Compounds for treatment of coronavirus infections

Abstract

The present invention generally relates to inhibitors of SARS-CoV-2-related 3C-like protease (Mpro) useful for the treatment of coronavirus infections, characterized by comprising the following formula (A): # imgabs0 #

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present invention claims priority to U.S. Provisional Patent Application Serial No. 63 / 353,354 filed on June 17, 2022, entitled “Compounds for Treating Coronavirus Infections” and U.S. Provisional Patent Application Serial No. 63 / 414,287 filed on October 7, 2022, entitled “Compounds for Treating Coronavirus Infections”, the disclosures of which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0002] The present invention relates to inhibitors of coronavirus replication activity. The inhibitors of the present invention can be used to treat diseases caused by coronavirus infection, including COVID-19 caused by SARS-CoV-2 infection. Specifically, the present invention relates to compounds and pharmaceutical compositions that inhibit SARS-CoV-2-associated 3C-like proteases, methods for treating coronavirus infection, and methods for synthesizing these compounds. Background Art

[0003] Coronaviruses are a large family of viruses that typically cause mild to moderate upper respiratory tract illnesses in people. However, three coronaviruses have caused more severe and fatal illnesses in people: SARS coronavirus (SARS-CoV), which emerged in November 2002 and caused severe acute respiratory syndrome (SARS); MERS coronavirus (MERS-CoV), which emerged in 2012 and caused Middle East respiratory syndrome (MERS); and SARS-CoV-2, which emerged in 2019 and causes coronavirus disease 2019 (COVID-19).

[0004] Infection with severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2, causes coronavirus disease 2019 (COVID-19).

[0005] The virus that causes COVID-19 spreads easily from person to person. Data shows that COVID-19 spreads mainly between people who are in close contact (within about 6 feet or 2 meters). COVID-19 can spread from people who are infected but don't have symptoms. This is called asymptomatic spread. COVID-19 can also spread from people who are infected but don't yet have symptoms. This is called presymptomatic spread. It's possible to get COVID-19 after being infected with SARS-CoV-2 again, and this can happen more than once.

[0006] Whole-genome sequencing shows that SARS-CoV-2 shares 79.6% sequence identity with SARS-CoV. SARS-CoV-2 appears to have a relatively high rate of transmission among humans and causes severe and fatal pneumonia and other lesions, threatening people of all ages, but particularly the elderly and those with pre-existing conditions, including immunodeficiency, lung disease, metabolic disorders, and other diseases. With the rapid increase in infections and deaths, the development of drugs against COVID-19 is urgently needed.

[0007] SARS-CoV-2 is a complex virus composed of three open reading frames expressing a polyprotein. The polyprotein is converted to its mature, active form under proteolytic processing. Although the spike glycoprotein is cleaved by the cucurbit proteases cathepsin L and TMPRSS2, the remaining proteolytic processing steps are mediated by one of two virally encoded proteases designated as the main protease (Mpro or 3C-like protease (3CLpro)) and the papain-like protease PLpro. Mpro plays a crucial role in the maturation of viral proteins required for RNA replication and is a preferred 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] Given the ongoing spread of SARS-CoV-2, which has caused the current worldwide COVID-19 outbreak, it is desirable to have new methods to inhibit SARS-CoV-2 viral replication and treat COVID-19 in patients. Summary of the Invention

[0009] Generally speaking, the present invention relates to compounds comprising formula (A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug or tautomer thereof, in: C is a heterocycle selected from the group consisting of: Wherein: 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; Among them: key is selected from single bonds and double bonds; p is an integer selected from 0, 1; E is selected from C (O) and N; provided that when the bond is a single bond, p is 1 and E is C(O), and when the bond When is a double bond, p is 0 and E is N; m is an integer selected from 0, 1, 2; Where: Each key and is a single bond or a double bond; when When it is a double bond, each bond is a single bond, when When it is a single key, each key are independently selected from single bonds or double bonds; each p is an integer independently selected from 0 and 1; provided that when is a single bond, then p is 1, and when is a double bond, then p is 0; k is an integer selected from 0 and 1; provided that when the bond is a single bond and the bond is a single bond, then k is 1, and when the bond The key When it is a double bond, k is 0; as well as in: R N Selected from H, C1-C6 alkyl, cycloalkyl; R 1 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 replaced by one or more R 16 replace; R 2 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 replaced by one or more R 16 replace; or R 1 and R 2 Together is oxo; or R 2 and R 3 together to form a double bond; 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 replaced by one or more R 16 replace; R 4 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 replaced by one or more R 16 replace; or R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 16 replace; R 5 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, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 16 replace; R 5 '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, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 16 replace; or R 5 and R 5 'formation of oxo; R 6 Selected from H, C1-C6 alkyl, cycloalkyl, halogen, -CN, -OH; R 7 、R 8 、R 9 and R 10are each independently selected from H, alkyl; or R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; or R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; R 11 、R 12 、R 13 Each is independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R 15 Each independently selected from H, C1-C6 alkyl; or R 14 and R 15 Together with the atoms to which it is attached and any intervening atoms, it forms a heterocyclyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; R 16 Independently selected from halogen, –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 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)-, wherein the alkyl or heteroaryl group is optionally substituted with one or more halogen, -OH, -CN; n is an integer selected from 0, 1, and 2; u is an integer selected from 0, 1, and 2; in, Cycloalkyl is a monocyclic or polycyclic saturated carbocyclic 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 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged or spiro) or 11-14 membered tricyclic ring system (fused, bridged or spiro) having one or more heteroatoms selected from O, N, S, P, Se or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic group having 5 to 24 ring atoms, wherein the monovalent monocyclic or polycyclic aromatic group contains one or more ring heteroatoms selected from N, O, S, P or B, and the remaining ring atoms are C; Provided that when in heterocycle (A-II), m is 0; A and B are CH; R 1 and R 2 is CH3, H, deuterium, or R 1 It is OH, or R 1 and R 2 Together is oxo; n is 1; R 8 and R 9 is a C1-C6 alkyl group, or R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclopropyl or cyclohexyl group, or R 9 and R 10 Together with the atoms to which it is attached and any intermediate atoms, it forms a cyclobutyl, a cyclohexyl, or R 9 is cyclopentyl; R 11 、R 12 、R 13 Each is CH3; and when X is CN, then Y is not CF3C(O)-, (CH3)3CS(O)2-, ClCH2C(O)-, (CH3)2CHC(O)-, CH3CH2C(O)-, CH3C(O)-; Provided that when in heterocycle (A-II), m is 1; A and B are CH; R 1 and R 2 is CH3 or H; n is 1; R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, they form a cyclopropyl, cyclopentyl, or cyclohexyl group, or R 9 and R 10 Together with the atoms to which it is attached and any intermediate atoms, it forms a cyclobutyl, a cyclohexyl, or R 9 When it is a cyclopentyl group, Y is not CF3C(O)-; and provided that when in heterocycle (A-II), m is 0; A and B are CH; R 1 and R 2 Both are H; n is 2; R 9 or R 10When it is a C1-C6 alkyl group, Y is not CF3C(O)- or CH3S(O)2.

[0010] A first aspect of the present invention relates to compounds comprising formula (II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug or tautomer thereof, in: A is selected from CR 4 and N; B is selected from CR 6 and N; R N Selected from H, C1-C6 alkyl, cycloalkyl; R 1 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 replaced by one or more R 16 replace; R 2 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 replaced by one or more R 16 replace; or R 1 and R 2 Together is 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 replaced by one or more R 16 replace; R 4 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 replaced by one or more R 16replace; or R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 16 replace; or R 3 and R 4 Together is oxo; R 6 Selected from H, C1-C6 alkyl, cycloalkyl, halogen, -CN, -OH; R 7 、R 8 、R 9 and R 10 Each is independently selected from H, C1-C6 alkyl, cycloalkyl; or R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; or R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; R 11 、R 12 、R 13 Each is independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R 15 Each independently selected from H, C1-C6 alkyl; or R 14 and R 15 Together with the atoms to which it is attached and any intervening atoms, it forms a heterocyclyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; R 16 Independently selected from 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; 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 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)-, wherein the alkyl or heteroaryl group is optionally substituted with one or more halogen, -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; in, Cycloalkyl is a monocyclic or polycyclic saturated carbocyclic 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 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged or spiro) or 11-14 membered tricyclic ring system (fused, bridged or spiro) having one or more heteroatoms selected from O, N, S, P, Se or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic group having 5 to 24 ring atoms, wherein the monovalent monocyclic or polycyclic aromatic group contains one or more ring heteroatoms selected from N, O, S, P or B, and the remaining ring atoms are C; The conditions are when m is 0; A and B are CH; R 1 and R 2 is CH3, H, or R 1 It is OH, or R 1 and R 2 Together is oxo; n is 1; R 8 and R 9 is a C1-C6 alkyl group, or R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclopropyl or cyclohexyl group, or R 9 and R 10 Together with the atoms to which it is attached and any intermediate atoms, it forms a cyclobutyl, a cyclohexyl, or R 9 is cyclopentyl; R 11 、R 12 、R 13 Each is CH3; and when X is CN, then Y is not CF3C(O)-, (CH3)3CS(O)2-, ClCH2C(O)-, (CH3)2CHC(O)-, CH3CH2C(O)-, CH3C(O)-; The conditions are when m is 1; A and B are CH; R 1 and R 2 is CH3 or H; n is 1; R 8 and R 9 Together with the atoms to which they are attached and any intervening atoms, they form a cyclopropyl, cyclopentyl, or cyclohexyl group, or R 9 and R 10 Together with the atoms to which it is attached and any intermediate atoms, it forms a cyclobutyl, a cyclohexyl, or R 9 When it is a cyclopentyl group, Y is not CF3C(O)-; And the conditions are that when m is 0; A and B are CH; R 1 and R 2 Both are H; n is 2; R 9 or R 10 When it is a C1-C6 alkyl group, Y is not CF3C(O)- or CH3S(O)2.

[0011] A second aspect of the present invention relates to compounds comprising formula (III): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug or tautomer thereof, in: The key 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; The condition is that when the key is a single bond, p is 1, E is C(O), and when the bond When it is a double bond, p is 0 and E is N; R N Selected from H, C1-C6 alkyl, cycloalkyl; R 1 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 replaced by one or more R 16 replace; R 4 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 replaced by one or more R 16 replace; or R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 16 replace; R 7 、R 8 、R 9 and R 10 Each is independently selected from H, C1-C6 alkyl, cycloalkyl; or R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; or R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; R 11 、R 12 、R 13 Each is independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R 15 Each independently selected from H, C1-C6 alkyl; or R 14 and R 15 Together with the atoms to which it is attached and any intervening atoms, it forms a heterocyclyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; R 16 Independently selected from 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; 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 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)-, wherein the alkyl or heteroaryl group is optionally substituted with one or more halogen, -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; in, Cycloalkyl is a monocyclic or polycyclic saturated carbocyclic 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 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged or spiro) or 11-14 membered tricyclic ring system (fused, bridged or spiro) having one or more heteroatoms selected from O, N, S, P, Se or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic group having 5 to 24 ring atoms, which contains one or more ring heteroatoms selected from N, O, S, P or B, and the remaining ring atoms are C.

[0012] A third aspect of the present invention relates to compounds comprising formula (IV): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug or tautomer thereof, in: Each key and Is a single bond or a double bond; when When it is a double bond, each bond is a single bond, when When it is a single key, each key are independently selected from a single bond or a double bond; Each p is an integer independently selected from 0 and 1; The condition is when is a single bond, then p is 1, and when When it is a double bond, p is 0; k is an integer selected from 0 and 1; The condition is that when the key is a single bond and the bond is a single bond, k is 1, and when the bond or the key When it is a double bond, k is 0; Each R N Independently selected from H, C1-C6 alkyl, cycloalkyl; R 5 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, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 16 replace; R 5 '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, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 16 replace; or R 5 and R 5 'formation of oxo; R 7 、R 8 、R 9 and R 10 Each is independently selected from H, C1-C6 alkyl, cycloalkyl; or R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; or R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; R 11 、R 12、R 13 Each is independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R 15 Each independently selected from H, C1-C6 alkyl; or R 14 and R 15 Together with the atoms to which it is attached and any intervening atoms, it forms a heterocyclyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; R 16 Independently selected from 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; 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 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)-, wherein the alkyl or heteroaryl group is optionally substituted with one or more halogen, -OH, -CN; n is an integer selected from 0, 1, and 2; u is an integer selected from 0, 1, and 2; in, Cycloalkyl is a monocyclic or polycyclic saturated carbocyclic 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 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged or spiro) or 11-14 membered tricyclic ring system (fused, bridged or spiro) having one or more heteroatoms selected from O, N, S, P, Se or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic group having 5 to 24 ring atoms, which contains one or more ring heteroatoms selected from N, O, S, P or B, and the remaining ring atoms are C.

[0013] A fourth aspect of the present invention relates to compounds comprising formula (V): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug or tautomer thereof, in: R 1 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 replaced by one or more R 16 replace; R 4 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 replaced by one or more R 16 replace; or R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 16 replace; R 7 、R 8 、R 9 and R 10 Each is independently selected from H, C1-C6 alkyl, cycloalkyl; or R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; or R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; R 11 、R 12 、R 13 Each is independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R15 Each independently selected from H, C1-C6 alkyl; or R 14 and R 15 Together with the atoms to which it is attached and any intervening atoms, it forms a heterocyclyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; R 16 Independently selected from halogen, –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 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)-, wherein the alkyl or heteroaryl group is optionally substituted with one or more halogen, -OH, -CN; n is an integer selected from 0, 1, and 2; u is an integer selected from 0, 1, and 2; in, Cycloalkyl is a monocyclic or polycyclic saturated carbocyclic 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 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged or spiro) or 11-14 membered tricyclic ring system (fused, bridged or spiro) having one or more heteroatoms selected from O, N, S, P, Se or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic group having 5 to 24 ring atoms, which contains one or more ring heteroatoms selected from N, O, S, P or B, and the remaining ring atoms are C.

[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 may further include 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 may further include 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 may further include 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 may further include an excipient, a diluent or a surfactant.

[0018] Another aspect of the present invention relates to a method for treating coronavirus infection (such as COVID-19). The method comprises administering 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 to a patient in need of treatment for coronavirus infection (such as COVID-19).

[0019] Another aspect of the present invention relates to a method for inhibiting or preventing SARS-CoV-2 virus replication. The method involves 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 comprising Formula (II), Formula (III), Formula (IV), Formula (V) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof, which is used to prepare a medicament for inhibiting or preventing SARS-CoV-2 virus replication.

