15 are each H.

[0282] In some embodiments, R 14 and R 15 are each methyl.

[0283] In some embodiments, R 14 and R 15 together with the atom to which they are attached and any intervening atoms form a heterocyclyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0284] In some embodiments, R 16 is independently selected from halogen, -OH, -OH, -CN, -NO2, -NR 13 R 14 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C(O)OR 13 , -C(O)N-NR 13 R 14 , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl.

[0285] In some embodiments, X is hydrogen, halogen, OH, CN, NO2, CONR 13 R 14, selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl is optionally substituted with cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0286] In some embodiments, X is -CN.

[0287] In some embodiments, X is CONR 13 R 14 is.

[0288] In some embodiments, X is CONH2.

[0289] In some embodiments, X is selected from C1-C6 alkyl optionally substituted with cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0290] In some embodiments, X is selected from C1-C6 alkyl substituted with heterocyclyl.

[0291] In some embodiments, X is

Chemical formula

[0292] In some embodiments, X is

Chemical formula

[0293] In some embodiments, Y is selected from C1-C6 alkyl-S(O) u -, C1-C6 alkyl-C(O)-, wherein the alkyl is optionally substituted with one or more halogens, -OH, -CN.

[0294] In some embodiments, u is an integer selected from 0, 1, and 2.

[0295] In some embodiments, u is 0.

[0296] In some embodiments, u is 1.

[0297] In some embodiments, u is 2.

[0298] In some embodiments, Y is CF3(O)-.

[0299] In some embodiments, Y is CH3S(O)2-.

[0300] In some embodiments, Y is CF3S(O)2-.

[0301] In some embodiments, Y is CF3CH2S(O)2-.

[0302] In another aspect, the present disclosure provides a compound of formula (IV) and its pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotope derivatives, and tautomers. [Chemical formula] Here, R 5 、R 5’ 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R N 、X, Y, k, n, and p are as described herein.

[0303] For the compound of formula (IV), R 5 、R 5’ 、R 7 、R 8 、R 9 、R 10 、R11 , R 12 , R 13 , R N , X, Y, k, n, and p can each, where applicable, be selected from the groups described herein, and R 5 , R 5’ , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R N , any of the groups described herein for any of X, Y, k, n, and p can, where applicable, be R 5 , R 5’ , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R N , and it is understood that it can be combined with any of the groups described herein for one or more of the remaining X, Y, k, n, and p.

[0304] In some embodiments, bond JPEG2025520539000056.jpg2542 and JPEG2025520539000057.jpg2642 are single or double bonds; bond if JPEG2025520539000058.jpg2642 is a double bond, each bond JPEG2025520539000059.jpg2542 is a single bond, if JPEG2025520539000060.jpg2642 is a single bond, each bond JPEG2025520539000061.jpg2542 is independently selected from single or double bonds; each p is an integer independently selected from 0 and 1; provided that When 2542 is a single bond, p is 1, When 2542 is a double bond, p is 0; k is an integer selected from 0 and 1; However, for the bond When 2542 is a single bond and the bond When 2642 is a single bond, k is 1, and for the bond When 2542 or the bond When 2642 is a double bond, k is 0; R 5 is selected from hydrogen, halogen, -OH, -CN, -NO2, -NR 14 R 15 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C(O)OR 13 , -C(O)N-NR 14 R 15 , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 ; R 5 ' is selected from hydrogen, halogen, -OH, -CN, -NO2, -NR 14 R 15 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C(O)OR 14 , -C(O)N-NR 14 R 15 , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16is optionally replaced; or R 5 and R 5’ form an oxo; R 7 、R 8 、R 9 and R 10 are each independently selected from H, alkyl; or R 8 and R 9 together with the atoms to which they are attached and any intervening atoms form a cycloalkyl optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; or R 9 and R 10 together with the atoms to which they are attached and any intervening atoms form a cycloalkyl optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; R 11 、R 12 、R 13 are each independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R 15 are each independently selected from H, C1-C6 alkyl; or R 14 and R 15 together with the atoms to which they are attached and any intervening atoms form a heterocyclyl optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; R 16 is independently selected from halogen, -OH, -OH, -CN, -NO2, -NR 14 R 15 、C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C(O)OR 14 、-C(O)N-NR 14 R 15 、cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl; each R Nis independently selected from H, C1-C6 alkyl, cycloalkyl; X is selected from hydrogen, halogen, OH, CN, NO2, CONH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and the alkyl is optionally substituted with cycloalkyl, heterocyclyl, aryl, and heteroaryl; Y is C1-C6 alkyl-S(O) u -, C1-C6 alkyl-C(O)-, and the alkyl is optionally substituted with one or more halogens, -OH, -CN; n is an integer selected from 0, 1, 2; u is an integer selected from 0, 1, 2.

[0305] In some embodiments, the bond JPEG2025520539000068.jpg2642 is a double bond, each bond JPEG2025520539000069.jpg2542 is a single bond, k is 0, and each p is 1.

[0306] In some embodiments, the bond JPEG2025520539000070.jpg2642 is a single bond, each bond JPEG2025520539000071.jpg2542 is a double bond, k is 0, and each p is 0.

[0307] In some embodiments, the bond JPEG2025520539000072.jpg2642 is a single bond, each bond JPEG2025520539000073.jpg2542 is a single bond, k is 1, and each p is 1.

[0308] In some embodiments, R 5 is hydrogen, halogen, -OH, -CN, -NO2, -NR14 R 15 、 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C(O)OR 13 、 -C(O)N-NR 14 R 15 、 selected from cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl, and alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 s.

[0309] In some embodiments, R 5 is H.

[0310] In some embodiments, R 5’ is hydrogen, halogen, -OH, -CN, -NO2, -NR 14 R 15 、 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C(O)OR 14 、 -C(O)N-NR 14 R 15 、 selected from cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl, and alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 s.

[0311] In some embodiments, R 5’ is H.

[0312] In some embodiments, R 5 and R 5’ form an oxo.

[0313] In some embodiments, each R N is independently selected from H, C1-C6 alkyl, cycloalkyl.

[0314] In some embodiments, each R N is independently selected from H and C1-C6 alkyl.

[0315] In some embodiments, the compound of formula (IV) is a compound of formula (IV’):

Chemical formula

[0316] In some embodiments, the compound of formula (IV) is a compound of formula (IV’’):

Chemical formula

[0317] In some embodiments, the compound of formula (IV) is a compound of formula (IV’’’):

Chemical formula

[0318] In some embodiments, n is an integer selected from 0, 1, and 2.

[0319] In some embodiments, n is 2.

[0320] In some embodiments, n is 1.

[0321] In some embodiments, n is 0.

[0322] In some embodiments, R 7 , R 8 , R 9 and R 10 are each independently selected from H and C1-C6 alkyl.

[0323] In some embodiments, R 8 and R 9Together with the atoms to which they are attached and any intervening atoms, they form a cycloalkyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0324] In some embodiments, R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, they form a cyclopropane ring optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0325] In some embodiments, R 9 and R 10 Together with the atoms to which they are attached and any intervening atoms, they form a cycloalkyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0326] In some embodiments, R 7 and R 8 are each H, and R 9 and R 10 are each C1-C6 alkyl.

[0327] In some embodiments, R 7 and R 8 are each H, and R 9 and R 10 are each CH3.

[0328] In some embodiments, n is 2, and R 7 and R 8 are each H, and R 9 and R 10 are each C1-C6 alkyl.

[0329] In some embodiments, n is 2, and R 7 and R 8 are each H, and R 9 and R 10 are each CH3.

[0330] In some embodiments, n is 2, and R 9 and R 10 together with the atoms to which they are attached and any intervening atoms form a cycloalkyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0331] In some embodiments, n is 2, and R 9 and R 10 together with the atoms to which they are attached and any intervening atoms form a cyclopropane ring optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0332] In some embodiments, n is 1, and R 8 and R 9 together with the atoms to which they are attached and any intervening atoms form a cycloalkyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0333] In some embodiments, n is 1, and R 8 and R 9 together with the atoms to which they are attached and any intervening atoms form a cyclopropane ring optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0334] In some embodiments, n is 1, and R 8 and R 9 together with the atoms to which they are attached and any intervening atoms form a cyclopropane ring optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0335] In some embodiments, n is 1, and R 8 and R 9Together with the atoms to which they are attached and any intervening atoms, they form a cyclopropane ring optionally substituted with one or more C1-C6 alkyls.

[0336] In some embodiments, n is 1, and R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, they form a cyclopropane ring optionally substituted with two C1-C6 alkyls.

[0337] In some embodiments, n is 1, and R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, they form a cyclopropane ring optionally geminally substituted with two C1-C6 alkyls.

[0338] In some embodiments, n is 1, and R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, they form a cyclopropane ring optionally geminally substituted with two methyls.

[0339] In some embodiments, R 11 , R 12 , R 13 are each independently selected from H, C1-C6 alkyl, cycloalkyl, halogen, -CN.

[0340] In some embodiments, R 11 , R 12 , R 13 are each C1-C6 alkyl.

[0341] In some embodiments, R 11 , R 12 , R 13 are each methyl.

[0342] In some embodiments, R11 , R 12 , R 13 Each of them is a halogen.

[0343] In some embodiments, R 11 , R 12 , R 13 Each is F.

[0344] In some embodiments, R 11 is methyl, and R 12 and R 13 Each is F.

[0345] In some embodiments, R 14 and R 15 Each is independently selected from H, C1-C6 alkyl.

[0346] In some embodiments, R 14 and R 15 Each is H.

[0347] In some embodiments, R 14 and R 15 Each is methyl.

[0348] In some embodiments, R 14 and R 15 Together with the atom to which they are attached and any intervening atoms, form a heterocyclyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0349] In some embodiments, R 16 is independently halogen, -OH, -OH, -CN, -NO2, -NR 13 R 14 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C(O)OR 13 , -C(O)N-NR 13 R 14selected from cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl.

[0350] In some embodiments, X is hydrogen, halogen, OH, CN, NO2, CONR 13 R 14 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and the alkyl is optionally substituted with cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0351] In some embodiments, X is -CN.

[0352] In some embodiments, X is CONR 13 R 14 .

[0353] In some embodiments, X is CONH2.

[0354] In some embodiments, X is selected from C1-C6 alkyl optionally substituted with cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0355] In some embodiments, X is selected from C1-C6 alkyl substituted with heterocyclyl.

[0356] In some embodiments, X is [Chemical formula] .

[0357] In some embodiments, X is [Chemical formula] .

[0358] In some embodiments, Y is selected from C1-C6 alkyl-S(O) u -, C1-C6 alkyl-C(O)-, wherein the alkyl is optionally substituted with one or more halogens, -OH, -CN.

[0359] In some embodiments, u is an integer selected from 0, 1, 2.

[0360] In some embodiments, u is 0.

[0361] In some embodiments, u is 1.

[0362] In some embodiments, u is 2.

[0363] In some embodiments, Y is CF3(O)-.

[0364] In some embodiments, Y is CH3S(O)2-.

[0365] In some embodiments, Y is CF3S(O)2-.

[0366] In some embodiments, Y is CF3CH2S(O)2-.

[0367] In another aspect, the present disclosure provides compounds of formula (V) and their pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotope derivatives, and tautomers.

Chemical formula

[0368] For the compound of formula (V), R 1 , R 4 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , X, Y, and n can each, when applicable, be selected from the groups described herein, and R 1 , R 4 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , for any one of X, Y, and n, any group described herein can, when applicable, be combined with R 1 , R 4 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , X, Y, and the remaining one or more of n can be combined with any group described herein, it is understood.

[0369] In some embodiments, R 1 is selected from hydrogen, halogen, -OH, -CN, -NO2, -NR 14 R 15 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 ; R 4 is selected from hydrogen, halogen, -OH, -CN, -NO2, -NR 13 R 14, selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 ; alternatively, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, and the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted with one or more R 16 ; R 7 , R 8 , R 9 and R 10 are each independently selected from H, alkyl; alternatively, R 8 and R 9 together with the atoms to which they are attached and any intervening atoms form a cycloalkyl optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; alternatively, R 9 and R 10 together with the atoms to which they are attached and any intervening atoms form a cycloalkyl optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; R 11 , R 12 , R 13 are each independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R 15 are each independently selected from H, C1-C6 alkyl; alternatively, R 14 and R 15combine with the atoms to which they are attached and any intervening atoms to form a heterocyclyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl; R 16 are independently selected from halogen, -OH, -OH, -CN, -NO2, -NR 13 R 14 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C(O)OR 13 , -C(O)N-NR 13 R 14 , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl; X is selected from hydrogen, halogen, OH, CN, NO2, CONH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl is optionally substituted with cycloalkyl, heterocyclyl, aryl, and heteroaryl; Y is selected from C1-C6 alkyl-S(O) u -, C1-C6 alkyl-C(O)-, wherein the alkyl is optionally substituted with one or more halogens, -OH, -CN; n is an integer selected from 0, 1, 2; u is an integer selected from 0, 1, 2.

[0370] In some embodiments, R 1 is selected from hydrogen, halogen, -OH, -CN, -NO2, -NR 14 R 15 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 .

[0371] In some embodiments, R 1 is H.

[0372] In some embodiments, R 1 is C1-C6 alkyl.

[0373] In some embodiments, R 1 is methyl.

[0374] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, and the cycloalkyl, aryl, heterocycle or heteroaryl is optionally substituted with one or more R 16 .

[0375] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl, which is optionally substituted with one or more R 16 .

[0376] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 6-membered unsubstituted aryl.

[0377] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl, which is substituted with one or more halogens.

[0378] In some embodiments, R 1 and R 4Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one or more Fs.

[0379] In some embodiments, R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one F.

[0380] In some embodiments, R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one or more Cls.

[0381] In some embodiments, R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one Cl.

[0382] In some embodiments, R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is optionally substituted with one or more C1-C6 alkyls.

[0383] In some embodiments, R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one or more methyls.

[0384] In some embodiments, R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one methyl.

[0385] In some embodiments, R1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl which is optionally substituted with one or more C1-C6 alkoxy groups.

[0386] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl which is substituted with one or more methoxy groups.

[0387] In some embodiments, R 1 and R 4 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl which is substituted with one methoxy group.

[0388] In some embodiments, R 4 is selected from hydrogen, halogen, -OH, -CN, -NO2, -NR 14 R 15 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 16 .

[0389] In some embodiments, R 4 is H.

[0390] In some embodiments, R 4 is C1-C6 alkyl.

[0391] In some embodiments, R 4 is methyl.

[0392] In some embodiments, R 4 and R 1together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle or heteroaryl is optionally substituted with one or more R 16 groups.

[0393] In some embodiments, R 4 and R 1 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl, which is optionally substituted with one or more R 16 groups.

[0394] In some embodiments, R 4 and R 1 together with the atoms to which they are attached and any intervening atoms form an unsubstituted 6-membered aryl.

[0395] In some embodiments, R 4 and R 1 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl, which is substituted with one or more halogens.

[0396] In some embodiments, R 4 and R 1 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl, which is substituted with one or more F.

[0397] In some embodiments, R 4 and R 1 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl, which is substituted with one F.

[0398] In some embodiments, R 4 and R 1Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one or more Cl.

[0399] In some embodiments, R 4 and R 1 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one Cl.

[0400] In some embodiments, R 4 and R 1 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is optionally substituted with one or more C1-C6 alkyls.