[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 treating a disease or condition associated with SARS-CoV-2 virus infection.

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

[0023] Another aspect of the present invention relates to a method for treating or preventing coronavirus infection (such as COVID-19) in a subject in need thereof. The method involves 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 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 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 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 or pharmaceutical composition thereof 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 or pharmaceutical composition thereof in the treatment of coronavirus infection.

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

[0030] The present invention provides a virus replication activity inhibitor, which is a therapeutic agent for treating coronavirus infection.

[0031] The present invention provides a SARS-CoV-2 related 3C-like protease inhibitor, which is a therapeutic agent for treating coronavirus infection.

[0032] The present invention provides a SARS-CoV-2 related Mpro protease inhibitor, which is a therapeutic agent for treating coronavirus infection.

[0033] The present invention further provides compounds and compositions with improved efficacy and safety relative to known SARS-CoV-2-associated 3C-like protease inhibitors.

[0034] The present invention further provides a method for treating a disease or condition associated with coronavirus infection, comprising 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 treating coronavirus infection.

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

[0037] The present invention further provides compounds and compositions with improved efficacy and safety compared to known SARS-CoV-2 associated 3C-like protease inhibitors. The present invention further provides agents with a novel mechanism of action against SARS-CoV-2 associated 3C-like proteases in the treatment of coronavirus infections.

[0038] The present invention further provides compounds and compositions with improved efficacy and safety relative to known SARS-CoV-2 related Mpro protease inhibitors. The present invention also provides agents with a new mechanism of action on 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 condition 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); 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 aspects, the invention provides a compound obtainable by or obtained by a process for preparing a compound described herein (eg, a process comprising one or more of the steps described in the general procedures).

[0042] In some aspects, the present invention provides an intermediate as described herein, which is suitable for use in a method of preparing a compound as described herein (eg, the intermediate is selected from the intermediates described in Preparation Section - P1-P65).

[0043] In some aspects, the present invention provides a method of preparing a compound of the present invention.

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

[0045] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those generally understood by those of ordinary skill in the art to which the present invention belongs. In this specification, unless the context clearly provides otherwise, the singular also includes the plural. Although methods and materials similar to or equivalent to the methods and materials described in the present invention can be used in the practice or test of the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned in the present invention are incorporated by reference. The references cited in the present invention are not considered to be prior art of the claimed invention. In the event of a conflict, this specification (including definitions) will be taken as the criterion. In addition, materials, methods and examples are only illustrative and are not intended to be restrictive. In the event of a conflict between the chemical structure and the name of the compound disclosed in the present invention, the chemical structure will be taken as the criterion.

[0046] Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. DETAILED DESCRIPTION

[0047] The present invention provides a method for treating, preventing or ameliorating viral infections associated with coronaviruses by administering a therapeutically effective amount of a compound as disclosed herein to a subject in need thereof.

[0048] The details of the present invention are set forth in the following accompanying description. Although methods and materials similar or equivalent to the methods and materials described in the present invention can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Based on the description and claims, other features, objects and advantages of the present invention will become apparent. In this specification and the appended claims, unless the context clearly provides otherwise, the singular form also includes the plural form. Unless otherwise defined, all technical terms and scientific terms used in the present invention have the same meaning as those of ordinary skill in the art to which the present invention belongs. All patents and disclosures cited in this specification are incorporated herein by reference as a whole. definition

[0049] The articles "a" and "an" are used herein to refer to one or to more than one (ie, to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0050] Unless otherwise stated, the term "and / or" is used in the present invention to mean "and" or "or".

[0051] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) may (but is not required to) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group may be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have one or more substituents other than hydrogen. For example, the same optionally substituted alkyl group may be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any point along the chain. Thus, the term "optionally substituted" means that a given chemical moiety may contain other functional groups, but does not necessarily have any additional functional groups. Substituents suitable for use in optional substitutions 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, -O -C(O)NH(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and -S(O)N((C1-C6)alkyl). The substituents themselves may be optionally substituted. As used herein, "optionally substituted" also refers to substituted or unsubstituted, each having the meanings described below.

[0052] As used herein, the term "substituted" means that the specified group or moiety bears one or more suitable substituents, wherein the substituents may be attached to the specified group or moiety at one or more positions. For example, an aryl group substituted with a cycloalkyl group may indicate that the cycloalkyl group is attached to an atom of the aryl group by a bond or by being fused with the aryl group and sharing two or more common atoms.

[0053] As used herein, the term "unsubstituted" means that the designated group bears no substituents.

[0054] Unless otherwise specifically 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. In the case of containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be joined at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group can optionally be substituted with one or more substituents (e.g., 1 to 5 substituents) at any point of attachment. 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 themselves may be optionally substituted. In addition, when containing two fused rings, the aryl group defined in the present invention may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, benzonaphthyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzoannulyl, etc.

[0055] Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic group of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P or B, the remaining ring atoms being C. Polycyclic aromatic groups include two or more fused rings and may further include two or more spirofused rings, for example, bicyclic, tricyclic, tetracyclic, etc. Unless otherwise specifically defined, "fused" means two rings sharing two ring atoms. Unless otherwise specifically defined, "spirofused" means two rings sharing one ring atom. Heteroaryl as defined herein also means a bicyclic heteroaromatic group, wherein the heteroatoms are selected from N, O, S, P or B. Heteroaryl as defined herein also means a tricyclic aromatic group containing one or more ring heteroatoms 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. Aromatic groups are optionally substituted independently with one or more substituents described herein.Examples include, but are not limited to, furanyl, thienyl, pyrrolyl, pyridinyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thien-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazolyl, indazolyl, 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, dihydrobenzothienyl, 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, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridinyl, [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]pyrrolyl, 3H-indolyl and derivatives thereof. Additionally, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated rings fused to one or more fully unsaturated aromatic rings.In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated rings may be further fused to the saturated or partially unsaturated rings described herein. In addition, when containing three or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated spiro-fused rings. Any saturated or partially unsaturated ring described herein is optionally substituted with one or more oxo-substituted rings. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyrrolidone, oxazin-9-yl, 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3-b]pyridino[1,2-d][1,4]oxazin-9'-yl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, benzo[c][1,2]oxaborolan-1(3H)-oxazolyl, 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]pyridino[1,2-d][1,4]oxazin]-9'-onyl.

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

[0057] Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms. Examples of (C1-C6) alkyl 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 or branched chain saturated hydrocarbon containing 1-12 carbon atoms, containing a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy.

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

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

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

[0062] "Cycloalkyl" means a monocyclic or polycyclic saturated carbocyclic ring containing 3 to 18 carbon atoms. A polycyclic cycloalkyl group can be a fused bicyclic cycloalkyl group, a bridged bicyclic cycloalkyl group, or a spirofused bicyclic cycloalkyl group. A polycyclic cycloalkyl group includes at least one non-aromatic ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 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", "heterocycle" or "heterocycloalkyl" monocyclic or polycyclic ring containing 3-24 atoms, the atoms including carbon and one or more heteroatoms selected from N, O, S, P or B, and wherein the ring is not aromatic. The heterocycloalkyl ring structure can be substituted with one or more substituents. The substituents themselves can be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetane, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxaalkynyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepine, oxapine, diazepine, tropanyl, oxazolidinone and homotropanyl.

[0064] The term "aromatic" means a planar ring having 4n+2 electrons in a conjugated system. As used herein, a "conjugated system" refers to a system of connected p orbitals having delocalized electrons, and the system may include lone electron pairs.

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

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

[0067] As used herein, the term "cyano" refers to a substituent having a carbon atom connected to a nitrogen atom via a triple bond, ie, C≡N.

[0068] "Spiroalkyl" or "spirocyclyl" means a carbon-derived bicyclic ring system in which the two rings are connected by a single atom. The size and properties of the rings may be different or the size and properties may be the same. Examples include spiropentanes, spirohexanes, spiroheptanes, spirooctanes, spirononanes, or spirodecanes. One or both of the rings in the spirocycle may be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in the spirocycle may be substituted with a heteroatom (e.g., O, N, S, or P). (C3-C 12 ) Spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms, one or more of which may be substituted by a heteroatom.

[0069] The term "spiroheterocycloalkyl," "spiroheterocycle," or "spiroheterocyclyl" is understood to mean a spirocycle wherein at least one of the rings is a heterocycle (eg, at least one of the rings is furanyl, morpholinyl, or piperidinyl).

[0070] The term "solvate" refers to a complex having a variable stoichiometry formed by a solute and a solvent. Such solvents for the purposes of the present invention may not 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 commonly referred to as 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 having the same composition and molecular weight but differing in physical and / or chemical properties. The structural differences may lie in composition (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, compounds of formula (A) may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereomers.

[0072] The present invention also contemplates isotopically labeled compounds of formula (A) (e.g., 2 H and 14 C-labeled ones). Tritiated (i.e., 2 H or D) and carbon-14 (i.e., 14 C) isotopes are particularly preferred because of their ease of preparation and detectability. In addition, substitution with heavier isotopes (such as deuterium) can provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) resulting from greater metabolic stability, and therefore may be preferred in certain cases. Isotopically labeled compounds of formula (A) can generally be prepared by replacing non-isotopically labeled reagents with appropriate isotopically labeled reagents following procedures similar to those disclosed in the schemes and / or examples below.

[0073] The present invention also includes pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compound 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, camphorsulfonate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, propionate lauryl sulfate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycolyl p-aminophenylarsonic acid salt, hexafluorophosphate, hexylresorcinol salt, hydramin (hydramin). bamine), hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothiosulfate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, methanesulfonate, methyl bromide, methylnitrate, methylsulfate, mucate, naphthenate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, theocyanate, toluenesulfonate, triethyl iodide, and valerate.

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

[0075] When used in conjunction with a compound, an "effective amount" refers to an amount effective to treat or prevent a disease in a subject as described herein.

[0076] As used in the present invention, the term "carrier" encompasses carriers, excipients, and diluents, and means a material, composition, or vehicle such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material that is involved in carrying or transporting an agent from one organ or part of the body to another organ or part of the body of a subject.

[0077] The term "treating" with respect to a subject refers to ameliorating at least one symptom of a condition in the subject. Treatment includes curing, ameliorating, or at least partially alleviating a condition.

[0078] Unless otherwise indicated, the term "disorder" is used herein to refer to, and is used interchangeably with, the terms disease, condition, or illness.

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

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

[0081] The term "salt" refers to pharmaceutically acceptable salts.

[0082] The term "pharmaceutically acceptable salt" also refers to salts of the compositions of the present invention having an acidic functional group (such as a carboxylic acid functional group) and a base.

[0083] As used herein, “SARS-CoV-2 associated 3C-like protease inhibitors” refer to compounds of formula (II), formula (III), formula (IV) or formula (V) and / or compositions comprising compounds of formula (II), formula (III), formula (IV) or formula (V) that inhibit SARS-CoV-2 associated 3C-like protease.

[0084] As used herein, “SARS-CoV-2 viral replication inhibitor” refers to a compound of Formula (II), Formula (III), Formula (IV) or Formula (V) and / or a composition comprising a compound of Formula (II), Formula (III), Formula (IV) or Formula (V) that inhibits SARS-CoV-2 viral replication.

[0085] The term "SARS-CoV-2 inhibitor" means any 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 SARS-CoV-2 replication in any 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. Typically, in order to administer a therapeutic agent for therapeutic purposes (e.g., a compound or composition of Formula (II), (III), (IV), or (V) described herein (and / or another medicament)), the therapeutic agent is administered in a pharmacologically effective dose.

[0087] "Pharmacologically effective amount," "pharmacologically effective dose," "therapeutically effective amount," or "effective amount" refers to an amount sufficient to produce a desired physiological effect or an amount capable of achieving a desired result, particularly an amount for treating coronavirus infection. An effective amount as used herein will include an amount sufficient, for example, to delay the development of symptoms of a condition or disease, to change the course of symptoms of a condition or disease (e.g., to slow the progression of symptoms of a disease), to alleviate or eliminate one or more symptoms or manifestations of a condition or disease, and to reverse the symptoms of a condition or disease. Therapeutic benefit also includes preventing or slowing the progression of a potential disease or condition, whether or not improvement is achieved. Compounds of the present invention

[0088] In one aspect, the present invention provides compounds comprising formula (II) and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives and tautomers thereof: where 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 are as described in the present invention.

[0089] It should be understood that for 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 in the present invention where applicable, and the present invention is directed to 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 any of the groups described can be combined with the group described in the present invention for R N、R 1 、R 2 、R 3 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 , any combination of groups described by one or more of the remaining parts of 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 Selected from H, C1-C6 alkyl, cycloalkyl; R 1 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 replaced by one or more R 16 replace; R 2 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 replaced by one or more R 16 replace; or R 1 and R 2 Together is 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 replaced by one or more R 16 replace; R 4 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 replaced by one or more R 16 replace; or R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 16 replace; or R 3 and R 4 Together is oxo; R 6 Selected from H, C1-C6 alkyl, cycloalkyl, halogen, -CN, -OH; R 7 、R 8 、R 9 and R 10 Each is independently selected from H, C1-C6 alkyl, cycloalkyl; or R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; or R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; R 11 、R 12 、R 13 Each is independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R 15 Each independently selected from H, C1-C6 alkyl; or R 14 and R 15 Together with the atoms to which it is attached and any intervening atoms, it forms a heterocyclyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; R 16 Independently selected from halogen, –OH, –CN, –NO2, –NR 14 R 15 , C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, -C(O)OR14 、-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, wherein 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)-, wherein the alkyl or heteroaryl group is optionally substituted with one or more halogen, -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.

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

[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 .

[0096] In some embodiments, B is CH.

[0097] In some embodiments, B is N.

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

[0099] In some embodiments, R N It’s H.

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

[0101] In some embodiments, R N It's methyl.

[0102] In some embodiments, R N It's ethyl.

[0103] In some embodiments, R NIt is a cycloalkyl group.

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

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

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

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

[0108] In some embodiments, R 1 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 replaced by one or more R 16 replace.

[0109] In some embodiments, R 1 It's hydrogen.

[0110] In some embodiments, R 1 It's deuterium.

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

[0112] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 16 Substituted 6-membered aryl.

[0113] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered unsubstituted aryl group.

[0114] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more halogens.

[0115] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more Fs.

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

[0117] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intermediate atoms, it forms a 6-membered aryl group substituted with one or more Cl groups.