[0401] In some embodiments, R 4 and R 1 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one or more methyls.

[0402] In some embodiments, R 4 and R 1 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one methyl.

[0403] In some embodiments, R 4 and R 1 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is optionally substituted with one or more C1-C6 alkoxys.

[0404] In some embodiments, R 4 and R 1 Together with the atoms to which they are attached and any intervening atoms, they form a 6-membered aryl which is substituted with one or more methoxys.

[0405] In some embodiments, R 4 and R 1 together with the atoms to which they are attached and any intervening atoms form a 6-membered aryl which is substituted with one methoxy group.

[0406] In some embodiments, n is an integer selected from 0, 1, 2.

[0407] In some embodiments, n is 2.

[0408] In some embodiments, n is 1.

[0409] In some embodiments, n is 0.

[0410] In some embodiments, R 7 , R 8 , R 9 and R 10 are each independently selected from H, C1-C6 alkyl, cycloalkyl.

[0411] In some embodiments, R 8 and R 9 together with the atoms to which they are attached and any intervening atoms form a cycloalkyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0412] In some embodiments, R 8 and R 9 together with the atoms to which they are attached and any intervening atoms form a cyclopropane ring optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0413] In some embodiments, R 9 and R 10Together with the atoms to which they are attached and any intervening atoms, they form a cycloalkyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0414] In some embodiments, R 7 and R 8 are each H, and R 9 and R 10 are each C1-C6 alkyl.

[0415] In some embodiments, R 7 and R 8 are each H, and R 9 and R 10 are each CH3.

[0416] In some embodiments, n is 2, and R 7 and R 8 are each H, and R 9 and R 10 are each C1-C6 alkyl.

[0417] In some embodiments, n is 2, and R 7 and R 8 are each H, and R 9 and R 10 are each CH3.

[0418] In some embodiments, n is 2, and R 9 and R 10 Together with the atoms to which they are attached and any intervening atoms, form a cycloalkyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0419] In some embodiments, n is 2, and R 9 and R 10Together with the atoms to which they are attached and any intervening atoms, they form a cyclopropane ring optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0420] In some embodiments, n is 1, and R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, they form a cycloalkyl optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0421] In some embodiments, n is 1, and R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, they form a cyclopropane ring optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0422] In some embodiments, n is 1, and R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, they form a cyclopropane ring optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl.

[0423] In some embodiments, n is 1, and R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, they form a cyclopropane ring optionally substituted with one or more C1-C6 alkyl.

[0424] In some embodiments, n is 1, and R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, they form a cyclopropane ring optionally substituted with two C1-C6 alkyl.

[0425] In some embodiments, n is 1, and R8 and R 9 together with the atoms to which they are attached and any intervening atoms form a cyclopropane ring optionally geminally substituted with two C1-C6 alkyls.

[0426] In some embodiments, n is 1, and R 8 and R 9 together with the atoms to which they are attached and any intervening atoms form a cyclopropane ring optionally geminally substituted with two methyls.

[0427] In some embodiments, R 11 , R 12 , R 13 are each independently selected from H, C1-C6 alkyl, cycloalkyl, halogen, -CN.

[0428] In some embodiments, R 11 , R 12 , R 13 are each C1-C6 alkyl.

[0429] In some embodiments, R 11 , R 12 , R 13 are each methyl.

[0430] In some embodiments, R 11 , R 12 , R 13 are each halogen.

[0431] In some embodiments, R 11 , R 12 , R 13 are each F.

[0432] In some embodiments, R 11 is methyl, and R 12 and R 13 are each F.

[0433] In some embodiments, R 14 and R 15 are each independently selected from H, C1-C6 alkyl.

[0434] In some embodiments, R 14 and R 15 are each H.

[0435] In some embodiments, R 14 and R 15 are each methyl.

[0436] In some embodiments, R 14 and R 15 together with the atom to which they are attached and any intervening atoms form one or more optionally substituted with one or more halogens, -OH, -CN, C1-C6 alkyl heterocyclyl.

[0437] In some embodiments, R 16 is independently selected from halogen, -OH, -OH, -CN, -NO2, -NR 13 R 14 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C(O)OR 13 , -C(O)N-NR 13 R 14 , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl.

[0438] In some embodiments, X is selected from hydrogen, halogen, OH, CN, NO2, CONR 13 R 14 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl is optionally substituted with cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0439] In some embodiments, X is -CN.

[0440] In some embodiments, X is CONR 13 R 14 is.

[0441] In some embodiments, X is CONH2.

[0442] In some embodiments, X is selected from C1-C6 alkyl optionally substituted with cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0443] In some embodiments, X is selected from C1-C6 alkyl substituted with heterocyclyl.

[0444] In some embodiments, X is

Chemical formula

[0445] In some embodiments, X is

Chemical formula

[0446] In some embodiments, Y is C1-C6 alkyl-S(O) u -, C1-C6 alkyl-C(O)-, and the alkyl is optionally substituted with one or more halogens, -OH, -CN.

[0447] In some embodiments, u is an integer selected from 0, 1, 2.

[0448] In some embodiments, u is 0.

[0449] In some embodiments, u is 1.

[0450] In some embodiments, u is 2.

[0451] In some embodiments, Y is CF3C(O)-.

[0452] In some embodiments, Y is CH3S(O)2-.

[0453] In some embodiments, Y is CF3S(O)2-.

[0454] In some embodiments, Y is CF3CH2S(O)2-.

[0455] In some embodiments, the compound is of formula (II-I):

Chemical formula

[0456] In some embodiments, the compound is of formula (II-II):

Chemical formula

[0457] In some embodiments, the compound is of formula (II-III):

Chemical formula

[0458] In some embodiments, the compound is of formula (II-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0459] In some embodiments, the compound is of formula (II-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0460] In some embodiments, the compound is of formula (II-B-a) or formula (II-B-b): [Chemical formula] [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0461] In some embodiments, the compound is of formula (II-I-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0462] In some embodiments, the compound is of formula (II-I-A*): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0463] In some embodiments, the compound is of formula (II-I-A-A):

Chemical formula

[0464] In some embodiments, the compound is of formula (II-I-A-A*):

Chemical formula

[0465] In some embodiments, the compound is of formula (II-I-A-A-A):

Chemical formula

[0466] In some embodiments, the compound is of formula (II-I-A-A-A*):

Chemical formula

[0467] In some embodiments, the compound is of formula (II-I-A-A-A-I): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0468] In some embodiments, the compound is of formula (II-I-A-A-A-I*): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0469] In some embodiments, the compound is of formula (II-I-A-A-A-I-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein w is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, and all other variables are as defined herein.

[0470] In some embodiments, the compound is of formula (II-I-A-A-A-I-A*): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein w is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, and all other variables are as defined herein.

[0471] In some embodiments, the compound is of formula (II-I-A-A-A-I-A-1) or formula (II-I-A-A-A-I-A-2):

Chem.

[0472] In some embodiments, the compound is of formula (II-I-A-A-A-I-A-1*) or formula (II-I-A-A-A-I-A-2*):

Chem.

Chem.

[0473] In some embodiments, the compound is of formula (II-I-A-A-A-I-B):

Chem.

[0474] In some embodiments, the compound is of formula (II-I-A-A-A-I-B*):

Chem.

[0475] In some embodiments, the compound is of formula (II-I-A-A-A-I-B-1) or formula (II-I-A-A-A-I-B-2):

Chemical formula

[0476] In some embodiments, the compound is of formula (II-I-A-A-A-I-B-1*) or formula (II-I-A-A-A-I-B-2*):

Chemical formula

[0477] In some embodiments, the compound is of formula (II-3):

Chemical formula

[0478] In some embodiments, the compound is of formula (II-I-3):

Chemical formula

[0479] In some embodiments, the compound is of formula (II-I-A-A-A-I-3):

Chem.

[0480] In some embodiments, the compound is of formula (II-I-A-A-A-I-3*):

Chem.

[0481] In some embodiments, the compound is of formula (II-I-A-A-A-II):

Chem.

[0482] In some embodiments, the compound is of formula (II-I-A-A-A-II*):

Chem.

[0483] In some embodiments, the compound is of formula (II-I-A-A-A-II-1) or formula (II-I-A-A-A-II-2):

Chemical formula

[0484] In some embodiments, the compound is of formula (II-I-A-A-A-II-1*) or formula (II-I-A-A-A-II-2*):

Chemical formula

[0485] In some embodiments, the compound is of formula (II-I-A-A-A-III):

Chemical formula

[0486] In some embodiments, the compound is of formula (II-I-A-A-A-III*):

Chemical formula

[0487] In some embodiments, the compound is of formula (II-I-A-A-A-III-1) or formula (II-I-A-A-A-III-2):

Chem.

[0488] In some embodiments, the compound is of formula (II-I-A-A-A-III-1*) or formula (II-I-A-A-A-III-2*):

Chem.

[0489] In some embodiments, the compound is of formula (II-I-A-A-B):

Chem.

[0490] In some embodiments, the compound is of formula (II-I-A-A-B*):

Chem.

[0491] In some embodiments, the compound is of formula (II-I-A-A-B-I):

Chem.

[0492] In some embodiments, the compound is of formula (II-I-A-A-B-I*): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0493] In some embodiments, the compound is of formula (II-I-A-A-B-I-1) or formula (II-I-A-A-B-I-2): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0494] In some embodiments, the compound is of formula (II-I-A-A-B-I-1*) or formula (II-I-A-A-B-I-2*): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0495] In some embodiments, the compound is of formula (II-I-A-A-C): [Chemical formula] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0496] In some embodiments, the compound is of formula (II-I-A-A-C*):

Chemical formula

[0497] In some embodiments, the compound is of formula (II-I-A-A-C-I):

Chemical formula

[0498] In some embodiments, the compound is of formula (II-I-A-A-C-I*):

Chemical formula

[0499] In some embodiments, the compound is of formula (II-I-A-A-C-I-1) or formula (II-I-A-A-C-I-2):

Chemical formula

[0500] In some embodiments, the compound is of formula (II-I-A-A-C-I-1*) or formula (II-I-A-A-C-I-2*):

Chem.

Chem.

[0501] In some embodiments, the compound is of formula (II-I-A-A-D):

Chem.

[0502] In some embodiments, the compound is of formula (II-I-A-A-D*):

Chem.

[0503] In some embodiments, the compound is of formula (II-I-A-A-D-I):

Chem.

[0504] In some embodiments, the compound is of formula (II-I-A-A-D-I*): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0505] In some embodiments, the compound is of formula (II-I-A-A-D-I-1) or formula (II-I-A-A-D-I-2): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0506] In some embodiments, the compound is of formula (II-I-A-A-D-I-1*) or formula (II-I-A-A-D-I-2*): [Chemical formula] [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0507] In some embodiments, the compound is of formula (II-I-A-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0508] In some embodiments, the compound is of formula (II-I-A-B*): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0509] In some embodiments, the compound is of formula (II-I-A-B-A):

Chem.

[0510] In some embodiments, the compound is of formula (II-I-A-B-A*):

Chem.

[0511] In some embodiments, the compound is of formula (II-I-A-B-A-I):

Chem.

[0512] In some embodiments, the compound is of formula (II-I-A-B-A-I*):

Chem.

[0513] In some embodiments, the compound is of formula (II-I-B):

Chem.

[0514] In some embodiments, the compound is of formula (II-I-B*):

Chem.

[0515] In some embodiments, the compound is of formula (II-I-B-A):

Chem.

[0516] In some embodiments, the compound is of formula (II-I-B-A*):

Chem.

[0517] In some embodiments, the compound is of formula (II-I-B-A-a) or formula (II-I-B-A-b):

Chem.

Chem.

[0518] In some embodiments, the compound is of formula (II-I-B-A-a*) or formula (II-I-B-A-b*):

Chem.

[0519] In some embodiments, the compound is of formula (II-I-B-A-A):

Chem.

[0520] In some embodiments, the compound is of formula (II-I-B-A-A*):

Chem.

[0521] In some embodiments, the compound is of formula (II-I-B-A-A-a) or formula (II-I-B-A-A-b):

Chem.

Chem.

[0522] In some embodiments, the compound is of formula (II-I-B-A-A-a*) or formula (II-I-B-A-A-b*):

Chemical formula

[0523] In some embodiments, the compound is of formula (II-I-B-A-A-I):

Chemical formula

[0524] In some embodiments, the compound is of formula (II-I-B-A-A-I*):

Chemical formula

[0525] In some embodiments, the compound is of formula (II-I-B-A-A-I-a) or formula (II-I-B-A-A-I-b):

Chemical formula

Chemical formula

[0526] In some embodiments, the compound is of formula (II-I-B-A-A-I-a*) or formula (II-I-B-A-A-I-b*):

Chemical formula

[0527] In some embodiments, the compound is of formula (II-II-A):

Chemical formula

[0528] In some embodiments, the compound is of formula (II-II-A*):

Chemical formula

[0529] In some embodiments, the compound is of formula (II-II-A-A):

Chemical formula

[0530] In some embodiments, the compound is of formula (II-II-A-A*):

Chemical formula

[0531] In some embodiments, the compound is of formula (II-II-A-A-A):

Chemical formula

[0532] In some embodiments, the compound is of formula (II-II-A-A-A*):

Chemical formula

[0533] In some embodiments, the compound is of formula (II-II-A-A-A-I):

Chemical formula

[0534] In some embodiments, the compound is of formula (II-II-A-A-A-I*):

Chemical formula

[0535] In some embodiments, the compound is of formula (II-II-A-A-A-I-1) or formula (II-II-A-A-A-I-2):

Chemical formula

Chemical formula

[0536] In some embodiments, the compound is of formula (II-II-A-A-A-I-1*) or formula (II-II-A-A-A-I-2*):

Chemical formula

[0537] In some embodiments, the compound is of formula (II-II-A-B):

Chemical formula

[0538] In some embodiments, the compound is of formula (II-II-A-B*):

Chem.

[0539] In some embodiments, the compound is of formula (II-II-A-B-A):

Chem.

[0540] In some embodiments, the compound is of formula (II-II-A-B-A*):

Chem.

[0541] In some embodiments, the compound is of formula (II-II-A-B-A-I):

Chem.

[0542] In some embodiments, the compound is of formula (II-II-A-B-A-I*):

Chem.

[0543] In some embodiments, the compound is of formula (II-II-A-B-A-I-1) or formula (II-II-A-B-A-I-2):

Chemical formula

[0544] In some embodiments, the compound is of formula (II-II-A-B-A-I-1*) or formula (II-II-A-B-A-I-2*):

Chemical formula

Chemical formula

[0545] In some embodiments, the compound is of formula (II-II-A-C):

Chemical formula

[0546] In some embodiments, the compound is of formula (II-II-A-C*):

Chemical formula

[0547] In some embodiments, the compound is of formula (II-II-A-C-A):

Chemical formula

[0548] In some embodiments, the compound is of formula (II-II-A-C-A*):

Chemical formula

[0549] In some embodiments, the compound is of formula (II-II-A-C-A-I):

Chemical formula

[0550] In some embodiments, the compound is of formula (II-II-A-C-A-I*):

Chemical formula

[0551] In some embodiments, the compound is of formula (II-II-A-C-A-I-1) or formula (II-II-A-C-A-I-2):

Chem.

[0552] In some embodiments, the compound is of formula (II-II-A-C-A-I-1*) or formula (II-II-A-C-A-I-2*):

Chem.