[0118] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intermediate atoms, it forms a 6-membered aryl group substituted with one Cl.

[0119] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group optionally having one or more C1-C6 alkyl groups.

[0120] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more methyl groups.

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

[0122] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group optionally having one or more C1-C6 alkoxy groups.

[0123] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more methoxy groups.

[0124] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one methoxy group.

[0125] In some embodiments, R 2 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 replaced by one or more R 16 replace.

[0126] In some embodiments, R 2 It’s H.

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

[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 replaced by one or more R 16 replace.

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

[0130] In some embodiments, R 3 It’s H.

[0131] In some embodiments, R 4 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 replaced by one or more R 16 replace.

[0132] In some embodiments, R 4 It’s H.

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

[0134] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 16 Substituted 6-membered aryl.

[0135] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered unsubstituted aryl group.

[0136] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more halogens.

[0137] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more Fs.

[0138] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one F.

[0139] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intermediate atoms, it forms a 6-membered aryl group substituted with one or more Cl groups.

[0140] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intermediate atoms, it forms a 6-membered aryl group substituted with one Cl.

[0141] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group optionally having one or more C1-C6 alkyl groups.

[0142] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more methyl groups.

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

[0144] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group optionally having one or more C1-C6 alkoxy groups.

[0145] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more methoxy groups.

[0146] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intermediate atoms, it forms a 6-membered aryl group substituted with a methoxy group.

[0147] In some embodiments, m is an integer selected from 0, 1, and 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, and 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 Each is independently selected from H, C1-C6 alkyl.

[0156] In some embodiments, R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group which is optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

[0157] In some embodiments, R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclopropane ring which is optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

[0158] In some embodiments, R 9and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group which is optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

[0159] In some embodiments, R 7 and R 8 H, R respectively 9 and R 10 Each is a C1-C6 alkyl group.

[0160] In some embodiments, R 7 and R 8 H, R respectively 9 and R 10 Each is CH3.

[0161] In some embodiments, n is 2, R 7 and R 8 H, R respectively 9 and R 10 Each is a C1-C6 alkyl group.

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

[0163] In some embodiments, n is 2, R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group which is optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

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

[0165] In some embodiments, n is 1, R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group which is optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

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

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

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

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

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

[0171] In some embodiments, n is 1, R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclopropane ring which is optionally geminally substituted with two methyl groups.

[0172] In some embodiments, R 11 、R 12 、R 13 Each is independently selected from H, C1-C6 alkyl, cycloalkyl, halogen, and -CN.

[0173] In some embodiments, R 11 、R 12 、R 13 Each is a C1-C6 alkyl group.

[0174] In some embodiments, R 11 、R 12 、R 13 Each is a methyl group.

[0175] In some embodiments, R 11 、R 12 、R 13 Each is a halogen.

[0176] In some embodiments, R 11 、R 12 、R 13 Each is F.

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

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

[0179] In some embodiments, R 14 and R 15 Each is H.

[0180] In some embodiments, R 14 and R 15 Each is a methyl group.

[0181] In some embodiments, R 14 and R 15 Together with the atoms to which it is attached and any intervening atoms, it forms a heterocyclic group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

[0182] In some embodiments, R 16 Independently selected from halogen, –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 by 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 a heterocyclyl.

[0189] In some embodiments, X is

[0190] In some embodiments, X is

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

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

[0201] In another aspect, the present invention provides compounds comprising formula (III) and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives and tautomers thereof: where 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 are as described in the present invention.

[0202] It should be understood that for 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 be selected from the groups described in the present invention where applicable, and the present invention is directed to 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 be combined with any of the groups described in the present invention for 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 any combination of groups described by one or more of the rest of p.

[0203] In some embodiments, The key 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; The condition is that when the key is a single bond, p is 1, and when the bond When it is a double bond, p is 0; And the condition is that when the key is a double bond, E is N, and the bond When it is a single bond, E is C(O); R N Selected from H, C1-C6 alkyl, cycloalkyl; R 1 Selected from hydrogen, halogen, –OH, –CN, –NO2, –NR 14 R15 , 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 replaced by one or more R 16 replace; R 4 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 replaced by one or more R 16 replace; or R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 16 replace; R 7 、R 8 、R 9 and R 10 Each is independently selected from H, C1-C6 alkyl, cycloalkyl; or R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; or R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; R 11 、R 12 、R 13 Each is independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R 15 Each independently selected from H, C1-C6 alkyl; or R 14 and R 15 Together with the atoms to which it is attached and any intervening atoms, it forms a heterocyclyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; R 16Independently selected from 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; 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 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 group is optionally substituted with one or more halogen, -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.

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

[0205] In some embodiments, the key 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 Selected from H, C1-C6 alkyl, cycloalkyl.

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

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

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

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

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

[0216] In some embodiments, R 1 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 replaced by one or more R 16 replace.

[0217] In some embodiments, R 1 It’s H.

[0218] In some embodiments, R 1 It is a C1–C6 alkyl group.

[0219] In some embodiments, R 1 It's methyl.

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

[0221] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 16 Substituted 6-membered aryl.

[0222] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered unsubstituted aryl group.

[0223] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more halogens.

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

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

[0226] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intermediate atoms, it forms a 6-membered aryl group substituted with one or more Cl groups.

[0227] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intermediate atoms, it forms a 6-membered aryl group substituted with one Cl.

[0228] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group optionally having one or more C1-C6 alkyl groups.

[0229] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more methyl groups.

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

[0231] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group optionally having one or more C1-C6 alkoxy groups.

[0232] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more methoxy groups.

[0233] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one methoxy group.

[0234] In some embodiments, R 2 Selected from hydrogen, halogen, –OH, –CN, –NO2, –NR14 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 replaced by one or more R 16 replace.

[0235] In some embodiments, R 4 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 replaced by one or more R 16 replace.

[0236] In some embodiments, R 4 It’s H.

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

[0238] In some embodiments, R 4 It's methyl.

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

[0240] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 16 Substituted 6-membered aryl.

[0241] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered unsubstituted aryl group.

[0242] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more halogens.

[0243] In some embodiments, R4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more Fs.

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

[0245] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intermediate atoms, it forms a 6-membered aryl group substituted with one or more Cl groups.

[0246] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intermediate atoms, it forms a 6-membered aryl group substituted with one Cl.

[0247] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group optionally having one or more C1-C6 alkyl groups.

[0248] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more methyl groups.

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

[0250] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group optionally having one or more C1-C6 alkoxy groups.

[0251] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more methoxy groups.

[0252] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one methoxy group.

[0253] In some embodiments, n is an integer selected from 0, 1, and 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 Each is independently selected from H, C1-C6 alkyl, and cycloalkyl.

[0258] In some embodiments, R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group which is optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

[0259] In some embodiments, R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclopropane ring which is optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

[0260] In some embodiments, R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group which is optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

[0261] In some embodiments, R 7 and R 8 H, R respectively 9 and R 10 Each is a C1-C6 alkyl group.

[0262] In some embodiments, R 7 and R 8 H, R respectively 9 and R 10 Each is CH3.

[0263] In some embodiments, n is 2, R 7 and R 8 H, R respectively 9 and R 10 Each is a C1-C6 alkyl group.

[0264] In some embodiments, n is 2, R 7 and R 8 H, R respectively9 and R 10 Each is CH3.

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

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

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

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

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

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

[0271] In some embodiments, n is 1, R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclopropane ring optionally substituted with two C1-C6 alkyl groups.

[0272] In some embodiments, n is 1, R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclopropane ring which is optionally geminally substituted with two C1-C6 alkyl groups.

[0273] In some embodiments, n is 1, R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclopropane ring which is optionally geminally substituted with two methyl groups.

[0274] In some embodiments, R 11 、R 12 、R 13 Each is independently selected from H, C1-C6 alkyl, cycloalkyl, halogen, and -CN.

[0275] In some embodiments, R 11 、R 12 、R 13 Each is a C1-C6 alkyl group.

[0276] In some embodiments, R 11 、R 12 、R 13 Each is a methyl group.

[0277] In some embodiments, R 11 、R 12 、R 13 Each is a halogen.

[0278] In some embodiments, R 11 、R 12 、R 13 Each is F.

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

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

[0281] In some embodiments, R 14 and R 15 Each is H.

[0282] In some embodiments, R 14 and R 15 Each is a methyl group.

[0283] In some embodiments, R 14 and R 15 Together with the atoms to which it is attached and any intervening atoms, it forms a heterocyclic group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

[0284] In some embodiments, R 16Independently selected from halogen, –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 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 by cycloalkyl, heterocyclyl, aryl and heteroaryl.

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

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

[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 a heterocyclyl.

[0291] In some embodiments, X is

[0292] In some embodiments, X is

[0293] In some embodiments, Y is selected from C1-C6 alkyl-S(O) u -, C1-C6 alkyl-C(O)-, wherein the alkyl group is optionally substituted with one or more halogen, -OH, or -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 CF3C(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 invention provides compounds comprising formula (IV) and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives and tautomers thereof: where 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 in the present invention.

[0303] It will be appreciated that for compounds of formula (IV), 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 can each be selected from the groups described in the present invention where applicable, and the present invention is directed to R 5 、R 5 '、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R N Any group described by any one of X, Y, k, n and p may be combined with any group described by any one of the present invention for R 5 、R 5 '、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R13 、R N , X, Y, k, n and any combination of groups described by one or more of the rest of p.

[0304] In some embodiments, Each key and Is a single bond or a double bond; When the key When it is a double bond, each bond is a single bond, when When it is a single key, each key are independently selected from a single bond or a double bond; Each p is an integer independently selected from 0 and 1; The condition is when is a single bond, then p is 1, and when When it is a double bond, p is 0; k is an integer selected from 0 and 1; The condition is that when the key is a single bond and the bond is a single bond, k is 1, and when the bond or the key When it is a double bond, k is 0; R 5 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, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 16 replace; R 5' 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, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 16 replace; or R 5 and R5 'formation of 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 it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; or R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; R 11 、R 12 、R 13 Each is independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R 15 Each independently selected from H, C1-C6 alkyl; or R 14 and R 15 Together with the atoms to which it is attached and any intervening atoms, it forms a heterocyclyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; R 16 Independently selected from 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; Each R N 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, wherein 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 group is optionally substituted with one or more halogen, -OH, -CN; n is an integer selected from 0, 1, and 2; u is an integer selected from 0, 1, and 2.

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

[0306] In some embodiments, the key Is a single key, each key is a double bond, k is 0, and each p is 0.

[0307] In some embodiments, the key Is a single key, each key is a single bond, k is 1, and each p is 1.

[0308] In some embodiments, R 5 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, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 16 replace.

[0309] In some embodiments, R 5 It’s H.

[0310] In some embodiments, R 5 '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, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 16 replace.

[0311] In some embodiments, R 5 'It's H.

[0312] In some embodiments, R 5 and R 5'Forming oxo.

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

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

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

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

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

[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 Each is independently selected from H, C1-C6 alkyl.

[0323] In some embodiments, R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group which is optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

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

[0325] In some embodiments, R 9 and R 10Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group which is optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

[0326] In some embodiments, R 7 and R 8 H, R respectively 9 and R 10 Each is a C1-C6 alkyl group.

[0327] In some embodiments, R 7 and R 8 H, R respectively 9 and R 10 Each is CH3.

[0328] In some embodiments, n is 2, R 7 and R 8 H, R respectively 9 and R 10 Each is a C1-C6 alkyl group.

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

[0330] In some embodiments, n is 2, R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group which is optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

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

[0332] In some embodiments, n is 1, R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group which is optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

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

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

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

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

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

[0338] In some embodiments, n is 1, R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclopropane ring which is optionally geminally substituted with two methyl groups.

[0339] In some embodiments, R 11 、R 12 、R 13 Each is independently selected from H, C1-C6 alkyl, cycloalkyl, halogen, and -CN.

[0340] In some embodiments, R 11 、R 12 、R 13 Each is a C1-C6 alkyl group.

[0341] In some embodiments, R 11 、R 12 、R 13 Each is a methyl group.

[0342] In some embodiments, R 11 、R 12 、R 13 Each is a halogen.

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

[0344] In some embodiments, R 11 is methyl, 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 a methyl group.

[0348] In some embodiments, R 14 and R 15 Together with the atoms to which it is attached and any intervening atoms, it forms a heterocyclic group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

[0349] In some embodiments, R 16 Independently selected from halogen, –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.

[0350] 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 by 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 a heterocyclyl.

[0356] In some embodiments, X is

[0357] In some embodiments, X is

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

[0359] In some embodiments, u is an integer selected from 0, 1, and 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 CF3C(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 invention provides compounds comprising formula (V) and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives and tautomers thereof: where R 1 、R 4 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 , X, Y and n are as described in the present invention.

[0368] It will be understood that for compounds of formula (V), R 1 、R 4 、R 7 、R 8 、R 9 、R10 、R 11 、R 12 、R 13 , X, Y and n can each be selected from the groups described in the present invention where applicable, and the present invention is directed to R 1 、R 4 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 Any group described by any one of X, Y and n may be combined with any group described by any one of the present invention for R 1 、R 4 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 , X, Y and any combination of groups described by one or more of the rest of n.

[0369] In some embodiments, R 1 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 replaced by one or more R 16 replace; R 4 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 replaced by one or more R 16 replace; or R 1 and R 4 Together with the atoms to which they are attached and any intervening atoms, they form a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 16 replace; R 7 、R8 、R 9 and R 10 are each independently selected from H, alkyl; or R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; or R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; R 11 、R 12 、R 13 Each is independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R 15 Each independently selected from H, C1-C6 alkyl; or R 14 and R 15 Together with the atoms to which it is attached and any intervening atoms, it forms a heterocyclyl group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl; R 16 Independently selected from halogen, –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 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 group is optionally substituted with one or more halogen, -OH, -CN; n is an integer selected from 0, 1, and 2; u is an integer selected from 0, 1, and 2.

[0370] In some embodiments, R 1Selected 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 replaced by one or more R 16 replace.

[0371] In some embodiments, R 1 It’s H.

[0372] In some embodiments, R 1 It is a C1–C6 alkyl group.

[0373] In some embodiments, R 1 It's methyl.

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

[0375] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 16 Substituted 6-membered aryl.

[0376] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered unsubstituted aryl group.

[0377] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more halogens.

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

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

[0380] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intermediate atoms, it forms a 6-membered aryl group substituted with one or more Cl groups.