[0553] In some embodiments, the compound is of formula (II-I-W):

Chem.

[0554] In some embodiments, the compound is of formula (II-I-W-A):

Chem.

[0555] In some embodiments, the compound is of formula (II-I-W-B):

Chemical formula

[0556] In some embodiments, the compound is of formula (II-I-W-C):

Chemical formula

[0557] In some embodiments, the compound is of formula (II-I-W-D):

Chemical formula

[0558] In some embodiments, the compound is of formula (II-I-W-A-I): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0559] In some embodiments, the compound is of formula (II-I-W-A-II): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0560] In some embodiments, the compound is of formula (II-I-W-A-III): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0561] In some embodiments, the compound is of formula (II-I-W-B-I): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, and all variables are as defined herein.

[0562] In some embodiments, the compound is of formula (II-I-W-B-II): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0563] In some embodiments, the compound is of formula (II-I-W-B-III): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0564] In some embodiments, the compound is of formula (II-I-W-B-IV): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0565] In some embodiments, the compound is of formula (II-I-W-B-V): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0566] In some embodiments, the compound is of formula (II-I-W-B-VI): [Chemical formula] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein all variables are as defined herein.

[0567] In some embodiments, the compound is of formula (II-I-W-C-I):

Chemical formula

[0568] In some embodiments, the compound is of formula (II-I-W-C-II):

Chemical formula

[0569] In some embodiments, the compound is of formula (II-I-W-C-III):

Chemical formula

[0570] In some embodiments, the compound is of formula (II-I-W-C-IV):

Chemical formula

[0571] In some embodiments, the compound is of formula (II-I-W-C-V):

Chemical formula

[0572] In some embodiments, the compound is of formula (II-I-W-C-VI):

Chemical formula

[0573] In some embodiments, the compound is of formula (II-I-W-C-VII):

Chemical formula

[0574] In some embodiments, the compound is of formula (II-I-W-C-VIII):

Chemical formula

[0575] In some embodiments, the compound is of formula (II-I-W-C-IX):

Chemical formula

[0576] In some embodiments, the compound is of formula (II-I-W-C-X):

Chemical formula

[0577] In some embodiments, the compound is of formula (II-I-W-D-I):

Chemical formula

[0578] In some embodiments, the compound is of formula (II-I-W-D-II):

Chemical formula

[0579] In some embodiments, the compound is of formula (II-I-W-D-III):

Chemical formula

[0580] In some embodiments, the compound is of formula (II-I-W-D-IV):

Chemical formula

[0581] In some embodiments, the compound is of formula (II-I-W-D-V):

Chemical formula

[0582] In some embodiments, the compound is of formula (II-I-W-D-VI):

Chemical formula

[0583] In some embodiments, the compound is of formula (II-I-W-D-VII):

Chemical formula

[0584] In some embodiments, the compound is of formula (II-I-W-A-I-a):

Chemical formula

[0585] In some embodiments, the compound is of formula (II-I-W-A-II-a):

Chemical formula

[0586] In some embodiments, the compound is of formula (II-I-W-A-III-a):

Chemical formula

[0587] In some embodiments, the compound is of formula (II-I-W-B-I-a):

Chemical formula

[0588] In some embodiments, the compound is of formula (II-I-W-B-II-a):

Chemical formula

[0589] In some embodiments, the compound is of formula (II-I-W-B-III-a):

Chemical formula

[0590] In some embodiments, the compound is of formula (II-I-W-B-IV-a):

Chemical formula

[0591] In some embodiments, the compound is of formula (II-I-W-B-V-a):

Chemical formula

[0592] In some embodiments, the compound is of formula (II-I-W-B-VI-a):

Chemical formula

[0593] In some embodiments, the compound is of formula (II-I-W-C-I-a):

Chemical formula

[0594] In some embodiments, the compound is of formula (II-I-W-C-II-a):

Chemical formula

[0595] In some embodiments, the compound is of formula (II-I-W-C-III-a): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0596] In some embodiments, the compound is of the formula (II-I-W-C-IV-a): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0597] In some embodiments, the compound is of the formula (II-I-W-C-V-a): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0598] In some embodiments, the compound is of the formula (II-I-W-C-VI-a): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0599] In some embodiments, the compound is of the formula (II-I-W-C-VII-a): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0600] In some embodiments, the compound is of the formula (II-I-W-C-VIII-a): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0601] In some embodiments, the compound is of the formula (II-I-W-C-IX-a): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0602] In some embodiments, the compound is of the formula (II-I-W-C-X-a): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0603] In some embodiments, the compound is of the formula (II-I-W-D-I-a): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0604] In some embodiments, the compound is of formula (II-I-W-D-II-a): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0605] In some embodiments, the compound is of formula (II-I-W-D-III-a): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0606] In some embodiments, the compound is of formula (II-I-W-D-IV-a): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0607] In some embodiments, the compound is of formula (II-I-W-D-V-a): [Chem.] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0608] In some embodiments, the compound is of formula (II-I-W-D-VI-a): [Chem.] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0609] In some embodiments, the compound is of formula (II-I-W-D-VII-a): [Chem.] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0610] In some embodiments, the compound is of formula (II-I-W-A-I-a-1): [Chem.] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0611] In some embodiments, the compound is of formula (II-I-W-A-I-a-2): [Chemistry] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0612] In some embodiments, the compound is of formula (II-I-W-A-II-a-1): [Chemistry] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0613] In some embodiments, the compound is of formula (II-I-W-A-II-a-2): [Chemistry] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0614] In some embodiments, the compound is of formula (II-I-W-A-III-a-1): [Chemistry] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0615] In some embodiments, the compound is of formula (II-I-W-A-III-a-2): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0616] In some embodiments, the compound is of formula (II-I-W-B-I-a-1): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, and all variables are as defined herein.

[0617] In some embodiments, the compound is of formula (II-I-W-B-I-a-2): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, and all variables are as defined herein.

[0618] In some embodiments, the compound is of formula (II-I-W-B-II-a-1): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, and all variables are as defined herein.

[0619] In some embodiments, the compound is of formula (II-I-W-B-II-a-2): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0620] In some embodiments, the compound is of formula (II-I-W-B-III-a-1):

Chemical formula

[0621] In some embodiments, the compound is of formula (II-I-W-B-III-a-2):

Chemical formula

[0622] In some embodiments, the compound is of formula (II-I-W-B-IV-a-1):

Chemical formula

[0623] In some embodiments, the compound is of formula (II-I-W-B-IV-a-2):

Chemical formula

[0624] In some embodiments, the compound is of formula (II-I-W-B-V-a-1):

Chem.

[0625] In some embodiments, the compound is of formula (II-I-W-B-V-a-2):

Chem.

[0626] In some embodiments, the compound is of formula (II-I-W-B-VI-a-1):

Chem.

[0627] In some embodiments, the compound is of formula (II-I-W-B-VI-a-2):

Chem.

[0628] In some embodiments, the compound is of formula (II-I-W-C-I-a-1):

Chem.

[0629] In some embodiments, the compound is of formula (II-I-W-C-I-a-2): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0630] In some embodiments, the compound is of formula (II-I-W-C-II-a-1): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0631] In some embodiments, the compound is of formula (II-I-W-C-II-a-2): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0632] In some embodiments, the compound is of formula (II-I-W-C-III-a-1): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0633] In some embodiments, the compound is of formula (II-I-W-C-III-a-2):

Chemical formula

[0634] In some embodiments, the compound is of formula (II-I-W-C-IV-a-1):

Chemical formula

[0635] In some embodiments, the compound is of formula (II-I-W-C-IV-a-2):

Chemical formula

[0636] In some embodiments, the compound is of formula (II-I-W-C-V-a-1):

Chemical formula

[0637] In some embodiments, the compound is of formula (II-I-W-C-V-a-2):

Chemical formula

[0638] In some embodiments, the compound is of formula (II-I-W-C-VI-a-1):

Chemical formula

[0639] In some embodiments, the compound is of formula (II-I-W-C-VI-a-2):

Chemical formula

[0640] In some embodiments, the compound is of formula (II-I-W-C-VII-a-1):

Chemical formula

[0641] In some embodiments, the compound is of formula (II-I-W-C-VII-a-2): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0642] In some embodiments, the compound is of formula (II-I-W-C-VIII-a-1): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0643] In some embodiments, the compound is of formula (II-I-W-C-VIII-a-2): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0644] In some embodiments, the compound is of formula (II-I-W-C-IX-a-1): [Chemistry] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0645] In some embodiments, the compound is of formula (II-I-W-C-IX-a-2): [Chemistry] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein

[0646] In some embodiments, the compound is of formula (II-I-W-C-X-a-1): [Chemistry] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0647] In some embodiments, the compound is of formula (II-I-W-C-X-a-2): [Chemistry] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0648] In some embodiments, the compound is of formula (II-I-W-D-I-a-1): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0649] In some embodiments, the compound is of formula (II-I-W-D-I-a-2): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0650] In some embodiments, the compound is of formula (II-I-W-D-II-a-1): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0651] In some embodiments, the compound is of formula (II-I-W-D-II-a-2): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0652] In some embodiments, the compound is of formula (II-I-W-D-III-a-1): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0653] In some embodiments, the compound is of formula (II-I-W-D-III-a-2): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0654] In some embodiments, the compound is of formula (II-I-W-D-IV-a-1): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0655] In some embodiments, the compound is of formula (II-I-W-D-IV-a-2): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0656] In some embodiments, the compound is of formula (II-I-W-D-V-a-1): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0657] In some embodiments, the compound is of formula (II-I-W-D-V-a-2): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0658] In some embodiments, the compound is of formula (II-I-W-D-VI-a-1): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0659] In some embodiments, the compound is of formula (II-I-W-D-VI-a-2): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0660] In some embodiments, the compound is of formula (II-I-W-D-VII-a-1): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0661] In some embodiments, the compound is of formula (II-I-W-D-VII-a-2):

Chem.

[0662] In some embodiments, the compound is of formula (II-I-W-A-I-a-1-A):

Chem.

[0663] In some embodiments, the compound is of formula (II-I-W-A-I-a-1-B):

Chem.

[0664] In some embodiments, the compound is of formula (II-I-W-A-II-a-1-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0665] In some embodiments, the compound is of the formula (II-I-W-A-II-a-1-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0666] In some embodiments, the compound is of the formula (II-I-W-A-III-a-1-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0667] In some embodiments, the compound is of the formula (II-I-W-A-III-a-1-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0668] In some embodiments, the compound is of the formula (II-I-W-A-III-a-2-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0669] In some embodiments, the compound is of the formula (II-I-W-A-III-a-2-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0670] In some embodiments, the compound is of the formula (II-I-W-B-I-a-1-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, and all variables are as defined herein.

[0671] In some embodiments, the compound is of the formula (II-I-W-B-I-a-1-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, and all variables are as defined herein.

[0672] In some embodiments, the compound is of the formula (II-I-W-B-I-a-2-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0673] In some embodiments, the compound is of formula (II-I-W-B-I-a-2-B):

Chemical formula

[0674] In some embodiments, the compound is of formula (II-I-W-B-II-a-1-A):

Chemical formula

[0675] In some embodiments, the compound is of formula (II-I-W-B-II-a-1-B):

Chemical formula

[0676] In some embodiments, the compound is of formula (II-I-W-B-II-a-2-A):

Chemical formula

[0677] In some embodiments, the compound is of formula (II-I-W-B-II-a-2-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0678] In some embodiments, the compound is of formula (II-I-W-B-III-a-1-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0679] In some embodiments, the compound is of formula (II-I-W-B-III-a-1-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0680] In some embodiments, the compound is of formula (II-I-W-B-III-a-2-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0681] In some embodiments, the compound is of formula (II-I-W-B-III-a-2-B): [Chemical formula] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0682] In some embodiments, the compound is of the formula (II-I-W-B-IV-a-1-A): [Chemical formula] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0683] In some embodiments, the compound is of the formula (II-I-W-B-IV-a-1-B): [Chemical formula] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0684] In some embodiments, the compound is of the formula (II-I-W-B-IV-a-2-A): [Chemical formula] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, wherein all variables are as defined herein.

[0685] In some embodiments, the compound is of the formula (II-I-W-B-IV-a-2-B): [Chemical formula] Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, and all variables are as defined herein.

[0686] In some embodiments, the compound is of formula (II-I-W-B-V-a-1-A):

Chemical formula

[0687] In some embodiments, the compound is of formula (II-I-W-B-V-a-1-B):

Chemical formula

[0688] In some embodiments, the compound is of formula (II-I-W-B-V-a-2-A):

Chemical formula

[0689] In some embodiments, the compound is of formula (II-I-W-B-V-a-2-B):

Chemical formula

[0690] In some embodiments, the compound is of formula (II-I-W-B-VI-a-1-A):

Chem.

[0691] In some embodiments, the compound is of formula (II-I-W-B-VI-a-1-B):

Chem.

[0692] In some embodiments, the compound is of formula (II-I-W-B-VI-a-2-A):

Chem.

[0693] In some embodiments, the compound is of formula (II-I-W-B-VI-a-2-B):

Chem.

[0694] In some embodiments, the compound is of formula (II-I-W-C-I-a-1-A):

Chem.

[0695] In some embodiments, the compound is of the formula (II-I-W-C-I-a-1-B):

Chemical formula

[0696] In some embodiments, the compound is of the formula (II-I-W-C-I-a-2-A):

Chemical formula

[0697] In some embodiments, the compound is of the formula (II-I-W-C-I-a-2-B):

Chemical formula

[0698] In some embodiments, the compound is of the formula (II-I-W-C-II-a-1-A):

Chemical formula

[0699] In some embodiments, the compound is of the formula (II-I-W-C-II-a-1-B):

Chemical formula

[0700] In some embodiments, the compound is of the formula (II-I-W-C-II-a-2-A):

Chemical formula

[0701] In some embodiments, the compound is of the formula (II-I-W-C-II-a-2-B):

Chemical formula

[0702] In some embodiments, the compound is of the formula (II-I-W-C-III-a-1-A): [Chemistry] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0703] In some embodiments, the compound is of the formula (II-I-W-C-III-a-1-B): [Chemistry] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0704] In some embodiments, the compound is of the formula (II-I-W-C-III-a-2-A): [Chemistry] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0705] In some embodiments, the compound is of the formula (II-I-W-C-III-a-2-B): [Chemistry] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0706] In some embodiments, the compound is of the formula (II-I-W-C-IV-a-1-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0707] In some embodiments, the compound is of the formula (II-I-W-C-IV-a-1-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0708] In some embodiments, the compound is of the formula (II-I-W-C-IV-a-2-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0709] In some embodiments, the compound is of the formula (II-I-W-C-IV-a-2-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0710] In some embodiments, the compound is of formula (II-I-W-C-V-a-1-A):

Chem.

[0711] In some embodiments, the compound is of formula (II-I-W-C-V-a-1-B):

Chem.

[0712] In some embodiments, the compound is of formula (II-I-W-C-V-a-2-A):

Chem.

[0713] In some embodiments, the compound is of formula (II-I-W-C-V-a-2-B):

Chem.