[0381] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intermediate atoms, it forms a 6-membered aryl group substituted with one Cl.

[0382] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group optionally having one or more C1-C6 alkyl groups.

[0383] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more methyl groups.

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

[0385] In some embodiments, R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group optionally having one or more C1-C6 alkoxy groups.

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

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

[0388] In some embodiments, R 4 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 replaced by one or more R 16 replace.

[0389] In some embodiments, R 4 It’s H.

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

[0391] In some embodiments, R 4 It's methyl.

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

[0393] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 16 Substituted 6-membered aryl.

[0394] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered unsubstituted aryl group.

[0395] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more halogens.

[0396] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more Fs.

[0397] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one F.

[0398] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intermediate atoms, it forms a 6-membered aryl group substituted with one or more Cl groups.

[0399] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intermediate atoms, it forms a 6-membered aryl group substituted with one Cl.

[0400] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group optionally having one or more C1-C6 alkyl groups.

[0401] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more methyl groups.

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

[0403] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group optionally having one or more C1-C6 alkoxy groups.

[0404] In some embodiments, R 4 and R 1 Together with the atoms to which it is attached and any intervening atoms, it forms a 6-membered aryl group substituted with one or more methoxy groups.

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

[0406] In some embodiments, n is an integer selected from 0, 1, and 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 Each is independently selected from H, C1-C6 alkyl, and cycloalkyl.

[0411] In some embodiments, R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group which is optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

[0412] In some embodiments, R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclopropane ring which is optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

[0413] In some embodiments, R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group which is optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

[0414] In some embodiments, R 7 and R 8 H, R respectively 9 and R 10 Each is a C1-C6 alkyl group.

[0415] In some embodiments, R 7 and R 8 H, R respectively 9 and R 10 Each is CH3.

[0416] In some embodiments, n is 2, R 7 and R 8 H, R respectively 9 and R 10 Each is a C1-C6 alkyl group.

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

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

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

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

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

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

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

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

[0425] In some embodiments, n is 1, R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclopropane ring which is optionally geminally substituted with two C1-C6 alkyl groups.

[0426] In some embodiments, n is 1, R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclopropane ring which is optionally geminally substituted with two methyl groups.

[0427] In some embodiments, R 11 、R 12 、R 13 Each is independently selected from H, C1-C6 alkyl, cycloalkyl, halogen, and -CN.

[0428] In some embodiments, R 11 、R 12 、R 13 Each is a C1-C6 alkyl group.

[0429] In some embodiments, R 11 、R 12 、R 13Each is a methyl group.

[0430] In some embodiments, R 11 、R 12 、R 13 Each is a halogen.

[0431] In some embodiments, R 11 、R 12 、R 13 Each is F.

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

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

[0434] In some embodiments, R 14 and R 15 Each is H.

[0435] In some embodiments, R 14 and R 15 Each is a methyl group.

[0436] In some embodiments, R 14 and R 15 Together with the atoms to which it is attached and any intervening atoms, it forms a heterocyclic group optionally substituted with one or more halogen, -OH, -CN, or C1-C6 alkyl.

[0437] In some embodiments, R 16 Independently selected from halogen, –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 by cycloalkyl, heterocyclyl, aryl and heteroaryl.

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

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

[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 a heterocyclyl.

[0444] In some embodiments, X is

[0445] In some embodiments, X is

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

[0447] In some embodiments, u is an integer selected from 0, 1, and 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 comprises formula (II-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0456] In some embodiments, the compound comprises formula (II-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0457] In some embodiments, the compound comprises Formula (II-III): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

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

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

[0460] In some embodiments, the compound comprises Formula (II-Ba) or Formula (II-Bb): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0461] In some embodiments, the compound comprises Formula (II-IA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0462] In some embodiments, the compound comprises formula (II-IA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0463] In some embodiments, the compound comprises formula (II-IAA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0464] In some embodiments, the compound comprises formula (II-IAA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0465] In some embodiments, the compound comprises Formula (II-IAAA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0466] In some embodiments, the compound comprises formula (II-IAAA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0467] In some embodiments, the compound comprises Formula (II-IAAAI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0468] In some embodiments, the compound comprises formula (II-IAAAI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0469] In some embodiments, the compound comprises Formula (II-IAAAIA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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 comprises formula (II-IAAAIA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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 comprises Formula (II-IAAAIA-1) or Formula (II-IAAAIA-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2, -CN, and all other variables are as defined herein.

[0472] In some embodiments, the compound comprises Formula (II-IAAAIA-1*) or Formula (II-IAAAIA-2*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2, -CN, and all other variables are as defined herein.

[0473] In some embodiments, the compound comprises Formula (II-IAAAIB): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1, 2, 3, 4; and all other variables are as defined herein.

[0474] In some embodiments, the compound comprises formula (II-IAAAIB*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1, 2, 3, 4; and all other variables are as defined herein.

[0475] In some embodiments, the compound comprises Formula (II-IAAAIB-1) or Formula (II-IAAAIB-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2, -CN, and all other variables are as defined herein.

[0476] In some embodiments, the compound comprises Formula (II-IAAAIB-1*) or Formula (II-IAAAIB-2*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2, -CN, and all other variables are as defined herein.

[0477] In some embodiments, the compound comprises formula (II-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X' is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and all other variables are as defined herein.

[0478] In some embodiments, the compound comprises formula (II-I-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0479] In some embodiments, the compound comprises formula (II-IAAAI-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0480] In some embodiments, the compound comprises formula (II-IAAAI-3*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0481] In some embodiments, the compound comprises formula (II-IAAA-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0482] In some embodiments, the compound comprises formula (II-IAAA-II*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0483] In some embodiments, the compound comprises Formula (II-IAAA-II-1) or Formula (II-IAAA-II-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0484] In some embodiments, the compound comprises Formula (II-IAAA-II-1*) or Formula (II-IAAA-II-2*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0485] In some embodiments, the compound comprises Formula (II-IAAA-III): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0486] In some embodiments, the compound comprises formula (II-IAAA-III*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0487] In some embodiments, the compound comprises Formula (II-IAAA-III-1) or Formula (II-IAAA-III-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0488] In some embodiments, the compound comprises Formula (II-IAAA-III-1*) or Formula (II-IAAA-III-2*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0489] In some embodiments, the compound comprises formula (II-IAAB): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0490] In some embodiments, the compound comprises formula (II-IAAB*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0491] In some embodiments, the compound comprises formula (II-IAABI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0492] In some embodiments, the compound comprises formula (II-IAABI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0493] In some embodiments, the compound comprises Formula (II-IAABI-1) or Formula (II-IAABI-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0494] In some embodiments, the compound comprises Formula (II-IAABI-1*) or Formula (II-IAABI-2*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0495] In some embodiments, the compound comprises formula (II-IAAC): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0496] In some embodiments, the compound comprises formula (II-IAAC*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0497] In some embodiments, the compound comprises formula (II-IAACI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0498] In some embodiments, the compound comprises formula (II-IAACI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0499] In some embodiments, the compound comprises Formula (II-IAACI-1) or Formula (II-IAACI-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0500] In some embodiments, the compound comprises Formula (II-IAACI-1*) or Formula (II-IAACI-2*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0501] In some embodiments, the compound comprises formula (II-IAAD): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0502] In some embodiments, the compound comprises formula (II-IAAD*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0503] In some embodiments, the compound comprises formula (II-IAADI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0504] In some embodiments, the compound comprises formula (II-IAADI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0505] In some embodiments, the compound comprises Formula (II-IAADI-1) or Formula (II-IAADI-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0506] In some embodiments, the compound comprises Formula (II-IAADI-1*) or Formula (II-IAADI-2*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0507] In some embodiments, the compound comprises Formula (II-IAB): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0508] In some embodiments, the compound comprises formula (II-IAB*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0509] In some embodiments, the compound comprises formula (II-IABA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0510] In some embodiments, the compound comprises formula (II-IABA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0511] In some embodiments, the compound comprises formula (II-IABAI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0512] In some embodiments, the compound comprises formula (II-IABAI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0513] In some embodiments, the compound comprises Formula (II-IB): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0514] In some embodiments, the compound comprises formula (II-IB*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0515] In some embodiments, the compound comprises formula (II-IBA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0516] In some embodiments, the compound comprises formula (II-IBA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0517] In some embodiments, the compound comprises Formula (II-IBAa) or Formula (II-IBAb): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0518] In some embodiments, the compound comprises Formula (II-IBAa*) or Formula (II-IBAb*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0519] In some embodiments, the compound comprises formula (II-IBAA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0520] In some embodiments, the compound comprises formula (II-IBAA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0521] In some embodiments, the compound comprises Formula (II-IBAAa) or Formula (II-IBAAb): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0522] In some embodiments, the compound comprises Formula (II-IBAAa*) or Formula (II-IBAAb*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0523] In some embodiments, the compound comprises formula (II-IBAAI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0524] In some embodiments, the compound comprises formula (II-IBAAI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0525] In some embodiments, the compound comprises Formula (II-IBAAIa) or Formula (II-IBAAIb): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2 and -CN, and all other variables are as defined herein.

[0526] In some embodiments, the compound comprises Formula (II-IBAAIa*) or Formula (II-IBAAIb*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2 and -CN, and all other variables are as defined herein.

[0527] In some embodiments, the compound comprises formula (II-II-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0528] In some embodiments, the compound comprises formula (II-II-A*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0529] In some embodiments, the compound comprises formula (II-II-AA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0530] In some embodiments, the compound comprises formula (II-II-AA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0531] In some embodiments, the compound comprises formula (II-II-AAA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0532] In some embodiments, the compound comprises formula (II-II-AAA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0533] In some embodiments, the compound comprises formula (II-II-AAAI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0534] In some embodiments, the compound comprises formula (II-II-AAAI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0535] In some embodiments, the compound comprises Formula (II-II-AAAI-1) or Formula (II-II-AAAI-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0536] In some embodiments, the compound comprises Formula (II-II-AAAI-1*) or Formula (II-II-AAAI-2*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0537] In some embodiments, the compound comprises formula (II-II-AB): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0538] In some embodiments, the compound comprises formula (II-II-AB*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0539] In some embodiments, the compound comprises formula (II-II-ABA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0540] In some embodiments, the compound comprises formula (II-II-ABA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0541] In some embodiments, the compound comprises formula (II-II-ABAI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0542] In some embodiments, the compound comprises formula (II-II-ABAI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0543] In some embodiments, the compound comprises Formula (II-II-ABAI-1) or Formula (II-II-ABAI-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0544] In some embodiments, the compound comprises Formula (II-II-ABAI-1*) or Formula (II-II-ABAI-2*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0545] In some embodiments, the compound comprises formula (II-II-AC): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0546] In some embodiments, the compound comprises formula (II-II-AC*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0547] In some embodiments, the compound comprises formula (II-II-ACA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0548] In some embodiments, the compound comprises formula (II-II-ACA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0549] In some embodiments, the compound comprises formula (II-II-ACAI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0550] In some embodiments, the compound comprises the formula (II-II-ACAI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0551] In some embodiments, the compound comprises Formula (II-II-ACAI-1) or Formula (II-II-ACAI-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0552] In some embodiments, the compound comprises Formula (II-II-ACAI-1*) or Formula (II-II-ACAI-2*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0553] In some embodiments, the compound comprises Formula (II-IW): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein ring W is selected from 3-10 membered cycloalkyl, 6-10 membered aryl, 3-14 membered heterocycle or 5-6 membered heteroaryl; w is an integer selected from 0, 1, 2, 3 and 4; and all other variables are as defined herein.

[0554] In some embodiments, the compound comprises formula (II-IWA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1, 2, 3 and 4; v is an integer selected from 1, 2 and 3; and all other variables are as defined herein.

[0555] In some embodiments, the compound comprises Formula (II-IWB): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0556] In some embodiments, the compound comprises Formula (II-IWC): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1, 2, 3 and 4; each G is independently selected from CH2, NH, O, S, S(O), S(O)2 and at least two Gs are CH2; and all other variables are as defined herein.

[0557] In some embodiments, the compound comprises formula (II-IWD): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; each K is independently selected from CH and N and at least two K are CH; and all other variables are as defined herein.

[0558] In some embodiments, the compound comprises Formula (II-IWAI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0559] In some embodiments, the compound comprises formula (II-IWA-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0560] In some embodiments, the compound comprises formula (II-IWA-III): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0561] In some embodiments, the compound comprises formula (II-IWBI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0562] In some embodiments, the compound comprises formula (II-IWB-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0563] In some embodiments, the compound comprises Formula (II-IWB-III): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0564] In some embodiments, the compound comprises Formula (II-IWB-IV): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0565] In some embodiments, the compound comprises Formula (II-IWBV): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0566] In some embodiments, the compound comprises Formula (II-IWB-VI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0567] In some embodiments, the compound comprises formula (II-IWCI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0568] In some embodiments, the compound comprises formula (II-IWC-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0569] In some embodiments, the compound comprises formula (II-IWC-III): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0570] In some embodiments, the compound comprises formula (II-IWC-IV): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0571] In some embodiments, the compound comprises Formula (II-IWCV): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0572] In some embodiments, the compound comprises Formula (II-IWC-VI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0573] In some embodiments, the compound comprises Formula (II-IWC-VII): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0574] In some embodiments, the compound comprises Formula (II-IWC-VIII): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0575] In some embodiments, the compound comprises formula (II-IWC-IX): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0576] In some embodiments, the compound comprises Formula (II-IWCX): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0577] In some embodiments, the compound comprises formula (II-IWDI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0578] In some embodiments, the compound comprises formula (II-IWD-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0579] In some embodiments, the compound comprises formula (II-IWD-III): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0580] In some embodiments, the compound comprises formula (II-IWD-IV): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0581] In some embodiments, the compound comprises Formula (II-IWDV): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0582] In some embodiments, the compound comprises Formula (II-IWD-VI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0583] In some embodiments, the compound comprises Formula (II-IWD-VII): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0584] In some embodiments, the compound comprises Formula (II-IWAIa): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0585] In some embodiments, the compound comprises formula (II-IWA-II-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0586] In some embodiments, the compound comprises formula (II-IWA-III-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0587] In some embodiments, the compound comprises Formula (II-IWBIa): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0588] In some embodiments, the compound comprises formula (II-IWB-II-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0589] In some embodiments, the compound comprises formula (II-IWB-III-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0590] In some embodiments, the compound comprises formula (II-IWB-IV-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0591] In some embodiments, the compound comprises Formula (II-IWBVa): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0592] In some embodiments, the compound comprises formula (II-IWB-VI-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0593] In some embodiments, the compound comprises Formula (II-IWCIa): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0594] In some embodiments, the compound comprises formula (II-IWC-II-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0595] In some embodiments, the compound comprises formula (II-IWC-III-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0596] In some embodiments, the compound comprises formula (II-IWC-IV-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0597] In some embodiments, the compound comprises Formula (II-IWCVa): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0598] In some embodiments, the compound comprises formula (II-IWC-VI-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0599] In some embodiments, the compound comprises Formula (II-IWC-VII-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0600] In some embodiments, the compound comprises formula (II-IWC-VIII-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0601] In some embodiments, the compound comprises formula (II-IWC-IX-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0602] In some embodiments, the compound comprises Formula (II-IWCXa): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0603] In some embodiments, the compound comprises Formula (II-IWDIa): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0604] In some embodiments, the compound comprises formula (II-IWD-II-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0605] In some embodiments, the compound comprises formula (II-IWD-III-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0606] In some embodiments, the compound comprises formula (II-IWD-IV-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0607] In some embodiments, the compound comprises Formula (II-IWDVa): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0608] In some embodiments, the compound comprises formula (II-IWD-VI-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0609] In some embodiments, the compound comprises formula (II-IWD-VII-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0610] In some embodiments, the compound comprises formula (II-IWAIa-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0611] In some embodiments, the compound comprises formula (II-IWAIa-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0612] In some embodiments, the compound comprises formula (II-IWA-II-a-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0613] In some embodiments, the compound comprises formula (II-IWA-II-a-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0614] In some embodiments, the compound comprises formula (II-IWA-III-a-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0615] In some embodiments, the compound comprises formula (II-IWA-III-a-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0616] In some embodiments, the compound comprises formula (II-IWBIa-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0617] In some embodiments, the compound comprises formula (II-IWBIa-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0618] In some embodiments, the compound comprises formula (II-IWB-II-a-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0619] In some embodiments, the compound comprises formula (II-IWB-II-a-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0620] In some embodiments, the compound comprises formula (II-IWB-III-a-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0621] In some embodiments, the compound comprises formula (II-IWB-III-a-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0622] In some embodiments, the compound comprises formula (II-IWB-IV-a-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0623] In some embodiments, the compound comprises formula (II-IWB-IV-a-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0624] In some embodiments, the compound comprises Formula (II-IWBVa-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0625] In some embodiments, the compound comprises Formula (II-IWBVa-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0626] In some embodiments, the compound comprises formula (II-IWB-VI-a-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0627] In some embodiments, the compound comprises formula (II-IWB-VI-a-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0628] In some embodiments, the compound comprises formula (II-IWCIa-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0629] In some embodiments, the compound comprises formula (II-IWCIa-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0630] In some embodiments, the compound comprises formula (II-IWC-II-a-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0631] In some embodiments, the compound comprises formula (II-IWC-II-a-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0632] In some embodiments, the compound comprises formula (II-IWC-III-a-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0633] In some embodiments, the compound comprises formula (II-IWC-III-a-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0634] In some embodiments, the compound comprises formula (II-IWC-IV-a-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0635] In some embodiments, the compound comprises formula (II-IWC-IV-a-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0636] In some embodiments, the compound comprises formula (II-IWCVa-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0637] In some embodiments, the compound comprises formula (II-IWCVa-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0638] In some embodiments, the compound comprises formula (II-IWC-VI-a-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0639] In some embodiments, the compound comprises formula (II-IWC-VI-a-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0640] In some embodiments, the compound comprises formula (II-IWC-VII-a-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0641] In some embodiments, the compound comprises formula (II-IWC-VII-a-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0642] In some embodiments, the compound comprises formula (II-IWC-VIII-a-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0643] In some embodiments, the compound comprises formula (II-IWC-VIII-a-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0644] In some embodiments, the compound comprises formula (II-IWC-IX-a-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0645] In some embodiments, the compound comprises formula (II-IWC-IX-a-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0646] In some embodiments, the compound comprises Formula (II-IWCXa-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0647] In some embodiments, the compound comprises Formula (II-IWCXa-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0648] In some embodiments, the compound comprises formula (II-IWDIa-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0649] In some embodiments, the compound comprises formula (II-IWDIa-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0650] In some embodiments, the compound comprises formula (II-IWD-II-a-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0651] In some embodiments, the compound comprises formula (II-IWD-II-a-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0652] In some embodiments, the compound comprises formula (II-IWD-III-a-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0653] In some embodiments, the compound comprises formula (II-IWD-III-a-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0654] In some embodiments, the compound comprises formula (II-IWD-IV-a-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0655] In some embodiments, the compound comprises formula (II-IWD-IV-a-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0656] In some embodiments, the compound comprises formula (II-IWDVa-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0657] In some embodiments, the compound comprises formula (II-IWDVa-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0658] In some embodiments, the compound comprises formula (II-IWD-VI-a-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0659] In some embodiments, the compound comprises formula (II-IWD-VI-a-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0660] In some embodiments, the compound comprises formula (II-IWD-VII-a-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0661] In some embodiments, the compound comprises formula (II-IWD-VII-a-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0662] In some embodiments, the compound comprises formula (II-IWAIa-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0663] In some embodiments, the compound comprises formula (II-IWAIa-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0664] In some embodiments, the compound comprises formula (II-IWA-II-a-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0665] In some embodiments, the compound comprises formula (II-IWA-II-a-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0666] In some embodiments, the compound comprises formula (II-IWA-III-a-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0667] In some embodiments, the compound comprises formula (II-IWA-III-a-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0668] In some embodiments, the compound comprises formula (II-IWA-III-a-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0669] In some embodiments, the compound comprises formula (II-IWA-III-a-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0670] In some embodiments, the compound comprises formula (II-IWBIa-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0671] In some embodiments, the compound comprises formula (II-IWBIa-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0672] In some embodiments, the compound comprises formula (II-IWBIa-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0673] In some embodiments, the compound comprises formula (II-IWBIa-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0674] In some embodiments, the compound comprises formula (II-IWB-II-a-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0675] In some embodiments, the compound comprises formula (II-IWB-II-a-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0676] In some embodiments, the compound comprises formula (II-IWB-II-a-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

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

[0678] In some embodiments, the compound comprises formula (II-IWB-III-a-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

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

[0680] In some embodiments, the compound comprises formula (II-IWB-III-a-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0681] In some embodiments, the compound comprises formula (II-IWB-III-a-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0682] In some embodiments, the compound comprises formula (II-IWB-IV-a-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0683] In some embodiments, the compound comprises formula (II-IWB-IV-a-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0684] In some embodiments, the compound comprises formula (II-IWB-IV-a-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0685] In some embodiments, the compound comprises formula (II-IWB-IV-a-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0686] In some embodiments, the compound comprises Formula (II-IWBVa-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0687] In some embodiments, the compound comprises Formula (II-IWBVa-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0688] In some embodiments, the compound comprises Formula (II-IWBVa-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0689] In some embodiments, the compound comprises Formula (II-IWBVa-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0690] In some embodiments, the compound comprises formula (II-IWB-VI-a-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0691] In some embodiments, the compound comprises formula (II-IWB-VI-a-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0692] In some embodiments, the compound comprises formula (II-IWB-VI-a-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0693] In some embodiments, the compound comprises formula (II-IWB-VI-a-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0694] In some embodiments, the compound comprises formula (II-IWCIa-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0695] In some embodiments, the compound comprises formula (II-IWCIa-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0696] In some embodiments, the compound comprises formula (II-IWCIa-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0697] In some embodiments, the compound comprises formula (II-IWCIa-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0698] In some embodiments, the compound comprises formula (II-IWC-II-a-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0699] In some embodiments, the compound comprises formula (II-IWC-II-a-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0700] In some embodiments, the compound comprises formula (II-IWC-II-a-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0701] In some embodiments, the compound comprises formula (II-IWC-II-a-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0702] In some embodiments, the compound comprises formula (II-IWC-III-a-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0703] In some embodiments, the compound comprises formula (II-IWC-III-a-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0704] In some embodiments, the compound comprises formula (II-IWC-III-a-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0705] In some embodiments, the compound comprises formula (II-IWC-III-a-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0706] In some embodiments, the compound comprises formula (II-IWC-IV-a-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0707] In some embodiments, the compound comprises formula (II-IWC-IV-a-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0708] In some embodiments, the compound comprises formula (II-IWC-IV-a-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0709] In some embodiments, the compound comprises formula (II-IWC-IV-a-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0710] In some embodiments, the compound comprises formula (II-IWCVa-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0711] In some embodiments, the compound comprises formula (II-IWCVa-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0712] In some embodiments, the compound comprises formula (II-IWCVa-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0713] In some embodiments, the compound comprises formula (II-IWCVa-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0714] In some embodiments, the compound comprises formula (II-IWC-VI-a-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0715] In some embodiments, the compound comprises formula (II-IWC-VI-a-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0716] In some embodiments, the compound comprises formula (II-IWC-VI-a-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0717] In some embodiments, the compound comprises formula (II-IWC-VI-a-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0718] In some embodiments, the compound comprises Formula (II-IWC-VII-a-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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 comprises formula (II-IWC-VII-a-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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 comprises formula (II-IWC-VII-a-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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 comprises formula (II-IWC-VII-a-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0722] In some embodiments, the compound comprises formula (II-IWC-VIII-a-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0723] In some embodiments, the compound comprises formula (II-IWC-VIII-a-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0724] In some embodiments, the compound comprises formula (II-IWC-VIII-a-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0725] In some embodiments, the compound comprises formula (II-IWC-VIII-a-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0726] In some embodiments, the compound comprises Formula (II-IWC-IX-a-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0727] In some embodiments, the compound comprises Formula (II-IWC-IX-a-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0728] In some embodiments, the compound comprises formula (II-IWC-IX-a-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0729] In some embodiments, the compound comprises formula (II-IWC-IX-a-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0730] In some embodiments, the compound comprises Formula (II-IWCXa-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0731] In some embodiments, the compound comprises Formula (II-IWCXa-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0732] In some embodiments, the compound comprises Formula (II-IWCXa-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0733] In some embodiments, the compound comprises Formula (II-IWCXa-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0734] In some embodiments, the compound comprises formula (II-IWDIa-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0735] In some embodiments, the compound comprises formula (II-IWDIa-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0736] In some embodiments, the compound comprises formula (II-IWDIa-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0737] In some embodiments, the compound comprises formula (II-IWDIa-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0738] In some embodiments, the compound comprises formula (II-IWD-II-a-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0739] In some embodiments, the compound comprises formula (II-IWD-II-a-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0740] In some embodiments, the compound comprises formula (II-IWD-II-a-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0741] In some embodiments, the compound comprises formula (II-IWD-II-a-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0742] In some embodiments, the compound comprises formula (II-IWD-III-a-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0743] In some embodiments, the compound comprises formula (II-IWD-III-a-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0744] In some embodiments, the compound comprises formula (II-IWD-III-a-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0745] In some embodiments, the compound comprises formula (II-IWD-III-a-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0746] In some embodiments, the compound comprises formula (II-IWD-IV-a-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0747] In some embodiments, the compound comprises formula (II-IWD-IV-a-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0748] In some embodiments, the compound comprises formula (II-IWD-IV-a-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0749] In some embodiments, the compound comprises formula (II-IWD-IV-a-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0750] In some embodiments, the compound comprises Formula (II-IWDVa-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0751] In some embodiments, the compound comprises formula (II-IWDVa-1-B):

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

[0753] In some embodiments, the compound comprises formula (II-IWDVa-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0754] In some embodiments, the compound comprises formula (II-IWDVa-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0755] In some embodiments, the compound comprises formula (II-IWD-VI-a-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0756] In some embodiments, the compound comprises formula (II-IWD-VI-a-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0757] In some embodiments, the compound comprises formula (II-IWD-VI-a-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0758] In some embodiments, the compound comprises formula (II-IWD-VI-a-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0759] In some embodiments, the compound comprises formula (II-IWD-VII-a-1-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0760] In some embodiments, the compound comprises formula (II-IWD-VII-a-1-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0761] In some embodiments, the compound comprises formula (II-IWD-VII-a-2-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0762] In some embodiments, the compound comprises formula (II-IWD-VII-a-2-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1 and 2; and all other variables are as defined herein.

[0763] In some embodiments, the compound comprises formula (III-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0764] In some embodiments, the compound comprises formula (III-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0765] In some embodiments, the compound comprises Formula (III-IIA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0766] In some embodiments, the compound comprises formula (III-IIAA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0767] In some embodiments, the compound comprises formula (III-IIAA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0768] In some embodiments, the compound comprises formula (III-IIAAA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0769] In some embodiments, the compound comprises formula (III-IIAAA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0770] In some embodiments, the compound comprises formula (III-IIAAAI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2 and -CN, and all other variables are as defined herein.

[0771] In some embodiments, the compound comprises formula (III-IIAAAI*):

[0772] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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 comprises formula (III-IIAAAIa): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0774] In some embodiments, the compound comprises formula (III-IIAAAIa*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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.

[0775] In some embodiments, the compound comprises formula (III-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0776] In some embodiments, the compound comprises formula (III-II-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0777] In some embodiments, the compound comprises formula (III-II-IA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0778] In some embodiments, the compound comprises formula (III-II-IA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0779] In some embodiments, the compound comprises formula (III-II-IAA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0780] In some embodiments, the compound comprises formula (III-II-IAA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0781] In some embodiments, the compound comprises formula (III-II-IAAI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2 and -CN, and all other variables are as defined herein.

[0782] In some embodiments, the compound comprises formula (III-II-IAAI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2 and -CN, and all other variables are as defined herein.

[0783] In some embodiments, the compound comprises formula (III-II-IAAIB): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2 and -CN, and all other variables are as defined herein.

[0784] In some embodiments, the compound comprises the formula (III-II-IAAIB*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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 comprises formula (III-II-IAAIB-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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 comprises formula (III-II-IAAIB-1*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic 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 comprises formula (IV-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0788] In some embodiments, the compound comprises formula (IV-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0789] In some embodiments, the compound comprises Formula (IV-III): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0790] In some embodiments, the compound comprises Formula (IV-IA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0791] In some embodiments, the compound comprises Formula (IV-IA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0792] In some embodiments, the compound comprises formula (IV-II-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0793] In some embodiments, the compound comprises formula (IV-II-A*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0794] In some embodiments, the compound comprises formula (IV-III-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0795] In some embodiments, the compound comprises formula (IV-III-A*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0796] In some embodiments, the compound comprises formula (IV-IAA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0797] In some embodiments, the compound comprises formula (IV-IAA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0798] In some embodiments, the compound comprises formula (IV-II-AA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0799] In some embodiments, the compound comprises formula (IV-II-AA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0800] In some embodiments, the compound comprises formula (IV-III-AA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0801] In some embodiments, the compound comprises formula (IV-III-AA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0802] In some embodiments, the compound comprises formula (IV-IAAI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2 and -CN, and all other variables are as defined herein.