[0714] In some embodiments, the compound is of formula (II-I-W-C-VI-a-1-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0715] In some embodiments, the compound is of formula (II-I-W-C-VI-a-1-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0716] In some embodiments, the compound is of formula (II-I-W-C-VI-a-2-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0717] In some embodiments, the compound is of formula (II-I-W-C-VI-a-2-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0718] In some embodiments, the compound is of formula (II-I-W-C-VII-a-1-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0719] In some embodiments, the compound is of formula (II-I-W-C-VII-a-1-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0720] In some embodiments, the compound is of formula (II-I-W-C-VII-a-2-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0721] In some embodiments, the compound is of formula (II-I-W-C-VII-a-2-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0722] In some embodiments, the compound is of formula (II-I-W-C-VIII-a-1-A):

Chemical formula

[0723] In some embodiments, the compound is of formula (II-I-W-C-VIII-a-1-B):

Chemical formula

[0724] In some embodiments, the compound is of formula (II-I-W-C-VIII-a-2-A):

Chemical formula

[0725] In some embodiments, the compound is of formula (II-I-W-C-VIII-a-2-B):

Chemical formula

[0726] In some embodiments, the compound is of formula (II-I-W-C-IX-a-1-A):

Chem.

[0727] In some embodiments, the compound is of formula (II-I-W-C-IX-a-1-B):

Chem.

[0728] In some embodiments, the compound is of formula (II-I-W-C-IX-a-2-A):

Chem.

[0729] In some embodiments, the compound is of formula (II-I-W-C-IX-a-2-B):

Chem.

[0730] In some embodiments, the compound is of the formula (II-I-W-C-X-a-1-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0731] In some embodiments, the compound is of the formula (II-I-W-C-X-a-1-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0732] In some embodiments, the compound is of the formula (II-I-W-C-X-a-2-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0733] In some embodiments, the compound is of the formula (II-I-W-C-X-a-2-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, 2, 3, and 4, and all other variables are as defined herein.

[0734] In some embodiments, the compound is of formula (II-I-W-D-I-a-1-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0735] In some embodiments, the compound is of formula (II-I-W-D-I-a-1-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0736] In some embodiments, the compound is of formula (II-I-W-D-I-a-2-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0737] In some embodiments, the compound is of formula (II-I-W-D-I-a-2-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0738] In some embodiments, the compound is of the formula (II-I-W-D-II-a-1-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0739] In some embodiments, the compound is of the formula (II-I-W-D-II-a-1-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0740] In some embodiments, the compound is of the formula (II-I-W-D-II-a-2-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0741] In some embodiments, the compound is of the formula (II-I-W-D-II-a-2-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0742] In some embodiments, the compound is of formula (II-I-W-D-III-a-1-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0743] In some embodiments, the compound is of formula (II-I-W-D-III-a-1-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0744] In some embodiments, the compound is of formula (II-I-W-D-III-a-2-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0745] In some embodiments, the compound is of formula (II-I-W-D-III-a-2-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0746] In some embodiments, the compound is of formula (II-I-W-D-IV-a-1-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0747] In some embodiments, the compound is of formula (II-I-W-D-IV-a-1-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0748] In some embodiments, the compound is of formula (II-I-W-D-IV-a-2-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0749] In some embodiments, the compound is of formula (II-I-W-D-IV-a-2-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0750] In some embodiments, the compound is of formula (II-I-W-D-V-a-1-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0751] In some embodiments, the compound is of formula (II-I-W-D-V-a-1-B): [Chemical formula]

[0752] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0753] In some embodiments, the compound is of formula (II-I-W-D-V-a-2-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0754] In some embodiments, the compound is of formula (II-I-W-D-V-a-2-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0755] In some embodiments, the compound is of formula (II-I-W-D-VI-a-1-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0756] In some embodiments, the compound is of formula (II-I-W-D-VI-a-1-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0757] In some embodiments, the compound is of formula (II-I-W-D-VI-a-2-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0758] In some embodiments, the compound is of formula (II-I-W-D-VI-a-2-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0759] In some embodiments, the compound is of formula (II-I-W-D-VII-a-1-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0760] In some embodiments, the compound is of formula (II-I-W-D-VII-a-1-B): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0761] In some embodiments, the compound is of formula (II-I-W-D-VII-a-2-A): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, where w is an integer selected from 0, 1, and 2, and all other variables are as defined herein.

[0762] In some embodiments, the compound is of formula (II-I-W-D-VII-a-2-B):

Chem.

[0763] In some embodiments, the compound is of formula (III-I):

Chem.

[0764] In some embodiments, the compound is of formula (III-I-I):

Chem.

[0765] In some embodiments, the compound is of formula (III-I-I-A):

Chem.

[0766] In some embodiments, the compound is of formula (III-I-I-A-A):

Chem.

[0767] In some embodiments, the compound is of formula (III-I-I-A-A*):

Chemical formula

[0768] In some embodiments, the compound is of formula (III-I-I-A-A-A):

Chemical formula

[0769] In some embodiments, the compound is of formula (III-I-I-A-A-A*):

Chemical formula

[0770] In some embodiments, the compound is of formula (III-I-I-A-A-A-I):

Chemical formula

[0771] In some embodiments, the compound is of formula (III-I-I-A-A-A-I*):

Chemical formula

[0772] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein X is selected from -C(O)NH2 and -CN, and all other variables are as defined herein.

[0773] In some embodiments, the compound is of formula (III-I-I-A-A-A-I-a):

Chemical formula

[0774] In some embodiments, the compound is of formula (III-I-I-A-A-A-I-a*):

Chemical formula

[0775] In some embodiments, the compound is of formula (III-II):

Chemical formula

[0776] In some embodiments, the compound is of formula (III-II-I):

Chemical formula

[0777] In some embodiments, the compound is of formula (III-II-I-A):

Chemical formula

[0778] In some embodiments, the compound is of formula (III-II-I-A*):

Chemical formula

[0779] In some embodiments, the compound is of formula (III-II-I-A-A):

Chemical formula

[0780] In some embodiments, the compound is of formula (III-II-I-A-A*):

Chemical formula

[0781] In some embodiments, the compound is of formula (III-II-I-A-A-I):

Chemical formula

[0782] In some embodiments, the compound is of formula (III-II-I-A-A-I*):

Chemical formula

[0783] In some embodiments, the compound is of formula (III-II-I-A-A-I-B):

Chemical formula

[0784] In some embodiments, the compound is of formula (III-II-I-A-A-I-B*): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein X is selected from -C(O)NH2 and -CN, and all other variables are as defined herein.

[0785] In some embodiments, the compound is of formula (III-II-I-A-A-I-B-1): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein w is an integer selected from 0, 1, 2, 3, 4, X is selected from -C(O)NH2 and -CN, and all other variables are as defined herein.

[0786] In some embodiments, the compound is of formula (III-II-I-A-A-I-B-1*): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, wherein w is an integer selected from 0, 1, 2, 3, 4, X is selected from -C(O)NH2 and -CN, and all other variables are as defined herein.

[0787] In some embodiments, the compound is of formula (IV-I): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative or tautomer thereof, and all variables are as defined herein.

[0788] In some embodiments, the compound is of formula (IV-II):

Chem.

[0789] In some embodiments, the compound is of formula (IV-III):

Chem.

[0790] In some embodiments, the compound is of formula (IV-I-A):

Chem.

[0791] In some embodiments, the compound is of formula (IV-I-A*):

Chem.

[0792] In some embodiments, the compound is of formula (IV-II-A):

Chem.

[0793] In some embodiments, the compound is of formula (IV-II-A*):

Chemical formula

[0794] In some embodiments, the compound is of formula (IV-III-A):

Chemical formula

[0795] In some embodiments, the compound is of formula (IV-III-A*):

Chemical formula

[0796] In some embodiments, the compound is of formula (IV-I-A-A):

Chemical formula

[0797] In some embodiments, the compound is of formula (IV-I-A-A*):

Chemical formula

[0798] In some embodiments, the compound is of formula (IV-II-A-A):

Chemical formula

[0799] In some embodiments, the compound is of formula (IV-II-A-A*):

Chemical formula

[0800] In some embodiments, the compound is of formula (IV-III-A-A):

Chemical formula

[0801] In some embodiments, the compound is of formula (IV-III-A-A*):

Chemical formula

[0802] In some embodiments, the compound is of formula (IV-I-A-A-I):

Chemical formula

[0803] In some embodiments, the compound is of formula (IV-I-A-A-I*):

Chemical formula

[0804] In some embodiments, the compound is of formula (IV-II-A-A-I):

Chemical formula

[0805] In some embodiments, the compound is of formula (IV-II-A-A-I*):

Chemical formula

[0806] In some embodiments, the compound is of formula (IV-III-A-A-I):

Chemical formula

[0807] In some embodiments, the compound is of formula (IV-III-A-A-I*):

Chemical formula

[0808] In some embodiments, the compound is of formula (V):

Chemical formula

[0809] In some embodiments, the compound is of formula (V-I):

Chemical formula

[0810] In some embodiments, the compound is of formula (V-A):

Chemical formula

[0811] In some embodiments, the compound is of formula (V-I-A):

Chemical formula

[0812] In some embodiments, the compound is of formula (V-A-A):

Chemical formula

[0813] In some embodiments, the compound is of formula (V-I-A-A):

Chemical formula

[0814] In some embodiments, the compound is of formula (V-A-A*):

Chemical formula

[0815] In some embodiments, the compound is of formula (V-I-A-A*):

Chemical formula

[0816] In some embodiments, the compound is of formula (V-A-A-I):

Chemical formula

[0817] In some embodiments, the compound is of formula (V-I-A-A-I):

Chemical formula

[0818] In some embodiments, the compound is of formula (V-A-A-I*):

Chemical formula

[0819] In some embodiments, the compound is of formula (V-I-A-A-I*):

Chemical formula

[0820] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure are, for example, acid addition salts of the compounds of the present disclosure that are sufficiently basic, for example, acid addition salts with inorganic acids or organic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid or maleic acid. Further, suitable pharmaceutically acceptable salts of the compounds of the present disclosure that are sufficiently acidic are alkali metal salts, for example sodium or potassium salts, alkaline earth metal salts, for example calcium or magnesium salts, ammonium salts or salts with organic bases that give pharmaceutically acceptable cations, for example, salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0821] It will be understood that any one of the compounds of the formula disclosed herein and any of its pharmaceutically acceptable salts include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of the said compounds.

[0822] In some embodiments, the compound is selected from the compounds described in Table 1, and its pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotope derivatives, or tautomers.

[0823] In some embodiments, the compound is selected from the compounds described in Table 1, and its prodrugs and pharmaceutically acceptable salts.

[0824] In some embodiments, the compound is selected from the compounds described in Table 1, and its pharmaceutically acceptable salts.

[0825] In some embodiments, the compound is selected from the prodrugs of the compounds described in Table 1 and their pharmaceutically acceptable salts.

[0826] In some embodiments, the compound is selected from the compounds described in Table 1.

[0827] Table 1. Specific examples of compounds of formula (A) JPEG2025520539000454.jpg194170JPEG2025520539000455.jpg203170JPEG2025520539000456.jpg203170JPEG2025520539000457.jpg194170JPEG2025520539000458.jpg194170JPEG2025520539000459.jpg194170JPEG2025520539000460.jpg194170JPEG2025520539000461.jpg194170JPEG2025520539000462.jpg194170JPEG2025520539000463.jpg194170JPEG2025520539000464.jpg203170JPEG2025520539000465.jpg194170JPEG2025520539000466.jpg194170JPEG2025520539000467.jpg83170

[0828] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 1.

[0829] In some embodiments, the compound is a lithium salt, sodium salt, potassium salt, calcium salt, or magnesium salt of any one of the compounds described in Table 1.

[0830] In some embodiments, the compound is a sodium salt or potassium salt of any one of the compounds described in Table 1.

[0831] In some embodiments, the compound is a salt of any acid described in Table 2 and any one of the compounds described in Table 1.

[0832] Table 2. Compounds of formula (A) form pharmaceutically acceptable acid addition salts. JPEG2025520539000468.jpg158170

[0833] In some embodiments, the compound is a salt of acetic acid and any one of the compounds described in Table 1.

[0834] In some embodiments, the compound is a salt of adipic acid and any one of the compounds described in Table 1.

[0835] In some embodiments, the compound is a salt of ascorbic acid (L) and any one of the compounds described in Table 1.

[0836] In some embodiments, the compound is a salt of hydrobromic acid and any one of the compounds described in Table 1.

[0837] In some embodiments, the compound is a salt of hydrochloric acid and any one of the compounds described in Table 1.

[0838] In some embodiments, the compound is a salt of citric acid and any one of the compounds described in Table 1.

[0839] In some embodiments, the compound is a salt of glutamic acid and any one of the compounds described in Table 1.

[0840] In some embodiments, the compound is a salt of oxalic acid and any one of the compounds described in Table 1.

[0841] In some embodiments, the compound is a salt of formic acid and any one of the compounds described in Table 1.

[0842] In some embodiments, the compound is a salt of sulfuric acid and any one of the compounds described in Table 1.

[0843] In some aspects, the present disclosure provides a compound that is an isotope derivative (e.g., an isotope-labeled compound) of any one of the compounds of the formula disclosed herein.

[0844] In some embodiments, the compound is an isotope derivative of any one of the compounds described in Table 1, as well as its prodrug and pharmaceutically acceptable salts.

[0845] In some embodiments, the compound is an isotope derivative of any one of the compounds described in Table 1 and its pharmaceutically acceptable salts.

[0846] In some embodiments, the compound is an isotope derivative of any one of the prodrugs of the compounds described in Table 1 and its pharmaceutically acceptable salts.

[0847] In some embodiments, the compound is an isotope derivative of any one of the compounds described in Table 1.

[0848] It is understood that the isotope derivatives can be prepared using any of the various techniques recognized in the art. For example, isotope derivatives can generally be prepared by using isotope-labeled reagents in place of non-isotope-labeled reagents and by carrying out the procedures disclosed in the schemes and / or examples described herein.

[0849] In some embodiments, the isotope derivative is a deuterium-labeled compound.

[0850] In some embodiments, the isotope derivative is a deuterium-labeled compound of any one of the compounds of the formula disclosed herein.

[0851] As used herein, the term "isotope derivative" refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, an isotope derivative of a compound of formula (A) is isotopically enriched or labeled with respect to one or more isotopes as compared to the corresponding compound of formula (A). In some embodiments, the isotope derivative is 2 H, 13 C, 14 C, 15 N, 18 O,29 Si, 31 P, and 34 is enriched or labeled with respect to one or more atoms selected from S. In some embodiments, the isotopic derivative is a deuterium-labeled compound (i.e., enriched with 2 H with respect to one or more of its atoms).

[0852] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1, as well as its prodrugs and pharmaceutically acceptable salts.

[0853] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1 and its pharmaceutically acceptable salts.

[0854] In some embodiments, the compound is a deuterium-labeled compound of any one of the prodrugs of the compounds described in Table 1 and its pharmaceutically acceptable salts.

[0855] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1.

[0856] It is understood that the deuterium-labeled compound contains deuterium atoms having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.

[0857] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor of at least 3500 (52.5% deuterium incorporation per deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each deuterium atom. As used herein, the term "deuterium enrichment factor" means the ratio of the amount of deuterium present to the natural abundance of deuterium.

[0858] It is understood that the deuterium-labeled compound can be prepared using any of a variety of techniques recognized in the art. For example, the deuterium-labeled compound can generally be prepared by using a deuterium-labeled reagent in place of a non-deuterium-labeled reagent and by carrying out the procedures disclosed in the schemes and / or examples described herein.