[0803] In some embodiments, the compound comprises formula (IV-IAAI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2 and -CN, and all other variables are as defined herein.

[0804] In some embodiments, the compound comprises formula (IV-II-AAI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2 and -CN, and all other variables are as defined herein.

[0805] In some embodiments, the compound comprises formula (IV-II-AAI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2 and -CN, and all other variables are as defined herein.

[0806] In some embodiments, the compound comprises formula (IV-III-AAI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2 and -CN, and all other variables are as defined herein.

[0807] In some embodiments, the compound comprises formula (IV-III-AAI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2 and -CN, and all other variables are as defined herein.

[0808] In some embodiments, the compound comprises Formula (V): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0809] In some embodiments, the compound comprises Formula (VI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1, 2, 3, 4, and all other variables are as defined herein.

[0810] In some embodiments, the compound comprises Formula (VA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0811] In some embodiments, the compound comprises Formula (VIA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1, 2, 3, 4, and all other variables are as defined herein.

[0812] In some embodiments, the compound comprises formula (VAA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0813] In some embodiments, the compound comprises Formula (VIAA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1, 2, 3, 4, and all other variables are as defined herein.

[0814] In some embodiments, the compound comprises the formula (VAA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0815] In some embodiments, the compound comprises formula (VIAA*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein w is an integer selected from 0, 1, 2, 3, 4, and all other variables are as defined herein.

[0816] In some embodiments, the compound comprises the formula (VAAI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2 and -CN, and all variables are as defined herein.

[0817] In some embodiments, the compound comprises formula (VIAAI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2 and -CN; w is an integer selected from 0, 1, 2, 3, 4, and all other variables are as defined herein.

[0818] In some embodiments, the compound comprises the formula (VAAI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2 and -CN, and all variables are as defined herein.

[0819] In some embodiments, the compound comprises the formula (VIAAI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein X is selected from -C(O)NH2 and -CN; w is an integer selected from 0, 1, 2, 3, 4, and all other variables are as defined herein.

[0820] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of the compounds of the present invention having sufficient basicity, for example, acid addition salts with, for example, inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citrate methanesulfonate or maleic acid. In addition, suitable pharmaceutically acceptable salts of the compounds of the present invention having sufficient acidity are alkali metal salts, such as sodium salts or potassium salts; alkaline earth metal salts, such as calcium salts or magnesium salts; ammonium salts; or salts with organic bases that provide pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0821] It should be understood that the compounds of any of the formulae disclosed herein and any pharmaceutically acceptable salts thereof include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of the compounds.

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

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

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

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

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

[0827] Table 1: Some examples of compounds of formula (A)

[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 of the acids described in Table 2 and any of the compounds described in Table 1.

[0832] Table 2: Pharmaceutically acceptable acids that form salts with compounds of formula (A).

[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 invention provides a compound that is an isotopic derivative (eg, an isotopically labeled compound) of any one of the compounds of the formulae disclosed herein.

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

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

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

[0847] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0848] It should be understood that any of a variety of art-recognized techniques can be used to prepare isotopic derivatives. For example, isotopic derivatives can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents and implementing the procedures disclosed in the schemes and / or examples described herein.

[0849] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0850] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any of the compounds of the formulae disclosed herein.

[0851] As used herein, the term "isotopic derivative" refers to a derivative of a compound that is isotopically enriched or labeled with one or more atoms. For example, an isotopic derivative of a compound of Formula (A) is isotopically enriched with respect to one or more isotopes, or is labeled with said one or more isotopes, compared to the corresponding compound of Formula (A). In some embodiments, an isotopic derivative is isotopically enriched with respect to one or more isotopes selected from 2 H. 13 C. 14 C. 15 N. 18 O. 29 4. 31 P and 34 In some embodiments, the isotopic derivative is a deuterium-labeled compound (i.e., a compound that is enriched in or labeled with one or more of its atoms). 2 H enrichment).

[0852] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1, as well as prodrugs and pharmaceutically acceptable salts thereof.

[0853] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0854] In some embodiments, the compound is a deuterium-labeled compound of any of the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0855] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1.

[0856] It will be understood that a deuterium-labeled compound comprises deuterium atoms in an abundance substantially greater than 0.015% of the natural abundance of deuterium.

[0857] In some embodiments, the deuterium enrichment factor per deuterium atom of the deuterium-labeled compound is 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 incorporation), 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). As used herein, the term "deuterium enrichment factor" refers to the ratio between the abundance of deuterium and the natural abundance of deuterium.

[0858] It should be understood that any of a variety of techniques recognized in the art can be used to prepare deuterium-labeled compounds. For example, deuterium-labeled compounds can generally be prepared by replacing non-deuterium-labeled reagents with deuterium-labeled reagents and implementing the procedures disclosed in the schemes and / or examples described herein.

[0859] The compounds of the present invention or pharmaceutically acceptable salts or solvates thereof containing the above-mentioned deuterium atoms are within the scope of the present invention. 2 H) may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).

[0860] In some embodiments, the compound is 18 F-labeled compound.

[0861] In some embodiments, the compound is 33 S-labeled compounds, 34 S-labeled compounds, 35 S-labeled compounds, 36 S-labeled compound or any combination thereof.

[0862] It will be appreciated that any of a variety of art-recognized techniques may be used to prepare 18 F. 33 S. 34 S. 35 S and / or 36 For example, deuterium-labeled compounds can be prepared by 18 F. 33 S. 34 S. 35 S and / or 36 S-labeled reagents can be prepared by following the procedures disclosed in the schemes and / or examples described herein, in place of non-isotopically labeled reagents.

[0863] Containing the above 18 F. 33 S. 34 S. 35 S and 36 Compounds of the invention or pharmaceutically acceptable salts or solvates thereof containing one or more of the S atoms are within the scope of the invention. 18 F. 33 S. 34 S. 35 S and / or 36 S) may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).

[0864] For the avoidance of doubt, it should be understood that throughout this specification, where a group is defined by "as described herein," that group encompasses the first occurring and broadest definition as well as each and all specific definitions for that group.

[0865] The various functional groups and substituents constituting the compound of formula (A) are typically selected so that the molecular weight of the compound is no more than 1000 daltons. More typically, the molecular weight of the compound will be less than 1000, for example, 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" refers to compounds that have the same molecular formula but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers," and stereoisomers that are non-superimposable mirror images of one another are termed "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed 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, "chiral isomer" means a compound having at least one chiral center. Compounds having more than one chiral center can exist as individual diastereomers or as a mixture of diastereomers (referred to as a "diastereomeric mixture"). When one chiral center is present, the stereoisomers can be characterized by the absolute configuration (R or S) of the chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents considered to be attached to the chiral center are ordered according to the "Sequence Rule" of Cahn, Ingold, and Prelog. (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 isomers" refers to the existence of diastereomers due to hindered rotation around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). The names of these configurations are distinguished by the prefixes cis and trans, or Z and E, which indicate whether the groups are on the same or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0870] It should be understood that the compounds of the present invention may be depicted as different chiral isomers or geometric isomers. It should also be understood that when a compound has chiral isomeric forms or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present invention, and the naming of the compound does not exclude any isomeric form, and it should be understood that not all isomers may have the same level of activity.

[0871] It should be understood that the structures and other compounds discussed herein include all atropisomers thereof. It should also be understood that not all atropisomers may have the same level of activity.

[0872] As used herein, the term "atropisomer" refers to a class of stereoisomers in which the atoms of the two isomers differ in their arrangement in space. Atropisomers exist due to restricted rotation caused by hindered rotation of bulky groups around a central bond. Such atropisomers typically exist as a mixture; however, recent advances in chromatography techniques have made it possible to separate mixtures of two atropisomers under selected circumstances.

[0873] As used in the present invention, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another form. This conversion causes the form migration of hydrogen atoms, accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric sets in solution. In solutions where tautomerism may occur, tautomers will reach chemical equilibrium. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that can be mutually converted by tautomerization is called tautomerism. Among possible multiple types of tautomerism, two tautomerisms are usually observed. In keto-enol tautomerism, electrons and hydrogen atoms are simultaneously shifted. Ring-chain tautomerism occurs because the aldehyde group (-CHO) in the sugar chain molecule reacts with one of the hydroxyl groups (-OH) in the same molecule to give it a cyclic (ring shape) form as shown by glucose.

[0874] It should be understood that the compounds of the present invention can be depicted as different tautomers. It should also be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present invention, and the naming of the compound does not exclude any tautomeric form. It should be understood that certain tautomers may have higher levels of activity than other tautomers.

[0875] Compounds that have the same molecular formula but differ in the nature or order of the bonding of their atoms or the spatial arrangement of their atoms are referred to as "isomers". Isomers whose atoms are arranged differently in space are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are referred to as "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described by the R- and S- sequencing rules of Cahn and Prelog or by the way in which the molecule rotates the plane of polarized light, and are designated as right-handed or left-handed (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is referred to as a "racemic mixture".

[0876] The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be produced as separate (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both a separate enantiomer and its racemic mixture or other mixture. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition, J.March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolution of racemic forms. Some of the compounds of the present invention may have geometric isomerization centers (E-isomers and Z-isomers). It should be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof with inflammasome inhibitory activity.

[0877] The present invention also encompasses compounds of the present invention as defined herein, which compounds include one or more isotopic substitutions.

[0878] It should be understood that the compounds of any formula described herein include the compounds themselves as well as their salts and solvates thereof (if applicable). For example, salts can be formed between anions and positively charged groups (e.g., amino groups) on the substituted compounds disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronide, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthylsulfonate, 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 cations and negatively charged groups (e.g., carboxylates) on the substituted compounds disclosed herein. Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium cations, such as tetramethylammonium ions or diethylamine ions. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0880] It should be understood that the compounds of the present invention (e.g., 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. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0881] As used herein, the term "solvate" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of a solvent. Some compounds have a tendency to trap fixed molar ratios of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with a molecule of a substance in which the water remains in its molecular state as HO.

[0882] As used herein, the term "analog" refers to a compound that is structurally similar to another compound but has a slightly different composition (e.g., by replacing one atom with an atom of a different element, or, in the case of a particular functional group, by replacing one functional group with another). Thus, an analog is a compound that is similar or equivalent to a reference compound in function and appearance, but not in structure or origin.

[0883] As used herein, the term "derivative" refers to compounds having a common core structure and substituted with various groups as described herein.

[0884] As used herein, the term "bioisostere" refers to a compound produced by exchanging one atom or group of atoms for another substantially similar atom or group of atoms. The purpose of bioisosteric substitution is to produce new compounds with similar biological properties to the parent compound. Bioisosteric substitution can be based on physical chemistry or topology. Examples of carboxylic acid bioisosteres 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 certain compounds of any of the formulas disclosed herein may exist in solvated as well as unsolvated forms (e.g., hydrated forms). Suitable pharmaceutically acceptable solvates are, for example, hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that the present invention encompasses all such solvated forms having inflammasome inhibitory activity.

[0886] It should also be understood that certain compounds of any one of the formulas disclosed herein may exhibit polymorphism, and the present invention encompasses all such forms or mixtures thereof having inflammasome inhibitory activity. It is generally known that crystalline materials can 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-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0887] The compound of any one of the formulas disclosed in the present invention can exist with multiple different tautomeric forms, and the quoting of the compound of formula (A) includes all such forms. For the avoidance of doubt, in the case where compound can exist with one of some tautomeric forms and only a kind of tautomeric form is specifically described or shown, all other tautomeric forms are still included by formula (A).The example of tautomeric form includes keto form, enol form and enolate form, for example, in following tautomerism pair: keto / enol (as shown below), imines / enamine, amides / imino alcohol, amidine / amidine (amidine / amidine), nitroso-group / oxime, thioketones / enethiol and nitro / acid nitro.

[0888] Compounds of any of the formulas disclosed herein containing amine functional groups can also form N-oxides. The present invention also includes N-oxides in reference to compounds of formula (A) containing amine functional groups. In the case where the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of nitrogen atoms of tertiary amines or nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, Jerry March, 4th edition, Wiley Interscience, p. 166. More specifically, N-oxides can be prepared by the procedure of LW Deany (Syn. Comm. 1977, 7, 509-514), wherein an amine compound is reacted with meta-chloroperbenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0889] The compounds of any of the formulae disclosed herein can be administered as prodrugs that are broken down in the human or animal body to release the compounds of the invention. Prodrugs can be used to modify the physical properties and / or pharmacokinetic properties of the compounds of the invention. Prodrugs can be formed when the compounds of the invention contain suitable groups or substituents to which property-modifying groups can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide groups in any of the formulae disclosed herein.

[0890] Thus, the present invention includes those compounds of any of the formulae disclosed herein as defined above, when obtainable by organic synthesis and when obtainable in the human or animal body by cleavage of a prodrug thereof. Thus, the present invention includes compounds of any of the formulae disclosed herein produced by organic synthesis, as well as such compounds produced in the human or animal body by metabolism of a precursor compound, i.e., compounds of any of the formulae disclosed herein may be synthetically produced compounds or metabolically produced compounds.

[0891] Suitable pharmaceutically acceptable prodrugs of the compounds of any of the formulae disclosed herein are prodrugs that are suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity, based on sound medical judgment. Various forms of prodrugs have been described, for example, in the following literature: a) Methods in Enzymology, Vol. 42, pp. 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", H. Bundgaard, pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Review, 1992. 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", ACS Symposium Series, Vol. 14; and h) E. Roche (ed.), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0892] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein having a hydroxyl group are, for example, esters or ethers thereof that are cleavable in vivo. An in vivo cleavable ester or ether of a compound of any of the formulae disclosed herein containing a hydroxyl group is, for example, a pharmaceutically acceptable ester or ether that is cleaved in the human or animal body to produce the parent hydroxyl compound. Pharmaceutically acceptable ester-forming groups suitable for hydroxyl groups include inorganic esters, such as phosphates (including aminophosphorocyclic esters). Other pharmaceutically acceptable ester-forming groups suitable for hydroxyl groups include C1-C 10 Alkanoyl, such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl; C1-C 10 Alkoxycarbonyl, such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2-carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Pharmaceutically acceptable ether-forming groups suitable for hydroxy groups include α-acyloxyalkyl, such as acetoxymethyl and pivaloyloxymethyl.

[0893] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein having a carboxyl group are, for example, in vivo cleavable amides thereof, such as 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 esters thereof.

[0894] Suitable pharmaceutically acceptable prodrugs of the compounds of any of the formulae disclosed herein having an amino group are, for example, amide derivatives thereof which can be cleaved in vivo. Suitable pharmaceutically acceptable amides derived from the amino group include, for example, C1-C 10 Amides formed with alkanoyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on 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 the compounds of any of the formulae disclosed herein can be exerted in part by one or more metabolites formed in the human or animal body after administration of the compounds of any of the formulae disclosed herein. As stated above, the in vivo effects of the compounds of any of the formulae disclosed herein can also be exerted by the metabolism of precursor compounds (prodrugs). Methods for synthesizing compounds

[0896] The compounds of the present invention can be prepared by a variety of methods, including standard chemistry. Suitable synthetic routes are described in the following schemes.

[0897] The compound of formula (A) can be prepared by methods known in the field of organic synthesis as described in part by the following synthesis scheme. In the scheme described below, it should be better understood that, according to general principles or chemistry, when necessary, a protecting group for sensitive groups or reactive groups is adopted. Protective groups are operated according to the standard method of organic synthesis (TW Greene and PGM Wuts, " Protective Groups in Organic Synthesis ", 3rd edition, Wiley Publishing Company (Wiley), New York 1999). These groups are removed using the obvious method of those skilled in the art at the convenient stage of compound synthesis. The selection process and reaction conditions and order of those skilled in the art will identify whether there is a stereo center in the compound of formula (A). Therefore, the present invention includes two possible stereoisomers (unless specified in the synthesis), and not only includes racemic compounds, but also includes independent enantiomers and / or diastereomers. When it is desired to use compound as single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by the resolution of final product or any convenient intermediate. The resolution of final products, intermediates or starting materials may be effected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds", EL Elliel, SH Wilen and LN Mander (Wiley-lnterscience, 1994).

[0898] The compounds described herein can be made from commercially available starting materials or synthesized using known organic, inorganic and / or enzymatic methods. Preparation of compounds

[0899] The compound of the present invention can be prepared by many methods well known to those skilled in the art of organic synthesis. By way of example, the compound of the present invention can be synthesized using the method described below, together with synthetic methods known in the field of synthetic organic chemistry or as understood by those skilled in the art, variations thereon. Suitable methods include but are not limited to those described below. The compound of the present invention can be synthesized by following the steps outlined in the general program (general scheme I, II, III, IV), which steps include assembling different orders of intermediates or compounds. Starting material is commercially available or prepared by known procedures in the reported literature or as shown below. General Procedures

[0900] It should be understood that the compound of formula (A) described in the present invention represents any one of the compound of formula (II), the compound of formula (III), the compound of formula (IV) and / or the compound of formula (V).

[0901] In general, compounds of formula (A) can be prepared using reactions well known to those skilled in the art of organic synthesis. General Scheme 1 shows possible synthetic routes for preparing compounds of formula (A) presented below:

[0902] All reagents can be commercially available compounds themselves or products synthesized from commercially available reagents. For each compound, one or more synthetic procedures can be used in the preparation, including but not limited to the procedures described in the preparation section of the present invention.

[0903] Possible synthetic routes for the preparation of compounds of formula (II) to formula (V) presented below:

[0904] It should be obvious to the expert in the art that any compound of formula (A) obtained according to the procedures described above may be the subject of further transformations and modifications to give other compounds of formula (A).

[0905] Any residue Y described herein can be introduced into the structure of the compound of formula (A) using different methods, some of which are presented in the following schemes.

[0906] In some embodiments, compounds of formula (A) can be subjected to further transformations to provide other compounds of formula (A): Bioassay

[0907] Once the compounds designed, selected and / or optimized by the methods described above 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, molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether they have the predicted activity, binding activity and / or binding specificity.

[0908] In addition, high throughput screening can be used to accelerate the analysis using such assays. Therefore, the activity of the molecules described in the present invention can be quickly screened using techniques known in the art. For example, Devlin (1998) "High Throughput Screening", Marcel Dekker; and U.S. Patent No. 5,763,263 describe a general method for performing high throughput screening. High throughput assays can use one or more different assay techniques, including but not limited to the assay techniques described below.

[0909] Various in vitro or in vivo bioassays can be suitable for detecting the effects of the compounds of the present invention. These in vitro or in vivo bioassays can include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein. Pharmaceutical composition

[0910] In some aspects, the present invention provides a pharmaceutical composition comprising a compound of the present invention as an active ingredient. In some embodiments, the present invention provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present invention 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 which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0912] The compounds of the present invention can be formulated into forms for oral administration, such as tablets, capsules (each of which includes a sustained-release or timed-release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of the present invention can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all of which use forms well known to those of ordinary skill in the pharmaceutical field.

[0913] The formulation of the present invention can be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component can include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include excipients selected from the group consisting of solubilizers, chelating agents, preservatives, tonicity agents, viscosity agents / suspending agents, buffers, and pH adjusting agents, and mixtures thereof.

[0914] Any suitable solubilizing agent can be used. The example of solubilizing agent includes cyclodextrin, such as cyclodextrin selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, random methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylamino)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, random methylated-γ-cyclodextrin and trimethyl-γ-cyclodextrin and mixtures thereof.

[0915] Any suitable chelating agent may be used. Examples of suitable chelating agents include chelating agents selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium ethylenediaminetetraacetate, trisodium ethylenediaminetetraacetate and tetrasodium ethylenediaminetetraacetate and mixtures thereof.

[0916] Any suitable preservative may be used. Examples of preservatives include preservatives selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropyl biguanide, butylparaben, and sorbic acid, and mixtures thereof.

[0917] In some embodiments, examples of preservatives include preservatives selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropyl biguanide and butylparaben and sorbic acid, and mixtures thereof.

[0918] The aqueous vehicle may also include a tonicity agent for adjusting tonicity (osmotic pressure). The tonicity agent may be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride and sodium chloride, and mixtures thereof. In some embodiments, the tonicity agent may be selected from the group consisting of glycols (such as propylene glycol, triethylene glycol), 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 those from the group consisting of cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycols (e.g., Macrogol 300, Macrogol 400), carboxymethylcellulose, hydroxypropylmethylcellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (carbopols, such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0920] In order to adjust the formulation to an acceptable pH (typically about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, specifically a pH range of 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 adjusting agent. The pH adjusting agent 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, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or alkaline pH adjusting agents are added to adjust the formulation to the target acceptable pH range. Therefore, it may not be necessary to use both acid and base simultaneously, depending on the formulation, and adding one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0921] The aqueous vehicle may also contain a buffer to stabilize the pH. When used, the buffer is selected from the group consisting of: phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffer (such as boric acid or a salt thereof, including disodium tetraborate), citrate buffer (such as citric acid or a salt thereof, including sodium citrate) and ε-aminocaproic acid, and mixtures thereof.

[0922] The formulation may further include a wetting agent. Suitable wetting agent classes include wetting agents 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), polyethylene glycol 40 stearate, fatty acid glycol esters, fatty acid glycerides, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0923] Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. The oral composition can be encapsulated in a gelatin capsule or compressed into a tablet. For the purpose of oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of a tablet, lozenge or capsule. Oral compositions can also be prepared using a fluid carrier used as a mouthwash, wherein the compound in the fluid carrier is orally administered and gargled and spit out or swallowed. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients or compounds with similar properties: a binder such as microcrystalline cellulose, tragacanth gum or gelatin; an excipient such as starch or lactose; a disintegrant such as alginic acid, sodium starch glycolate (Primogel) or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate or orange flavoring.

[0924] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[0925] In some embodiments, the pharmaceutical compositions described herein may further include one or more additional pharmaceutically active agents.

[0926] Additional therapeutic agents that can be used in the methods of the invention include Diosmin, Hesperidin, MK-3207, Venetoclax, Dihydroergocristine, Bolazine, R428, Ditercalinium, Etoposide, Teniposide, UK-432097, Irinotecan, Lumacaftor, Velpatasvir, Eluxadoline, Ledipasvir, Lopinavir / Ritonavir+Ribavirin, Alferon, and prednisone. Other additional agents that can be used in the methods of the invention include dexamethasone, azithromycin, and remdesivir, as well as boceprevir, umifenovir, and favipiravir.

[0927] The compositions of the present invention can be in a form suitable for oral use (e.g., tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs); topical use (e.g., creams, ointments, gels or aqueous or oily solutions or suspensions); administration by inhalation (e.g., as a finely divided powder or liquid aerosol); administration by insufflation (e.g., as a finely divided powder); or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as a suppository for rectal administration).

[0928] The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0929] A therapeutically effective amount of a compound of the invention for use in therapy is an amount sufficient to treat or prevent coronavirus infection, slow its progression, and / or reduce the symptoms associated with the condition.

[0930] According to well-known medical principles, the dosage of the compounds of formula (II) to (V) for therapeutic or preventive purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or subject, and the route of administration. How to use

[0931] In some aspects, the present disclosure provides a method of inhibiting SARS-CoV-2-associated 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 invention or a pharmaceutically acceptable salt thereof.

[0932] In some aspects, the present invention 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 invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0933] In some aspects, the present invention provides a method of treating a coronavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0934] In some embodiments, the disease or condition is associated with a coronavirus. In some embodiments, the disease or condition is a disease or condition associated with a coronavirus.

[0935] The compounds of the present invention are SARS-CoV-2 related 3C-like protease inhibitors.

[0936] In some embodiments, the compounds, compositions, and methods disclosed herein are used to prevent or treat diseases, disorders, or conditions associated with coronavirus infection.

[0937] The compounds of the present invention can also be used to treat diseases associated with coronavirus infection. For example, diseases and conditions that can be treated according to the methods of the present invention include COVID-19.

[0938] In some aspects, the present invention 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 invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0939] In some aspects, the present invention 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 invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0940] In some aspects, the present invention provides a method of treating a coronavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0941] In some aspects, the present invention 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 invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0942] In some aspects, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in inhibiting SARS-CoV-2-associated 3C-like protease (e.g., in vitro or in vivo).

[0943] In some aspects, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or condition disclosed herein.

[0944] In some aspects, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating a disease or condition disclosed herein.

[0945] In some aspects, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating or preventing a coronavirus infection in a subject in need thereof.

[0946] In some aspects, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating or preventing COVID-19 in a subject in need thereof.

[0947] In some aspects, the present invention provides a use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting SARS-CoV-2-associated 3C-like protease (e.g., in vitro or in vivo).

[0948] In some aspects, the present invention provides a use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease or condition disclosed herein.

[0949] In some aspects, the present invention provides a use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or condition disclosed herein.

[0950] In some aspects, the present invention provides a use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a coronavirus infection in a subject in need thereof.

[0951] In some aspects, the present invention provides a use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing COVID-19 in a subject in need thereof.

[0952] The present invention provides compounds that act as inhibitors of SARS-CoV-2-associated 3C-like proteases (e.g., in vitro or in vivo). Accordingly, the present invention provides a method of inhibiting SARS-CoV-2-associated 3C-like proteases in vitro or in vivo, the method comprising contacting a cell with a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof.

[0953] In some embodiments, the SARS-CoV-2-associated 3C-like protease inhibitor is a compound of the present invention.

[0954] The effectiveness of the compounds of the present invention can be determined by industry-accepted assays / disease models according to standard practices for the evaluation of compounds of the present invention as described in the art and within current general knowledge.

[0955] The present invention also provides a method for treating a disease or condition associated with coronavirus infection in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[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 invention, or pharmaceutical compositions comprising these compounds, may be administered to a subject by any convenient route of administration, whether systemically / peripherally or locally (ie, at the desired site of action).

[0958] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal sprays); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, e.g., by use of an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; by, for example, subcutaneous or intramuscular implantation of a depot or reservoir.

[0959] Abbreviations used in the following examples and elsewhere in this disclosure are: ACN acetonitrile AcOH acetic acid AcCl acetyl chloride anh. anhydrous aq. aqueous solution br. width Burgess reagent methyl N-(triethylammoniumsulfonyl)carbamate calc. calculated conc. concentrated d Doublet DCM dichloromethane DIPEA N,N-Diisopropylethylamine DMF dimethylformamide DMSO dimethyl sulfoxide ESI electrospray ionization h hour HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-hexafluorophosphate oxide Retention time high pressure liquid chromatography IPA Isopropyl alcohol LCMS liquid chromatography mass spectrometry m multiplet M Moore MHz Megahertz min Ms methanesulfonyl / mesyl MsCl methanesulfonyl chloride NMR Nuclear Magnetic Resonance q quartet rt room temperature s singlet peak s solid sat. saturated t temperature, triplet t R Retention time (in chromatography) TEA triethylamine TFA trifluoroacetic acid THF Tetrahydrofuran TLC thin layer chromatography Examples General synthetic procedures and examples of compound preparation. Synthesis of building blocks Synthesis of (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetylamino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (PA.4)

[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). To a solution of (1R, 2S, 5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester 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) at 0° C., HATU (9.09 g, 24.1 mmol) and N,N-diisopropylethylamine (8.55 g, 95.7 mmol) were added. The reaction mixture was then allowed to warm to 25° C. and then stirred for 16 hours. The mixture was treated with ethyl acetate, washed with water and 1M HCl. (水溶液) 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 give the desired product PA.1 (5.6 g, 67%). 1 H NMR (400MHz, DMSO-d6), δ: 6.72 (d, J=9.6Hz, 1H), 4.20 (s, 1H), 4.05–4.03 (m, 1H), 3.92 (d, J=10.4Hz, 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) was added lithium hydroxide (1.1 g, 44 mmol) and water (20 ml). The reaction mixture was stirred at 25 ° C for 17 hours and then concentrated to remove THF. The reaction mixture was then quenched by adding 1M HCl(水溶液) The residue was adjusted to pH 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.2 (6.16 g, crude). 1 H NMR (400MHz, DMSO-d6), δ: 6.67 (d, J = 9.2Hz, 1H), 4.11 (s, 1H), 4.05–4.03 (m, 1H), 3.90 (d, J = 10.4Hz, 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 of 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 4M HCl solution in 1,4-dioxane (21 ml) was added to a solution of PA.2 (6.16 g) in DCM (19 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.3 (4.7 g, crude). 1 H NMR(400MHz,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=7.6Hz,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-trifluoroacetylamino)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) in methanol (15 ml) was added triethylamine (13 ml) and ethyl trifluoroacetate (3.13 mL, 26.3 mmol) at 0°C. The mixture was allowed to warm to 60°C and then stirred for 16 hours. The mixture was concentrated and the residue was diluted with water and purified by adding 1 M HCl. (水溶液) Adjusted to pH 3. After extraction of the aqueous layer 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 (400MHz, DMSO-d6), δ: 9.43 (d, J = 8.6Hz, 1H), 4.43 (d, J = 8.6Hz, 1H), 4.14 (s, 1H), 3.84 (dd, J = 10.8, 5.6Hz ,1H),3.71(d,J=10.8Hz,1H),1.52(dd,J=7.6,5.2Hz,1H),1.42(d,J=7.6Hz,1H),1.00(s,12H),0.81(s,3H). Synthesis of (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(methylsulfonylamino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (PA.7)

[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). A solution of HCl in 1,4-dioxane (4M, 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 hours, the solvent was removed under reduced pressure to give the HCl salt of PA.5 (4.3 g, crude). 1 H NMR(400MHz,DMSO-d6),δ:8.35(br.s,3H),4.22(s,1H),3.83–3.79(m,2H),3.74–3.72(m,1 H), 3.65 (s, 3H), 1.57–1.56 (m, 1H), 1.46 (s, J = 7.6Hz, 1H), 1.02–1.01 (m, 12H), 0.96 (s, 3H).