[0859] The compounds of the disclosure containing the deuterium atom(s), or pharmaceutically acceptable salts or solvates thereof, are within the scope of the disclosure. Further, substitution with deuterium (i.e., 2 H) can provide certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or decreased required dose.

[0860] In some embodiments, the compound is 18 an

[0861] In some embodiments, the compound is 33 an 34 an 35 an 36 an

[0862] 18 F, 33 S, 34 S, 35 S, and / or 36 It is understood that the compounds labeled with S can be prepared using any of the various techniques recognized in the art. For example, deuterium-labeled compounds are generally prepared by performing the procedures disclosed in the schemes and / or examples described herein and using 18 F, 33 S, 34 S, 35 S, and / or 36 S-labeled reagents.

[0863] The above 18 F, 33 S, 34 S, 35 S, and 36 The disclosed compounds containing one or more of the S atoms (s), or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure. Further, substitution with isotopes (e.g., 18 F, 33 S, 34 S, 35 S and / or 36 S) can provide certain therapeutic advantages resulting from greater metabolic stability, e.g., an increase in in vivo half-life or a decrease in the required dose.

[0864] To avoid doubt, herein, when a group is limited by "described herein", it is to be understood that the group encompasses the broadest definition at its first occurrence, as well as each and every specific definition of that group.

[0865] The various functional groups and substituents constituting the compounds of formula (A) are typically selected such that the molecular weight of the compound does not exceed 1000 daltons. More usually, the molecular weight of the compound is less than 1000, e.g., less than 900, or less than 800, or less than 700, or less than 600, or less than 500.

[0866] As used herein, the term "isomerism" means compounds that have the same molecular formula but differ in the order of their atomic bonds or the arrangement of those atoms in space. Isomers that differ in the arrangement of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereoisomers", and stereoisomers that cannot be superimposed on their mirror images are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of the individual enantiomeric forms of opposite chirality is designated a "racemic mixture".

[0867] As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[0868] As used herein, the term "chiral isomer" means a compound having at least one chiral center. Compounds having multiple chiral centers can exist as individual diastereomers or as a mixture of diastereomers called a "mixture of diastereomers". When there is one chiral center, the stereoisomers are characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration refers to the spatial arrangement of the substituents bonded to the chiral center. The substituents bonded to the chiral center are ranked according to the Cahn, Ingold, and Prelog sequence rules. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0869] As used herein, the term "geometric isomer" means diastereomers that exist due to restricted rotation around double bonds or cycloalkyl linkers (e.g., 1,3-cyclobutyl). These configurations are distinguished by the prefixes cis and trans, or Z and E, indicating that the groups are on the same or opposite sides of the double bond within the molecule, according to the Cahn-Ingold-Prelog rules.

[0870] It should be understood that the compounds of the present disclosure can be presented as different chiral or geometric isomers. Also, when a compound has chiral or geometric isomeric forms, it is intended that all isomeric forms are included within the scope of the present disclosure, and that the naming of a compound does not exclude all isomeric forms, and it is understood that all isomers do not necessarily have the same level of activity.

[0871] It should be understood that the structures and other compounds discussed in the present disclosure include all of their atropisomers. It should also be understood that all atropisomers do not necessarily have the same level of activity.

[0872] As used herein, the term "atropic isomer" is a type of stereoisomer in which the atoms of two isomers are spatially arranged differently. Atropic isomers exist because rotation of large groups around the central bond is hindered and rotation is restricted. Such atropic isomers typically exist as a mixture, but as a result of recent advances in chromatography techniques, it has become possible to separate the mixture of two atropic isomers when selected.

[0873] As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another. This conversion results in a formal shift of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomers in solution. In a solution where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors such as temperature, solvent, and pH. The concept of tautomers that can be interconverted by tautomerization is called tautomerism. Of the various possible types of tautomerism, two are commonly observed. In keto-enol tautomerism, a simultaneous shift of an electron and a hydrogen atom occurs. Ring-chain tautomerism results from the reaction of the aldehyde group (-CHO) of a sugar molecule with one of the hydroxy groups (-OH) of the same molecule, giving rise to a cyclic (ring-shaped) form as shown by glucose.

[0874] It should be understood that the compounds of the present disclosure may be shown as different tautomers. When a compound has tautomeric forms, it is intended that all tautomeric forms are included within the scope of the present disclosure, and it should also be understood that the naming of the compound does not exclude any tautomeric form. It will be understood that a particular tautomer may have a higher level of activity than other tautomers.

[0875] Compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms, or in the arrangement of those atoms in space, are called "isomers". Isomers that differ in the arrangement of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called diastereomers, and stereoisomers that cannot be superimposed on their mirror images are called enantiomers. If a compound has an asymmetric center, for example, if it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described by the Cahn and Prelog R- and S-configuration rules, or by the way in which the molecule rotates the plane of polarization, and are called dextrorotatory or levorotatory (i.e., as the (+) or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal ratios of enantiomers is called a "racemic mixture".

[0876] The compounds of the present disclosure can have one or more asymmetric centers; such compounds can be produced as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in this specification and the claims is intended to include both the individual enantiomers and mixtures thereof, racemates or other mixtures. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by resolution of racemates (see the discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present disclosure can have geometric isomerism centers (E-isomers and Z-isomers). It should be understood that the present disclosure encompasses all optical isomers, diastereoisomers and geometric isomers having inflammasome inhibitory activity and mixtures thereof.

[0877] The present disclosure also encompasses the disclosed compounds as defined herein that include one or more isotope substitutions.

[0878] It should be understood that any of the compounds of the formulas described herein, where applicable, include the compounds themselves, as well as their salts and their solvates. For example, salts can be formed between an anion on a substituted compound disclosed herein and a positively charged group (e.g., amino). Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0879] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation on a substituted compound disclosed herein and a negatively charged group (e.g., carboxylate). Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and ammonium cations such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include salts containing a quaternary nitrogen atom.

[0880] It should be understood that the compounds of the present disclosure, such as salts of the compounds, can exist in hydrated or non-hydrated (anhydrous) forms, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc., and non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0881] As used herein, the term "solvate" means a solvate form containing a solvent in either a stoichiometric or non-stoichiometric amount. Some compounds tend to form solvates by trapping a certain molar ratio of solvent molecules in the crystalline solid state. When the solvent is water, the resulting solvate is a hydrate; when the solvent is an alcohol, the resulting solvate is an alcoholate. Hydrates are formed by the combination of one molecule of a substance in which water retains its molecular state as H2O and one or more molecules of water.

[0882] As used herein, the term "analogue" refers to a compound that is structurally similar to another but has a slightly different composition (e.g., substitution of one atom by an atom of a different element, or substitution of one atom in the presence of a particular functional group, or substitution of one functional group by another functional group). Thus, analogues are compounds that are similar or equivalent in function and appearance but differ from the reference compound in structure or origin.

[0883] As used herein, the term "derivative" refers to a compound having a common core structure and substituted with various groups as described herein.

[0884] As used herein, the term "biological equivalent" refers to a compound resulting from the exchange of an atom or group of atoms with another, broadly similar atom or group of atoms. The purpose of a bioequivalent substitution is to produce a new compound having biological properties similar to those of the parent compound. Bioequivalent substitutions can be based on physicochemistry or topology. Examples of carboxylic acid biological equivalents include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0885] It should also be understood that any particular compound of the formulas disclosed herein may exist in solvated and unsolvated forms, such as hydrated forms. Suitable pharmaceutically acceptable solvates are, for example, hydrates such as hemihydrate, monohydrate, dihydrate or trihydrate. It is understood that the present disclosure encompasses all such solvated forms having inflammasome inhibitory activity.

[0886] Also, it should be understood that any particular compound of the formulas disclosed herein may exhibit polymorphism, and that the present disclosure encompasses all such forms or mixtures thereof having inflammasome inhibitory activity. Crystalline materials can generally be analyzed using conventional techniques such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near infrared (NIR) spectroscopy, solution and / or solid nuclear magnetic resonance spectroscopy. The water content of such crystalline substances can be measured by Karl Fischer analysis.

[0887] Any compound of the formulas disclosed herein can exist in many different tautomeric forms, and reference to a compound of formula (A) includes all such forms. To avoid doubt, if a compound can exist in one of several tautomeric forms and only one is specifically described or illustrated, nevertheless all others are encompassed by formula (A). Examples of tautomeric forms include, for example, the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acid-nitro, such as keto-, enol-, and enolate-forms.

Chem.

[0888] Any one of the compounds of the formula disclosed herein containing an amine functional group can also form an N-oxide. As used herein, reference to a compound of formula (A) containing an amine functional group also includes the N-oxide. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be produced by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Jerry March, 4th Edition, Wiley Interscience, pages Advanced Organic Chemistry. More specifically, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509 - 514), where the amine compound reacts with meta-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0889] Any one of the compounds of the formula disclosed herein can be administered in the form of a prodrug that is decomposed in the human or animal body to release the disclosed compound. Prodrugs can be used to change the physical properties and / or pharmacokinetic properties of the compounds of the present disclosure. When the compounds of the present disclosure contain a suitable group or substituent to which a property-modifying group can be attached, a prodrug can be formed. Examples of prodrugs include derivatives containing an alkyl or acyl substituent cleavable in vivo on any one of the ester or amide groups of the formula disclosed herein.

[0890] Accordingly, the present disclosure includes these compounds of any of the formulas defined above as disclosed herein when made available by organic synthesis and when made available in the body of a human or animal by cleavage of its prodrug. Accordingly, the present disclosure also includes these compounds of any of the formulas disclosed herein produced by organic synthetic means and such compounds produced in the body of a human or animal by metabolism of a precursor compound, and the compounds of any of the formulas disclosed herein may be either compounds produced by synthesis or compounds produced by metabolism.

[0891] Suitable pharmaceutically acceptable prodrugs of any of the compounds of the formulas disclosed herein are based on reasonable medical judgment that they are suitable for administration to the human or animal body without undesirable pharmacological activity and excessive toxicity. Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987。

[0892] Suitable pharmaceutically acceptable prodrugs of compounds having a hydroxy group of any of the formulas disclosed herein are, for example, esters or ethers thereof that are cleavable in vivo. In vivo cleavable esters or ethers of compounds having a hydroxy group of any of the formulas disclosed herein are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the body of a human or animal to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include C1-C 10 alkanoyl groups, ethoxycarbonyl, N,N-(C1-C6 alkyl)2 carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups, etc. C1-C 10 alkoxycarbonyl groups. Examples of ring substituents of phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for a hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0893] Suitable pharmaceutically acceptable prodrugs of any one of the compounds having a carboxy group of the formulas disclosed herein are, for example, in vivo cleavable amides, for example, amides formed with amines such as ammonia, C 1-4 alkylamines such as methylamine, (C1-C4 alkyl)2 amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine, phenyl-C1-C4 alkylamines such as benzylamine, and amino acids such as glycine or its esters.

[0894] Suitable pharmaceutically acceptable prodrugs of any of the compounds of the formulas disclosed herein having an amino group are, for example, amide derivatives cleavable in vivo thereof. Suitable pharmaceutically acceptable amides derived from amino groups include, for example, acetyl, benzoyl, phenylacetyl, and C1-C 10 Amides formed with alkanoyl groups. Examples of ring substituents of phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0895] The in vivo effects of any of the compounds of any of the formulas disclosed herein may be exerted in part by one or more metabolites formed in the body of a human or animal after administration of any of the compounds of any of the formulas disclosed herein. As described above, the in vivo effects of any one of the compounds of any of the formulas disclosed herein may also be exerted by metabolism of the precursor compound (prodrug). Methods for synthesizing the compounds

[0896] The compounds of the present invention can be prepared by various methods including standard chemistry. Suitable synthetic routes are shown in the schemes below.

[0897] The compounds of formula (A) can be prepared by methods known in the art of organic synthesis, as defined in part by the following synthetic schemes. In the schemes described below, it will be well understood that protecting groups for sensitive or reactive groups may be employed, as appropriate, in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, 「Protective Groups in Organic Synthesis」, Third edition, Wiley, New York 1999). These groups are removed by methods readily apparent to one of ordinary skill in the art at a convenient stage of compound synthesis. Whether a stereocenter exists in the compounds of formula (A) can be recognized by one of ordinary skill in the art by the choice of process, as well as reaction conditions and sequence. Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis), including racemic compounds, as well as individual enantiomers and / or diastereomers. If a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by separation of the final product or any convenient intermediate. Separation of the final product, intermediate, or starting material can be effected by any suitable method known in the art. See, for example, 「Stereochemistry of Organic Compounds」 by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

[0898] The compounds described herein can also be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes. Preparation of Compounds

[0899] The compounds of the present invention can be prepared by many methods well known to those skilled in organic synthesis. By way of example, the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of organic synthetic chemistry, or modifications thereof understood by those skilled in the art. Suitable methods include, but are not limited to, these methods described below. The compounds of the present invention can be synthesized according to the steps outlined in general procedures (General Schemes I, II, III, IV) involving different sequences of intermediate compounds or compounds. The starting materials are either commercially available, or are prepared by any of the known procedures reported in the literature, or as shown below. General Procedure

[0900] It is understood that the compounds of formula (A) described herein represent any of the compounds of formula (II), formula (III), formula (IV) and / or formula (V).

[0901] In general, the compounds of formula (A) can be prepared using reactions well known to those skilled in the field of organic synthesis. General Scheme I shows a possible synthetic route for preparing the compounds of formula (A) shown below:

Chemical formula

[0902] All reagents may be commercially available compounds themselves or synthetic products from commercially available reagents. For each compound during the preparation, one-step or multi-step synthetic procedures can be used, including but not limited to the procedures described in the preparation section of this specification.

[0903] Possible synthetic routes for preparing the compounds of formula (II) to formula (V) are shown below:

Chemical formula

Chemical formula

[0904] It will be apparent to those skilled in the art that any of the compounds of formula (A) obtained according to the above procedure can be subject to further transformations and modifications leading to other compounds of formula (A).

[0905] Any of the residues Y described herein can be introduced into the structure of the compounds of formula (A) using different approaches, some of which are shown in the following schemes.

Chemical formula

[0906] In some embodiments, the compounds of formula (A) can undergo further transformations to obtain other compounds of formula (A).

Chemical formula

[0907] After the compounds designed, selected, and / or optimized by the above method are generated, they can be characterized using various assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays including but not limited to these assays described below to determine whether they have predicted activity, binding activity, and / or binding specificity.

[0908] Furthermore, the use of high-throughput screening can accelerate the analysis using such assays. As a result, it becomes possible to rapidly screen the activity of the molecules described herein using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. In high-throughput assays, one or more different assay techniques including but not limited to those described below can be used.

[0909] A variety of in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo biological assays include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein. Pharmaceutical composition

[0910] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of the formulas described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[0911] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product directly or indirectly resulting from the combination of the specified ingredients in the specified amounts.

[0912] The compounds of the present disclosure can be formulated for oral administration in forms such as tablets, capsules (including sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of the present disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, using forms well known to those skilled in the pharmaceutical arts in each case.

[0913] The formulations of the present disclosure may be in the form of an aqueous solution containing an aqueous vehicle. The aqueous vehicle component may include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubilizing agents, chelating agents, preservatives, isotonic agents, viscosity / suspending agents, buffering agents, and pH adjusters, and mixtures thereof.

[0914] Any suitable solubilizing agent can be used. Examples of solubilizing agents include cyclodextrins selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0915] Any suitable chelating agent can be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0916] Any suitable preservative can be used. Examples of preservatives include quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, mercaptobenzothiazole, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, and those selected from the group consisting of sorbic acid and mixtures thereof.

[0917] In some embodiments, examples of preservatives include quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, mercaptobenzothiazole, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, and those selected from the group consisting of sorbic acid and mixtures thereof.

[0918] Also, the aqueous vehicle may contain an isotonic agent to adjust the tonicity (osmotic pressure). The isotonic agent can be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, triethylene glycol, etc.), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof. In some embodiments, the isotonic agent is selected from the group consisting of glycols (such as propylene glycol, triethylene glycol, etc.), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0919] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400, etc.), carboxymethylcellulose, hydroxypropylmethylcellulose, and crosslinked acrylic acid polymers (carbomers) such as polyalkenyl ethers or divinyl glycol crosslinked polymers of acrylic acid (Carbopol - for example, Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0920] To adjust the formulation to an acceptable pH (typically in the pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically a mineral acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to the target acceptable pH range. Thus, it is not necessary to use both an acid and a base, and for some formulations, the desired pH range can be achieved by adding only one of the acid or base.

[0921] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffering agent is selected from the group consisting of phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or its salts containing disodium tetraborate), citrate buffers (such as citric acid or its salts containing sodium citrate), and ε - aminocaproic acid, and mixtures thereof.

[0922] The formulation may further contain a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0923] Oral compositions typically include an inert diluent or a pharmaceutically acceptable carrier for food use. They can also be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be mixed with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which case the compound in the fluid carrier is applied to the mouth and then rinsed and spat out or swallowed. Pharmaceutically compatible binders and / or auxiliary substances can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth gum or gelatin; excipients such as starch or lactose, disintegrants such as alginic acid, primogel or corn starch; lubricants such as magnesium stearate or sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavors such as peppermint, methyl salicylate, orange flavor.

[0924] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0925] In some embodiments, the pharmaceutical compositions described herein may further comprise one or more additional pharmaceutically active agents.

[0926] Additional therapeutic agents that can be used in the methods of the present invention include diosmin, hesperidin, MK-3207, venetoclax, dihydroergocristine, borazin, R428, ditelluracanium, etoposide, teniposide, UK-432097, irinotecan, lumacaftor, velpatasvir, elsucidrine, ledipasvir, lopinavir / ritonavir + ribavirin, interferon, and prednisone. Other additional agents useful in the methods of the present invention include dexamethasone, azithromycin, remdesivir, as well as boceprevir, umifenovir, and favipiravir.

[0927] The compositions of the present disclosure can be in a form suitable for oral use (e.g., tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, aqueous or oily solutions or suspensions), administration by inhalation (e.g., as finely divided powders or liquid aerosols), administration by inhalation (e.g., as finely divided powders), or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0928] The compositions of the present disclosure can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweetening agents, flavorings and / or preservatives.

[0929] A therapeutically effective amount of the compounds of the present disclosure for use in therapy is an amount sufficient to treat or prevent coronavirus infection, slow its progression, and / or alleviate the symptoms associated with the condition.

[0930] The dosage of the compounds of formula (II) - formula (V) for therapeutic or prophylactic purposes will naturally vary according to the nature and severity of the condition, the age and sex of the animal or subject, and the route of administration, in accordance with well-known medical principles. Method of Use

[0931] In some embodiments, the present disclosure provides a method of inhibiting a SARS-CoV-2 related 3C-like protease (e.g., in vitro or in vivo) comprising contacting a cell with a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0932] In some embodiments, the present disclosure provides a method of treating or preventing coronavirus infection in a subject in need of treatment or prevention of coronavirus infection, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0933] In some embodiments, the present disclosure provides a method of treating coronavirus infection in a subject in need of treatment of coronavirus infection, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0934] In some embodiments, the disease or disorder is associated with a coronavirus. In some embodiments, the disease or disorder is a disease or disorder in which a coronavirus is involved.

[0935] The compounds of the present invention are inhibitors of SARS-CoV-2 related 3C-like protease.

[0936] In some embodiments, the compounds, compositions, and methods disclosed herein are used for the prevention or treatment of diseases, disorders, or conditions associated with coronavirus infection.

[0937] The compounds of the present invention are also useful for the treatment of diseases associated with coronavirus infection. For example, diseases and conditions treatable according to the methods of the present invention include COVID-19.

[0938] In some embodiments, the present disclosure provides a method of treating or preventing coronavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0939] In some embodiments, the present disclosure provides a method of treating or preventing COVID-19 infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0940] In some embodiments, the present disclosure provides a method of treating coronavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0941] In some embodiments, the present disclosure provides a method of treating COVID-19 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0942] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting SARS-CoV-2-related 3C-like protease (e.g., in vitro or in vivo).

[0943] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease or disorder disclosed herein.

[0944] In some embodiments, the present disclosure provides the compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment of the diseases or disorders disclosed herein.

[0945] In some embodiments, the present disclosure provides the compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of coronavirus infection in a subject in need thereof.

[0946] In some embodiments, the present disclosure provides the compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of COVID-19 in a subject in need thereof.

[0947] In some embodiments, the present disclosure provides the use of the compounds of the present disclosure or pharmaceutically acceptable salts thereof in the manufacture of an agent for inhibiting SARS-CoV-2-related 3C-like protease (e.g., in vitro or in vivo).

[0948] In some embodiments, the present disclosure provides the use of the compounds of the present disclosure or pharmaceutically acceptable salts thereof in the manufacture of an agent for treating or preventing the diseases or disorders disclosed herein.

[0949] In some embodiments, the present disclosure provides the use of the compounds of the present disclosure or pharmaceutically acceptable salts thereof in the manufacture of an agent for treating the diseases or disorders disclosed herein.

[0950] In some embodiments, the present disclosure provides the use of the compounds of the present disclosure or pharmaceutically acceptable salts thereof in the manufacture of an agent for treating or preventing coronavirus infection in a subject in need thereof.

[0951] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing COVID-19 in a subject in need of such treatment or prevention of COVID-19.

[0952] The present disclosure provides compounds that function as inhibitors of SARS-CoV-2-related 3C-like protease (e.g., in vitro or in vivo). Accordingly, the present disclosure provides a method of inhibiting SARS-CoV-2-related 3C-like protease in vitro or in vivo, the method comprising contacting a cell with a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as defined herein.

[0953] In some embodiments, the inhibitor of SARS-CoV-2-related 3C-like protease is a compound of the present disclosure.

[0954] The effectiveness of the compounds of the present disclosure can be determined by assays / disease models that are accepted in the art and as found in current general knowledge as described in the art.

[0955] The present disclosure also provides a method of treating a disease or disorder in which a coronavirus infection is involved in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0956] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. Route of Administration

[0957] The compounds of the present disclosure or pharmaceutical compositions comprising these compounds can be administered to a subject by any convenient route of administration, whether systemically / peripherally or locally (i.e., the desired site of action).

[0958] The route of administration is not limited, but includes oral (e.g., by oral ingestion); buccal; sublingual; transdermal (e.g., including those by patch, plaster, etc.); transmucosal (e.g., including those by patch, plaster, etc.); intranasal (e.g., nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., via the mouth or nose, e.g., inhalation or insufflation therapy using an aerosol); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral by injection such as subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, intradermal, intraarticular, subarachnoid, intrasternal, etc.; including, for example, by implanting a reservoir or reservoir subcutaneously or intramuscularly.

[0959] The abbreviations used in the following examples and elsewhere in this specification are as follows: JPEG2025520539000475.jpg211170JPEG2025520539000476.jpg42170 (Example) General synthetic procedures and examples of compound preparation. Synthesis of building blocks (1R,2S,5S)-3-((S)-3,3-Dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (PA.4) synthesis [Chemical formula]

[0960] Preparation 1. (1R,2S,5S)-3-((S)-2-((tert-Butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (PA.1). A solution of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate HCl salt (4.5 g, 21.9 mmol) and N-(tert-butoxycarbonyl)-3-methyl-L-valine (5.58 g, 24.1 mmol) in a mixture of N,N-dimethylformamide (9.0 ml) and acetonitrile (81 ml) was treated with HATU (9.09 g, 24.1 mmol) and N,N-diisopropylethylamine (8.55 g, 95.7 mmol) at 0 °C. Next, the reaction mixture was warmed to 25 °C and stirred for 16 h. The mixture was treated with ethyl acetate and washed with water and 1 M HCl (aq) , and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate = 3:1) to afford the desired product PA.1 (5.6 g, 67%). 1 H NMR (400 MHz, DMSO-d6), δ: 6.72 (d, J = 9.6 Hz, 1H), 4.20 (s, 1H), 4.05 - 4.03 (m, 1H), 3.92 (d, J = 10.4 Hz, 1H), 3.80 - 3.76 (m, 1H), 3.64 (s, 3H), 1.53 - 1.50 (m, 1H), 1.41 - 1.39 (m, 1H), 1.34 (s, 9H), 1.00 (s, 3H), 0.92 (s, 9H), 0.84 (s, 3H).

[0961] Preparation 2. (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (PA.2). To a solution of PA.1 (5.6 g, 15 mmol) in THF (20 ml) were added lithium hydroxide (1.1 g, 44 mmol) and water (20 ml). The reaction mixture was stirred at 25 °C for 17 h, then concentrated to remove THF. Subsequently, 1 M HCl(aq) was added to the residue to adjust the pH to 2. The resulting mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain PA.2 (6.16 g, crude product). 1 H NMR (400 MHz, DMSO-d6), δ: 6.67 (d, J = 9.2 Hz, 1H), 4.11 (s, 1H), 4.05 - 4.03 (m, 1H), 3.90 (d, J = 10.4 Hz, 1H), 3.78 - 3.74 (m, 1H), 1.50 - 1.47 (m, 1H), 1.39 - 1.38 (m, 1H), 1.34 (s, 9H), 1.00 (s, 3H), 0.92 (s, 9H), 0.83 (s, 3H).

[0962] \Preparation 3. (1R,2S,5S)-3-((S)-2-Amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid hydrochloride (PA.3). A solution of 4 M HCl in 1,4-dioxane (21 ml) was added to a solution of PA.2 (6.16 g) in DCM (19 ml). The mixture was stirred at 25 °C for 16 h, then the solvent was removed under reduced pressure to obtain the HCl salt of PA.3 (4.7 g, crude product). 1 H NMR (400 MHz, DMSO-d6), δ: 8.31 (br. s, 2H), 4.15 (s, 1H), 3.80 - 3.76 (m, 2H), 3.72 - 3.69 (m, 1H), 1.55 - 1.52 (m, 1H), 1.43 (d, J = 7.6 Hz, 1H), 1.02 (s, 9H), 1.01 (s, 3H), 0.95 (s, 3H).

[0963] Preparation 4. (1R,2S,5S)-3-((S)-3,3-Dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (PA.4). To a solution of the HCl salt of PA.3 (4.7 g, crude product) in methanol (15 ml) was added triethylamine (13 ml) and ethyl trifluoroacetate (3.13 mL, 26.3 mmol) at 0 °C. The mixture was warmed to 60 °C and then stirred for 16 h. The mixture was concentrated, the residue was diluted with water, and 1M HCl (aq) was added to adjust the pH to 3. The aqueous layer was extracted with ethyl acetate, the combined organic layers were dried over sodium sulfate, filtered, and concentrated to give PA.4 (5.5 g), which was used in the next step without purification. 1 H NMR (400 MHz, DMSO-d6), δ: 9.43 (d, J = 8.6 Hz, 1H), 4.43 (d, J = 8.6 Hz, 1H), 4.14 (s, 1H), 3.84 (dd, J = 10.8, 5.6 Hz, 1H), 3.71 (d, J = 10.8 Hz, 1H), 1.52 (dd, J = 7.6, 5.2 Hz, 1H), 1.42 (d, J = 7.6 Hz, 1H), 1.00 (s, 12H), 0.81 (s, 3H). Synthesis of (1R,2S,5S)-3-((S)-3,3-Dimethyl-2-(methylsulfonamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (PA.7)

Chemical Structure

[0964] Preparation 5. Methyl (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (PA.5). The HCl solution in 1,4-dioxane (4 M, 20 ml) was added to a solution of PA.1 (5.0 g, 13.08 mmol) in DCM (20 ml). After the mixture was stirred at 25 °C for 16 h, the solvent was removed under reduced pressure to give the HCl salt of PA.5 (4.3 g, crude product). 1 H NMR (400 MHz, DMSO-d6), δ: 8.35 (br. s, 3H), 4.22 (s, 1H), 3.83 - 3.79 (m, 2H), 3.74 - 3.72 (m, 1H), 3.65 (s, 3H), 1.57 - 1.56 (m, 1H), 1.46 (s, J = 7.6 Hz, 1H), 1.02 - 1.01 (m, 12H), 0.96 (s, 3H).

[0965] Preparation 6. Methyl (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(methylsulfonamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (PA.6). To a solution of PA.5 (500 mg, 1.58 mmol) in DCM (10 ml) were added MsCl (270 mg, 2.36 mmol) and TEA (640 mg, 6.32 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 17 h. The mixture was concentrated and purified by silica gel column chromatography (n-hexane:ethyl acetate = 3:1) to give the desired product PA.6 (480 mg, 84% yield). 1 H NMR (400 MHz, DMSO-d6), δ: 5.25 (d, J = 10.0 Hz, 1H), 4.48 (s, 1H), 3.92 - 3.88 (m, 1H), 3.85 - 3.77 (m, 2H), 3.75 (s, 3H), 2.89 (s, 3H), 1.51 - 1.45 (m, 2H), 1.06 - 1.05 (m, 12H), 0.97 (s, 3H).

[0966] Preparation 7. (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(methylsulfonamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (PA.7) To a solution of PA.6 (480 mg, 1.33 mmol) in THF (4.0 mL) were added lithium hydroxide (96 mg, 4.0 mmol) and water (4.0 mL). After stirring the reaction mixture at 25 °C for 17 h, it was neutralized with 1 M HCl (aq) and then concentrated to give PA.7 (800 mg, crude product), which was used in the next step. 1 1H NMR (400 MHz, DMSO-d6), δ: 7.07 (d, J = 9.6 Hz, 1H), 4.12 (s, 1H), 3.82 - 3.76 (m, 2H), 3.40 - 3.67 (m, 1H), 2.83 (s, 3H), 1.54 - 1.51 (m, 1H), 1.40 (d, J = 8.4 Hz, 1H), 1.00 (s, 3H), 0.97 (s, 9H), 0.88 (s, 3H). Synthesis of (1R,2S,5S)-3-[(2S)-2-(methoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (PA.11)

Chemical Structure

[0967] Preparation 8. Methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3,3-dimethyl-2-(methylamino)butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate (PA.8). To a solution of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate HCl salt (10 g, 48.7 mmol) and N-(tert-butoxycarbonyl)-3-methyl-L-valine (5.58 g, 24.1 mmol) in a mixture of DMF (20 ml) and ACN (180 ml) were added HATU (20.2 g, 53.6 mmol) and DIPEA (18.9 g, 212.7 mmol) at 0 °C. Then the reaction mixture was warmed to 25 °C and stirred for 16 h. The mixture was treated with ethyl acetate, water and 1 M HCl (aq)and washed with saturated aqueous sodium chloride solution (18 g, 96%). 1 H NMR (400 MHz, DMSO-d6), δ: 6.72 (d, J=9.6 Hz, 1H), 4.20 (s, 1H), 4.05 (d, J= 10.4 Hz, 1H), 3.93 (d, J=10 Hz, 1H), 3.81-3.77 (m, 1H), 3.64 (s, 3H), 1.54-1.51 (m, 1H), 1.42-1.40 (m, 1H), 1.35 (s, 9H), 1.00 (s, 3H), 0.93 (s, 9H), 0.85 (s, 3H).

[0968] Preparation 9. Methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (PA.9). A solution of 4M HCl in 1,4-dioxane (20 ml) was added to a solution of PA.8 (9 g, 23.5 mmol) in DCM (20 ml). After the mixture was stirred at 25 °C for 3 h, the solvent was removed under reduced pressure to afford the HCl salt of PA.9 (6 g, 90%). 1 H NMR (400 MHz, DMSO-d6), δ: 8.21 (s, 2H), 4.25 (s, 1H), 3.83-3.79 (m, 2H), 3.72 (d, J=11.2 Hz, 1H), 3.67 (s, 3H), 3.56 (s, 3H), 1.61-1.58 (m, 1H),1.49 (d, J= 8Hz, 1H), 1.03 (s, 9H), 0.86 (s, 3H).

[0969] Preparation 10. Methyl (1R,2S,5S)-3-[(2S)-2-(methoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (PA.10). To a solution of PA.9 (0.8 g, 2.8 mmol) in DCM were added methyl chloroformate (0.295 g, 3.1 mmol) and DIPEA (0.830 g, 6.4 mmol). The mixture was stirred at 25 °C for 16 h. The mixture was treated with ethyl acetate, washed with aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated to afford PA.10 (0.906 g, 95%). LCMS (ESI) m / z C 17 H 28 Calculated for C17H28N2O5, 340.42; found, 341.6 [M + H] + .

[0970] Preparation 11. (1R,2S,5S)-3-[(2S)-2-(Methoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (PA.11). To a solution of PA.10 (0.906 g, 2.7 mmol) in THF were added lithium hydroxide (0.453 g, 10.8 mmol) and water. The reaction mixture was stirred at 25 °C for 17 h and then concentrated to remove THF. Then 1 M HCl(aq) was added to the residue to adjust the pH to 2. The resulting mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford PA.11 (0.416 g, 47.3%). 1 H NMR (400 MHz, DMSO-d6), δ: 7.11 (d, J = 10.6 Hz, 1H), 4.11 (s, 1H), 4.04 (d, J = 8.4 Hz, 1H), 3.80 (s, 2H), 3.50 (s, 3H), 1.46 (s, 1H), 1.38 (d, J = 7.6 Hz, 1H), 1.00 (s, 3H), 0.99 (dd, J=8.06, J=6.75, 1H), 0.95 (s, 9H), 0.85 (s, 3H). Synthesis of Methyl N-[(1S)-1-[(1S)-2-[[(1S)-1-Cyano-2-(1H-indol-3-yl)ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]carbamate (P2)

Chemical Structure

[0971] Preparation 12. Methyl N-[(1S)-1-[(1S)-2-[[(1S)-2-Amino-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]carbamate (P1) To a solution of PA.11 (0.196, 0.6 mmol) in DMF, (2S)-2-Amino-3-(1H-indol-3-yl)propanamide (0.150 g, 0.63 mmol), 2-Hydroxypyridine 1-oxide (17 mg, 0.15 mmol), DIPEA (0.310, 2.4 mmol), and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.121 g, 0.78 mmol) were added at 0 °C. The reaction mixture was stirred at 25 °C for 16 h, then diluted with ethyl acetate. The solution was washed with a mixture of water, 1 M HCl (aq) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to give P1 (0.184 g, 62%). LCMS (ESI) m / z C 27 H 37 Calculated for C H N5O5 511.61; Found, 512.6 [M + H] + .

[0972] Preparation 13. Methyl N-[(1S)-1-[(1S)-2-[[(1S)-1-Cyano-2-(1H-indol-3-yl)ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]carbamate (P2). A solution of P1 (0.184 g, 0.36 mmol) in DCM was added with the Burgess reagent (0.214 g, 0.9 mmol), and the resulting mixture was stirred for 16 h. The residue was diluted with a solution of EtOAc and washed with saturated NaHCO 3(aq) , 1N HCl (aq) , and brine. The organic layer was dried over MgSO 4(s) , filtered, and concentrated under reduced pressure to obtain P2 (0.105 g, 59%). LCMS (ESI) m / z C 27 H 35 N5O4 calculated value for 493.59; found, 494.7 [M + H] + . Synthesis of ethyl N-[(1S)-1-[(1S)-2-[[(1S)-1-cyano-2-(1H-indol-3-yl)ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]carbamate (P4)

Chemical formula

[0973] Preparation 14. Methyl (1R,2S,5S)-3-[(2S)-2-(ethoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (PA.12). To a solution of PA.9 (0.8 g, 2.8 mmol) in DCM were added ethyl chloroformate (0.334 g, 3.1 mmol) and DIPEA (0.905 g, 6.4 mmol). After the mixture was stirred at 25 °C for 16 h, the mixture was treated with ethyl acetate, washed with an aqueous NaHCO3 solution, dried over sodium sulfate, filtered, and concentrated to obtain PA.12 (0.813 g, 82%). LCMS (ESI) m / z C 18 H 30 N2O5 calculated value for 354.44; found, 355.6 [M + H] + .

[0974] Preparation 15. (1R,2S,5S)-3-[(2S)-2-(Ethoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (PA.13). To a solution of PA.12 (0.813 g, 2.3 mmol) in THF was added LiOH (0.386 g, 9.2 mmol) and water. The reaction mixture was stirred at 25 °C for 17 h, then concentrated to remove THF. Then 1M HCl(aq) was added to the residue to adjust the pH to 2. The resulting mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give PA.13 (0.468 g, 60%). 1 H NMR (400 MHz, DMSO-d6), δ: 12.61 (s, 1H), 7.06 (d, J = 8.8 Hz, 1H), 4.12 (s, 1H), 4.09 - 3.89 (m, 5H), 3.86 - 3.76 (m, 3H), 1.99 (s, 1H), 1.52 - 1.49 (m, 1H), 1.39 (d, J = 8Hz, 1H), 1.15 - 1.12 (m, 4H), 0.98 - 0.95 (m, 10H).

[0975] Preparation 16. Ethyl N-[(1S)-1-[(1S)-2-[[(1S)-2-Amino-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]carbamate (P3). To a solution of PA.13 (0.200, 0.59 mmol) in DMF were added (2S)-2-Amino-3-(1H-indol-3-yl)propanamide (0.148 g, 0.62 mmol), 2-Hydroxypyridine 1-oxide (16 mg, 0.15 mmol), DIPEA (0.301 g, 2.4 mmol), and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.119 g, 0.77 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h, then diluted with ethyl acetate. The solution was washed with water, 1M HCl(aq) It was washed with a mixed solution of and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain P3 (0.201 g, 65%). LCMS (ESI) m / z Calculated for C 28 H 39 N5O5 525.64; Found, 526.8 [M + H] + .

[0976] Preparation 17. Ethyl N-[(1S)-1-[(1S)-2-[[(1S)-1-cyano-2-(1H-indol-3-yl)ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]carbamate (P4). To a solution of P3 (0.201 g, 0.39 mmol) in DCM was added Burgess reagent (0.234 g, 0.98 mmol), and the resulting mixture was stirred for 16 h. The residue was diluted with a solution of EtOAc, saturated NaHCO 3(aq) 3, 1N HCl (aq) , and brine. The organic layer was dried over MgSO 4(s) , filtered, and concentrated under reduced pressure to obtain P4 (0.189 g, 96%). LCMS (ESI) m / z Calculated fo...

Claims

1. A compound of formula (A): 【Chemical 1】 or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, or tautomer thereof. [Wherein, C is a heterocyclic ring selected from the following: 【Chemical 2】 m is an integer selected from 0, 1, and 2; A is selected from CR ４ and N; B is selected from CR ６ and N; 【Chemical Formula 3】 bond 【Chem.】 is selected from single bonds and double bonds; p is an integer selected from 0 and 1; E is selected from C(O) and N; provided that when the bond 【Chem.】 is a single bond, p is 1, E is C(O), and the bond 【Chem.】 is a double bond, p is 0, and E is N; m is an integer selected from 0, 1, 2; [Chemical Formula 4] each bond 【Chem.】 and 【Chem.】 is a single bond or a double bond; 【Chem.】 when 【Chem.】 is a double bond, each bond 【Chem.】 is a single bond; [Chemical] when 【Chem.】 is a single bond, each bond 【Chem.】 is independently selected from a single bond or a double bond; each p is an integer independently selected from 0 and 1; provided that 【Chemical Formula 5】 when 【Chem.】 is a single bond, p is 1, 【Chemical Formula 6】 when 【Chem.】 is a double bond, p is 0; k is an integer selected from 0, 1; provided that when the bond is a single bond and the bond [Chemical Formula 7] R Ｎ is selected from H, C １ -C ６ alkyl, cycloalkyl; R １ is selected from hydrogen, halogen, -OH, -CN, -NO ２ , -NR １４ R １５ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R １６ ; R ２ is selected from hydrogen, halogen, -OH, -CN, -NO ２ , -NR １４ R １５ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R １６ ; Alternatively, R １ and R ２ are both oxo; Alternatively, R ２ and R ３ form a bond together; R ３ is selected from hydrogen, C １ -C ６ -alkyl, C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R １６ ; R ４ is selected from hydrogen, halogen, -OH, -CN, -NO ２ , -NR １３ R １４ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R １６ ; Alternatively, R １ and R ４ together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle or heteroaryl is optionally substituted with one or more R １６ ; R ５ is selected from hydrogen, halogen, -OH, -CN, -NO ２ , -NR １４ R １５ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, -C(O)OR １３ , -C(O)N-NR １４ R １５ , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R １６ ; R ５ ' is selected from hydrogen, halogen, -OH, -CN, -NO ２ , -NR １４ R １５ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, -C(O)OR １４ , -C(O)N-NR １４ R １５ , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R １６ ; Alternatively, R ５ and R ５’ form oxo; R ６ is selected from H, C １ -C ６ alkyl, cycloalkyl, halogen, -CN, -OH; R ７ 、 R ８ 、 R ９ and R １０ are each independently selected from H, alkyl; Alternatively R ８ and R ９ together with the atoms to which they are attached and any intervening atoms form one or more halogens, -OH, -CN, C １ -C ６ optionally substituted cycloalkyl formed by alkyl; Alternatively, R ９ and R １０ together with the atoms to which they are attached and any intervening atoms form one or more halogens, —OH, —CN, C １ —C ６ cycloalkyl optionally substituted with alkyl; R １１ 、R １２ 、R １３ are each independently selected from C １ -C ６ alkyl, cycloalkyl, halogen, -CN; R １４ and R １５ are each independently selected from H, C １ -C ６ alkyl; Alternatively, R １４ and R １５ together with the atoms to which they are attached and any intervening atoms form one or more halogens, —OH, —CN, C １ —C ６ heterocyclyl optionally substituted with alkyl; R １６ is independently selected from halogen, -OH, -CN, -NO ２ , -NR １３ R １４ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, -C(O)OR １３ , -C(O)N-NR １３ R １４ , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl; X is hydrogen, halogen, OH, CN, NO ２ , CONH ２ , C １ -C ６ alkyl, C １ -C ６ alkoxy, C １ -C ６ alkyl-C １ -C ６ alkoxy, C １ -C ６ alkyl-NHC １ -C ６ selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl is optionally substituted with cycloalkyl, heterocyclyl, aryl, and heteroaryl; Y is C １ -C ６ alkyl-S(O) ｕ -, C １ -C ６ selected from alkyl-S(O)-, C-alkyl-C(O)-, heteroaryl-C(O)-, wherein the alkyl or heteroaryl is optionally substituted with one or more halogens, -OH, -CN; is a single bond, k is 1, and when the bond or the bond is a double bond, k is 0; and n is an integer selected from 0, 1, 2; u is an integer selected from 0, 1, 2; However, in the complex ring (A-II), m is 0; A and B are CH; R １ and R ２ are CH ３ , H, deuterium, or R １ is OH, or R １ and R ２ together are oxo; n is 1; R ８ and R ９ are C １ -C ６ alkyl, or R ８ and R ９ together with the atoms to which they are attached and any intervening atoms form cyclopropyl or cyclohexyl, or R ９ and R １０ together with the atoms to which they are attached and any intervening atoms form cyclobutyl, cyclohexyl, or R ９ is cyclopentyl; R １１ , R １２ , R １３ are each CH ３ ; when X is CN, Y is not CF ３ C(O)-, (CH ３ ) ３ CS(O) ２ -, ClCH ２ C(O)-, (CH ３ ) ２ CHC(O)-, CH ３ CH ２ C(O)-, CH ３ C(O)-; However, in the complex ring (A-II), m is 1; A and B are CH; R １ and R ２ are CH ３ or H; n is 1; R ８ and R ９ together with the atoms to which they are attached and any intervening atoms form cyclopropyl, cyclopentyl or cyclohexyl, or R ９ and R １０ together with the atoms to which they are attached and any intervening atoms form cyclobutyl, cyclohexyl, or when R ９ is cyclopentyl, Y is not CF ３ C(O)-; However, in the complex ring (A-II), m is 0; A and B are CH; R １ and R ２ are both H; n is 2; R ９ or R １０ is C １ -C ６ alkyl, Y is not CF ３ C(O)-, CH ３ S(O) ２ . cycloalkyl is a monocyclic or polycyclic saturated carbon ring containing 3 to 18 carbon atoms; aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; [Chemical Formula 8] heterocyclyl is a saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused ring, bridged ring, or spiro ring), or 11- to 14-membered tricyclic ring system (fused ring, bridged ring, or spiro ring) having one or more heteroatoms selected from O, N, S, P, Se, or B; heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, and the remaining ring atoms are C; A is selected from CR ４ and N; B is selected from CR ６ and N; R Ｎ is selected from H, C １ -C ６ alkyl, cycloalkyl; R １ is selected from hydrogen, halogen, -OH, -CN, -NO ２ , -NR １４ R １５ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R １６ ; R ２ is selected from hydrogen, halogen, -OH, -CN, -NO ２ , -NR １４ R １５ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R １６ ; Alternatively, R １ and R ２ are both oxo; Alternatively, R ２ and R ３ form a bond together; R ３ is selected from hydrogen, C １ -C ６ -alkyl, C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R １６ ; R ４ is selected from hydrogen, halogen, -OH, -CN, -NO ２ , -NR １４ R １５ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R １６ ; Alternatively, R １ and R ４ together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle or heteroaryl is optionally substituted with one or more R １６ ; Alternatively, R ３ and R ４ are both oxo; R ６ is selected from H, C １ -C ６ alkyl, cycloalkyl, halogen, -CN, -OH; R ７ 、 R ８ 、 R ９ and R １０ are each independently selected from H, C １ -C ６ alkyl, cycloalkyl; Alternatively, R ８ and R ９ together with the atoms to which they are attached and any intervening atoms form one or more halogens, -OH, -CN, C １ -C ６ optionally substituted cycloalkyl formed by alkyl; Alternatively R ９ and R １０ together with the atoms to which they are attached and any intervening atoms form one or more halogens, -OH, -CN, C １ -C ６ optionally substituted cycloalkyl formed by alkyl; R １１ 、 R １２ 、 R １３ are each independently selected from C １ -C ６ -alkyl, cycloalkyl, halogen, -CN; R １４ and R １５ are each independently selected from H, C １ -C ６ alkyl; Alternatively R １４ and R １５ together with the atoms to which they are attached and any intervening atoms form one or more halogens, -OH, -CN, C １ -C ６ heterocyclyl optionally substituted with alkyl; R １６ is independently selected from halogen, -OH, -OH, -CN, -NO ２ , -NR １４ R １５ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, -C(O)OR １４ , -C(O)N-NR １４ R １５ , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl; X is hydrogen, halogen, OH, CN, NO ２ , CONH ２ , C １ -C ６ alkyl, C １ -C ６ alkoxy, C １ -C ６ alkyl-C １ -C ６ alkoxy, C １ -C ６ alkyl-NHC １ -C ６ selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl is optionally substituted with cycloalkyl, heterocyclyl, aryl, and heteroaryl; Y is C １ -C ６ alkyl-S(O) ｕ -, C １ -C ６ selected from alkyl-S(O)-, C-alkyl-C(O)-, heteroaryl-C(O)-, wherein the alkyl or heteroaryl is optionally substituted with one or more halogens, -OH, -CN;

2. The compound according to claim 1, wherein the compound is of formula (II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, or tautomer thereof. [Wherein, m is an integer selected from 0, 1, 2; n is an integer selected from 0, 1, 2; u is an integer selected from 0, 1, 2; cycloalkyl is a monocyclic or polycyclic saturated carbon ring containing 3 to 18 carbon atoms; aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated monocyclic ring of 3 to 10 members, bicyclic ring of 7 to 12 members (fused ring, bridged ring, or spiro ring), or tricyclic ring system of 11 to 14 members (fused ring, bridged ring, or spiro ring) having one or more heteroatoms selected from O, N, S, P, Se, or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, and the remaining ring atoms are C; However, m is 0; A and B are CH; R １ and R ２ are CH ３ , H, deuterium, or R １ is OH, or R １ and R ２ together are oxo; n is 1; R ８ and R ９ are C １ -C ６ alkyl, or R ８ and R ９ together with the atoms to which they are attached and any intervening atoms form cyclopropyl or cyclohexyl, or R ９ and R １０ together with the atoms to which they are attached and any intervening atoms form cyclobutyl, cyclohexyl, or R ９ is cyclopentyl; R １１ , R １２ , R １３ are each CH ３ ; when X is CN, Y is CF ３ C(O)-, (CH ３ ) ３ CS(O) ２ -, ClCH ２ C(O)-, (CH ３ ) ２ CHC(O)-, CH ３ CH ２ C(O)-, CH ３ C(O)- is not; However, m is 1; A and B are CH; R １ and R ２ are CH ３ or H; n is 1; R ８ and R ９ together with the atoms to which they are attached and any intervening atoms form cyclopropyl, cyclopentyl or cyclohexyl, or R ９ and R １０ together with the atoms to which they are attached and any intervening atoms form cyclobutyl, cyclohexyl, or when R ９ is cyclopentyl, Y is not CF ３ C(O)-; However, m is 0; A and B are CH; R １ and R ２ are both H; n is 2; R ９ or R １０ is C １ -C ６ alkyl, Y is not CF ３ C(O)-, CH ３ S(O) ２ . Claim 3 The compound is of formula (III): 【Chemical Formula 9】 Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, or tautomer thereof, the compound according to claim 1. [Wherein, Bond [Chemical] Is selected from a single bond and a double bond; p is an integer selected from 0 and 1; E is selected from C(O) and N; Provided that when the bond 【Chem.】 Is a single bond, p is 1 and E is C(O), and when the bond 【Chem.】 Is a double bond, p is 0 and E is N; R Ｎ is selected from H, C １ -C ６ alkyl, cycloalkyl; R １ is selected from hydrogen, halogen, -OH, -CN, -NO ２ , -NR １４ R １５ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R １６ ; R ４ is selected from hydrogen, halogen, -OH, -CN, -NO ２ , -NR １４ R １５ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R １６ ; Alternatively, R １ and R ４ together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle or heteroaryl is optionally substituted with one or more R １６ ; R ７ 、 R ８ 、 R ９ and R １０ are each independently selected from H, C １ -C ６ alkyl, cycloalkyl; Alternatively, R ８ and R ９ together with the atoms to which they are attached and any intervening atoms form one or more halogens, -OH, -CN, C １ -C ６ optionally substituted cycloalkyl formed by alkyl; Alternatively, R ９ and R １０ together with the atoms to which they are attached and any intervening atoms form one or more halogens, —OH, —CN, C １ —C ６ cycloalkyl optionally substituted with alkyl; R １１ 、R １２ 、R １３ are each independently selected from C １ -C ６ -alkyl, cycloalkyl, halogen, -CN; R １４ and R １５ are each independently selected from H, C １ -C ６ alkyl; Alternatively R １４ and R １５ together with the atoms to which they are attached and any intervening atoms form one or more halogens, -OH, -CN, C １ -C ６ heterocyclyl optionally substituted with alkyl; R １６ is independently selected from halogen, -OH, -OH, -CN, -NO ２ , -NR １４ R １５ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, -C(O)OR １４ , -C(O)N-NR １４ R １５ , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl; X is hydrogen, halogen, OH, CN, NO ２ , CONH ２ , C １ -C ６ alkyl, C １ -C ６ alkoxy, C １ -C ６ alkyl-C １ -C ６ alkoxy, C １ -C ６ alkyl-NHC １ -C ６ selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl is optionally substituted with cycloalkyl, heterocyclyl, aryl, and heteroaryl; Y is C １ -C ６ alkyl-S(O) ｕ -, C １ -C ６ selected from alkyl-S(O)-, C-alkyl-C(O)-, heteroaryl-C(O)-, wherein alkyl or heteroaryl is optionally substituted with one or more halogens, -OH, -CN; m is an integer selected from 0, 1, and 2; n is an integer selected from 0, 1, and 2; u is an integer selected from 0, 1, and 2; Cycloalkyl is a monocyclic or polycyclic saturated carbon ring containing 3 to 18 carbon atoms; Aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated monocyclic ring of 3 to 10 members, bicyclic ring of 7 to 12 members (fused ring, bridged ring, or spiro ring), or tricyclic ring system of 11 to 14 members (fused ring, bridged ring, or spiro ring) having one or more heteroatoms selected from O, N, S, P, Se, or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, and the remaining ring atoms are C.] Claim 4 The compound is of formula (IV): 【Chemical 10】 Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, or tautomer thereof, the compound according to claim 1. [Wherein, Bond [Chemical] And 【Chem.】 Are a single bond or a double bond; 【Chem.】 When it is a double bond, each bond 【Chem.】 Is a single bond, and when 【Chem.】 Is a single bond, each bond 【Chem.】 Is independently selected from a single bond and a double bond; Each p is an integer independently selected from 0 and 1; Provided that when 【Chem.】 Is a single bond, p is 1, 【Chem.】 When it is a double bond, p is 0; k is an integer selected from 0 and 1; However, the bond 【Chemical Formula 11】 is a single bond, and the bond [Chemical] is a single bond, k is 1, and the bond 【Chemical Formula 12】 or the bond 【Chem.】 is a double bond, k is 0; Each R Ｎ is independently selected from H, C １ -C ６ alkyl, cycloalkyl; R ５ is selected from hydrogen, halogen, -OH, -CN, -NO ２ , -NR １４ R １５ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, -C(O)OR １３ , -C(O)N-NR １４ R １５ , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R １６ ; R ５ ' is selected from hydrogen, halogen, -OH, -CN, -NO ２ , -NR １４ R １５ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, -C(O)OR １４ , -C(O)N-NR １４ R １５ , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R １６ ; Alternatively, R ５ and R ５’ form oxo; R ７ 、 R ８ 、 R ９ and R １０ are each independently selected from H, C １ -C ６ alkyl, cycloalkyl; Alternatively R ８ and R ９ together with the atoms to which they are attached and any intervening atoms form one or more halogens, -OH, -CN, C １ -C ６ optionally substituted cycloalkyl formed by alkyl; Alternatively, R ９ and R １０ together with the atoms to which they are attached and any intervening atoms form one or more halogens, —OH, —CN, C １ —C ６ cycloalkyl optionally substituted with alkyl; R １１ 、R １２ 、R １３ are each independently selected from C １ -C ６ alkyl, cycloalkyl, halogen, -CN; R １４ and R １５ are each independently selected from H, C １ -C ６ alkyl; Alternatively R １４ and R １５ together with the atoms to which they are attached and any intervening atoms form one or more halogens, -OH, -CN, C １ -C ６ heterocyclyl optionally substituted with alkyl; R １６ is independently selected from halogen, -OH, -OH, -CN, -NO ２ , -NR １４ R １５ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, -C(O)OR １４ , -C(O)N-NR １４ R １５ , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl; X is hydrogen, halogen, OH, CN, NO ２ , CONH ２ , C １ -C ６ alkyl, C １ -C ６ alkoxy, C １ -C ６ alkyl-C １ -C ６ alkoxy, C １ -C ６ alkyl-NHC １ -C ６ selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl is optionally substituted with cycloalkyl, heterocyclyl, aryl, and heteroaryl; Y is C １ -C ６ alkyl-S(O) ｕ -, C １ -C ６ selected from alkyl-S(O)-, C-alkyl-C(O)-, heteroaryl-C(O)-, wherein the alkyl or heteroaryl is optionally substituted with one or more halogens, -OH, -CN; n is an integer selected from 0, 1, and 2; u is an integer selected from 0, 1, and 2; [In the formula, Cycloalkyl is a monocyclic or polycyclic saturated carbon ring containing 3 to 18 carbon atoms; Aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused ring, bridged ring, or spiro ring), or 11- to 14-membered tricyclic ring system (fused ring, bridged ring, or spiro ring) having one or more heteroatoms selected from O, N, S, P, Se, or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, and the remaining ring atoms are C. ]

5. The compound is of formula (V): 【Chemical 13】 Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, or tautomer thereof, the compound according to claim 1. [In the formula, R １ is selected from hydrogen, halogen, -OH, -CN, -NO ２ , -NR １４ R １５ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R １６ ; R ４ is selected from hydrogen, halogen, -OH, -CN, -NO ２ , -NR １３ R １４ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R １６ ; Alternatively, R １ and R ４ together with the atoms to which they are attached and any intervening atoms form a 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocycle, or 5- to 6-membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle or heteroaryl is optionally substituted with one or more R １６ ; R ７ 、 R ８ 、 R ９ and R １０ are each independently selected from H, C １ -C ６ alkyl, cycloalkyl; Alternatively, R ８ and R ９ together with the atoms to which they are attached and any intervening atoms form one or more halogens, -OH, -CN, C １ -C ６ cycloalkyl optionally substituted with alkyl; Alternatively R ９ and R １０ together with the atoms to which they are attached and any intervening atoms form one or more halogens, -OH, -CN, C １ -C ６ optionally substituted cycloalkyl formed by alkyl; R １１ 、R １２ 、R １３ are each independently selected from C １ -C ６ alkyl, cycloalkyl, halogen, -CN; R １４ and R １５ are each independently selected from H, C １ -C ６ alkyl; Alternatively R １４ and R １５ together with the atoms to which they are attached and any intervening atoms form one or more halogens, -OH, -CN, C １ -C ６ heterocyclyl optionally substituted with alkyl; R １６ is independently selected from halogen, -OH, -OH, -CN, -NO ２ , -NR １３ R １４ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, -C(O)OR １３ , -C(O)N-NR １３ R １４ , cycloalkyl, -O-cycloalkyl, aryl, heterocyclyl, and heteroaryl; X is hydrogen, halogen, OH, CN, NO ２ , CONH ２ , C １ -C ６ alkyl, C １ -C ６ alkoxy, C １ -C ６ alkyl-C １ -C ６ alkoxy, C １ -C ６ alkyl-NHC １ -C ６ selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl is optionally substituted with cycloalkyl, heterocyclyl, aryl, and heteroaryl; Y is C １ -C ６ alkyl-S(O) ｕ -, C １ -C ６ selected from alkyl-S(O)-, C-alkyl-C(O)-, heteroaryl-C(O)-, wherein alkyl or heteroaryl is optionally substituted with one or more halogens, -OH, -CN; n is an integer selected from 0, 1, and 2; u is an integer selected from 0, 1, and 2; [In the formula, Cycloalkyl is a monocyclic or polycyclic saturated carbon ring containing 3 to 18 carbon atoms; Aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused ring, bridged ring, or spiro ring), or 11- to 14-membered tricyclic ring system (fused ring, bridged ring, or spiro ring) having one or more heteroatoms selected from O, N, S, P, Se, or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, and the remaining ring atoms are C. ]

6. The compound is of formula (II-I-A-A-A-I), (II-I-A-A-A-II), (II-I-A-A-A-III), (II-I-A-A-B-I), (II-I-A-A-C-I), (II-I-A-A-D-I), (II-I-A-B-A-I), (II-I-B-A-A-I), (II-II-A-A-A-I), (II-II-A-B-A-I), or (II-II-A-C-A-I): 【Chemical Formula 14】 【Chemical Formula 15】 【Chemical 16】 【Chemical 17】 The compound according to claim 2, or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

7. The compound is of formula (II-I-A-A-A-I-A) or (II-I-A-A-A-I-B): 【Chemical Formula 18】 【Chemical Formula 19】 Or, the compound according to claim 2, which is a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, and w is an integer selected from 0, 1, 2, 3, and 4.

8. The compound is of formula (II-I-W) 【Chemical 20】 Or, the compound according to claim 2, which is a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotope derivative, or tautomer thereof, and ring W is selected from 3- to 10-membered cycloalkyl, 6- to 10-membered aryl, 3- to 14-membered heterocyclic ring, or 5- to 6-membered heteroaryl; w is an integer selected from 0, 1, 2, 3, and 4; and all other variables are as defined herein.

9. The compound is of formula (III-I-I-A-A-A-I) or (III-II-I-A-A-I): 【Chemical 21】 【Chemical 22】 The compound according to claim 3, or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

10. The compound is of formula (IV-I-A-A-I), (IV-II-A-A-I), or (IV-III-A-A-I): 【Chemical 23】 【Chemical 24】 The compound according to claim 4, or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

11. The compound is of formula (V-I-A-A-I): 【Chemical 25】 Or, the compound according to claim 5, which is a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, and w is an integer selected from 0, 1, 2, 3, 4.

12. A compound selected from the following: Or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to claim 13, further comprising an additional pharmaceutically active agent.

15. A method for inhibiting the replication of a coronavirus, comprising administering to a subject the compound according to any one of claims 1 to 12, or the pharmaceutical composition according to any one of claims 13 or 14.

16. A method for treating a disease or disorder associated with a coronavirus infection, comprising administering to a subject the compound according to any one of claims 1 to 12, or the pharmaceutical composition according to any one of claims 13 or 14.

17. A method for treating a coronavirus infection, comprising administering to a subject in need of treatment the compound according to any one of claims 1 to 12, or the pharmaceutical composition according to any one of claims 13 or 14.

18. The method according to claim 17, wherein the coronavirus infection is COVID-19.

19. The method according to any one of claims 15 to 18, wherein the subject is a mammal.

20. The method according to claim 19, wherein the subject is a human.

Images