[0965] Preparation 6. Methyl (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(methylsulfonylamino)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) was 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 hours. 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 (400MHz, DMSO-d6), δ: 5.25 (d, J=10.0Hz, 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-(methylsulfonylamino)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) was added lithium hydroxide (96 mg, 4.0 mmol) and water (4.0 mL). The reaction mixture was stirred at 25 °C for 17 h and then washed with 1 M HCl. (水溶液) Neutralization and then concentration gave PA.7 (800 mg, crude), which was used in the next step. 1 H NMR (400MHz, DMSO-d6), δ: 7.07 (d, J=9.6Hz, 1H), 4.12 (s, 1H), 3.82–3.76 (m, 2H), 3.40–3.67 (m, 1 H), 2.83 (s, 3H), 1.54–1.51 (m, 1H), 1.40 (d, J = 8.4Hz, 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-butyryl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (PA.11)

[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 (1R, 2S, 5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester 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) at 0° C., HATU (20.2 g, 53.6 mmol) and DIPEA (18.9 g, 212.7 mmol) were added. The reaction mixture was then allowed to warm to 25° C. and then stirred for 16 hours. The mixture was treated with ethyl acetate, washed with water and 1M HCl. (水溶液) and washed with saturated aqueous sodium chloride solution (18 g, 96%). 1 H NMR (400MHz, DMSO-d6), δ: 6.72 (d, J = 9.6Hz, 1H), 4.20 (s, 1H), 4.05 (d, J = 10.4Hz, 1H), 3.93 (d, J = 10Hz, 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. (1R,2S,5S)-3-[(2S)-2-Amino-3,3-dimethyl-butyryl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester (PA.9). 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 hours, the solvent was removed under reduced pressure to give the HCl salt of PA.9 (6 g, 90%). 1 H NMR (400MHz, DMSO-d6), δ: 8.21 (s, 2H), 4.25 (s, 1H), 3.83-3.79 (m, 2H), 3.72 (d, J = 11.2Hz, 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. (1R,2S,5S)-3-[(2S)-2-(Methoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester (PA.10). To a solution of PA.9 (0.8 g, 2.8 mmol) in DCM was added methyl chloroformate (0.295 g, 3.1 mmol) and DIPEA (0.830 g, 6.4 mmol). After 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 give PA.10 (0.906 g, 95%). LCMS (ESI) m / z C 17 H 28 Calculated value for N2O5: 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 was added lithium hydroxide (0.453 g, 10.8 mmol) and water. The reaction mixture was stirred at 25°C for 17 hours and then concentrated to remove THF. The mixture was then quenched by adding 1 M HCl. (水溶液) The residue was adjusted to pH 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(400MHz, DMSO-d6), δ:7.11(d,J=10.6Hz,1H),4.11(s,1H),4.04(d,J=8.4Hz,1H),3.80(s,2H),3.50(s,3 H), 1.46 (s, 1H), 1.38 (d, J = 7.6Hz, 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)

[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 g, 0.6 mmol) in DMF at 0°C were added (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 g, 2.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.121 g, 0.78 mmol). The reaction mixture was stirred at 25°C for 16 hours and then diluted with ethyl acetate. The solution was washed with water, 1 M HCl, and 4% HCl. (水溶液) 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 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). To a solution of P1 (0.184 g, 0.36 mmol) in DCM was added Burgess reagent (0.214 g, 0.9 mmol), and the resulting mixture was stirred for 16 h. The residue was diluted with EtOAc solution and washed with saturated NaHCO 3(水溶液) , 1NHCl (水溶液) The organic layer was washed with MgSO 4(s) Dry, filter and concentrate under reduced pressure to give P2 (0.105 g, 59%). LCMS (ESI) m / z C 27 H 35 Calculated for N5O4: 493.59; Found: 494.7 [M+H] + . Synthesis of 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]carbamic acid ethyl ester (P4)

[0973] Preparation 14. (1R,2S,5S)-3-[(2S)-2-(Ethoxycarbonylamino)-3,3-dimethyl-butyryl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester (PA.12). To a solution of PA.9 (0.8 g, 2.8 mmol) in DCM was 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 aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated to give PA.12 (0.813 g, 82%). LCMS (ESI) m / z C 18 H 30 Calculated for N2O5: 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 hours and then concentrated to remove THF. The mixture was then quenched by adding 1 M HCl. (水溶液) The residue was adjusted to pH 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 (400MHz, DMSO-d6), δ: 12.61 (s, 1H), 7.06 (d, J = 8.8Hz, 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 g, 0.59 mmol) in DMF at 0°C 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). The reaction mixture was stirred at 25°C for 16 hours and then diluted with ethyl acetate. The solution was washed with water, 1 M HCl, and 4% HCl. (水溶液) The organic layer was dried over sodium sulfate, filtered and concentrated to give P3 (0.201 g, 65%). LCMS (ESI) m / z C 28 H 39 Calculated value for 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 EtOAc solution and washed with saturated NaHCO 3(水溶液) , 1NHCl (水溶液) The organic layer was washed with MgSO 4(s) Dry, filter and concentrate under reduced pressure to give P4 (0.189 g, 96%). LCMS (ESI) m / z C 28 H 37 Calculated value for N5O4: 507.62; Found: 508.4 [M+H] + . Synthesis of (1R,2S,5S)-N-[1-cyano-3-(1H-indol-3-yl)propyl]-6,6-dimethyl-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butyryl]-3-azabicyclo[3.1.0]hexane-2-carboxamide (P8)

[0977] Preparation 18. 3-(1H-Indol-3-yl)propan-1-ol (P5). To keep the speed of gentle reflux, to the suspension of lithium aluminum hydride (2.5g, 66mmol) in anhydrous ether (100mL) of rapid stirring, add 3-(1H-indol-3-yl) propionic acid (5g, 26.4mmol) in anhydrous ether (100ml).During the addition process, a white suspension is formed.Then the mixture is stirred for another 3 hours under reflux and then stirred at room temperature overnight.By slowly adding water (5mL), the 1:3 mixture of sulfuric acid (95%) / water (150mL) is subsequently added to decompose excessive lithium aluminum hydride.The ether layer is separated, and the water layer is extracted with ether (3x 250mL).The ether fractions merged are dried, and the evaporation solvent obtains P5 (4g, 86%). 1 H NMR (400MHz, DMSO-d6), δ: 10.71 (s, 1H), 7.49 (d, J=7.9Hz, 1H), 7.35–7.28 (m, 1H), 7.05 (ddd, J=15.1, 7.8, 1.8Hz, 2H), 6 .95(ddd,J=8.0,6.9,1.1Hz,1H),4.42(t,J=5.1Hz,1H),3.46(q,J=6.2Hz,2H),2.70(t,J=7.6Hz,2H),1.84–1.73(m,2H).

[0978] Preparation 19. 3-(1H-Indol-3-yl)propanal (P6). To a solution of P5 (500 mg, 2.85 mmol) in EtOAc (20 ml) was added Dess-Martin periodinane (2.4 g, 8.55 mmol). The mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure, diluted with saturated NaHCO (100 ml), extracted with DCM (3 x 50 ml), dried over NaSO, filtered and concentrated under reduced pressure, and the crude P6 was used in the next step without purification.

[0979] Preparation 20. 2-Amino-4-(1H-indol-3-yl)butanenitrile (P7). To a solution of P6 (500 mg, 2.85 mmol) in 3M NH 3 in MeOH (50 ml) was added TMSCN (340 mg, 3.42 mmol). The mixture was stirred at room temperature for 16 h and concentrated under reduced pressure, and the crude P7 was used in the next step without purification.

[0980] Preparation 21. (1R,2S,5S)-N-[1-Cyano-3-(1H-indol-3-yl)propyl]-6,6-dimethyl-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide (P8). To the mixture of PA.4 (457mg, 1.25mmol) and HATU (501mg, 1.31mmol) in MeCN (10ml), DIEA (195mg, 1.5mmol) is added. The mixture is stirred at room temperature for 30 minutes, and P7 (250mg, 1.25mmol) is added and stirred overnight. The reaction mixture is diluted with ethyl acetate (50ml), and washed with water (3x 50ml), salt solution (2x 50mL), at Na SO Upper drying, and under reduced pressure concentrated, and crude product is purified by flash chromatography on silica gel (hexane / EtOAc-2: 1), to obtain title compound P8 (650mg, 95%). 1 H NMR (400MHz, DMSO-d6), δ: 10.81 (d, J=17.5Hz, 1H), 9.41–9.31 (m, 1H), 7.53 (t, J=7.2Hz, 1H), 7.37–7. 31(m,1H),7.17–7.03(m,2H),6.97(t,J=7.6Hz,1H),4.81–4.64(m,1H),4.41(dd,J=8.4,5.1Hz,1H),4 .26(d,J=8.2Hz,1H),3.90(dt,J=9.7,7.5Hz,1H),3.70(dd,J=14.3,10.5Hz,1H),2.91–2.72(m,1H),2 .13(q,J=7.2Hz,2H),1.61–1.49(m,1H),1.31(t,J=8.1Hz,1H),1.08–0.95(m,11H),0.94–0.80(m,3H). Synthesis of (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propionamide hydrochloride (P2.6)

[0981] Preparation 22. tert-Butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (P2.5). A solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (10 g, 35 mmol) and ammonia in methanol (90 mL) was stirred at room temperature for 24 hours. The reaction mixture was concentrated to provide P2.5 (9.5 g, 100%) as a yellow solid, which was used in the next step without further purification. 1 H NMR (400MHz, CD3OD), δ: 4.10 (dd, J=11.0, 4.0Hz, 1H), 3.37–3.32 (m, 2H), 2.57–2.42 (m, 1H), 2.42–2.25 (m ,1H),2.10–1.97(m,1H),1.95–1.79(m,1H),1.79–1.66(m,1H),1.45(s,9H); LCMS(ESI+)m / z:271.9[M+H] + .

[0982] Preparation 23. (S)-2-Amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide hydrochloride (P2.6). A solution of P2.5 (9.0 g, 33 mmol) and HCl (3 M in methanol, 55 mL) in IPA (200 mL) was stirred at room temperature for 48 h. The reaction mixture was filtered and the collected solids were washed with IPA to give P2.6 (4.78 g, 70%) as a yellow solid. 1 H NMR (400MHz, CD3OD), δ: 4.04 (dd, J=9.2, 4.4Hz, 1H), 3.43–3.36 (m, 2H), 2.83–2.70 (m, 1H) ),2.50–2.38(m,1H),2.12–1.95(m,2H),1.95–1.79(m,1H); LRMS(ESI+)m / z:172.0[M+H] + . Synthesis of (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (P2.8)

[0983] Preparation 24. tert-Butyl N-[(1S)-1-[(1R,2S,5S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]carbamate (P2.7). To a solution of PA.2 (1.00 g, 2.72 mmol) in butan-2-one (8.0 mL) was added P2.6 (675 mg, 3.26 mmol, HCl salt), 2-hydroxypyridine 1-oxide (76 mg, 0.68 mmol), N,N-diisopropylethylamine (1.4 g, 10.88 mmol), and EDCI HCl (675 mg, 3.54 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 16 hours. The mixture was concentrated and purified by reverse phase column chromatography (5-100% MeOH / water) to afford P2.7 (1.2 g, 85% yield). 1 H NMR(400MHz, CDCl3), δ:8.19(s,1H),7.17(s,1H),6.20(br.s,1H),5.73(br.s,1H), 5.20(br.d,1H),4.47–4.41(m,1H),4.23–4.21(m,2H),4.08–4.04(m,1H),3.98(d,J= 10.4Hz,1H),3.46(s,1H),3.35–3.32(m,2H),2.48–2.34(m,2H),2.07–2.04(m,2H), 2.00–1.95(m,1H),1.87–1.82(m,1H),1.38(s,9H),1.01–0.99(m,12H),0.87(s,3H).

[0984] Preparation 25. (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (P2.8). To a solution of P2.7 (100 mg, 0.19 mmol) in DCM (2.0 mL) was added TFA (0.2 mL) at room temperature. The reaction mixture was stirred at 25 ° C for 17 hours. The mixture was concentrated and purified by reverse phase column chromatography (5-100% MeOH / water) to obtain the desired product P2.8 (40 mg, 50% yield). 1H NMR(400MHz, CDCl3), δ:8.42(s,1H),8.28(br.s,1H),7.22(br.s,1H),5.85(br.s,1H), 5.56(br.s,1H),5.32(br.s,1H),4.45–4.40(m,1H),4.33–4.26(m,1H),4.13–4.00(m,1 H),3.67–3.55(m,1H),3.38–3.35(m,2H),3.22–3.00(m,1H),2.49–2.37(m,2H),2.16–2 .11(m,1H),1.97–1.86(m,2H),1.51–1.42(m,2H),1.05–1.01(m,9H),0.96–2.94(m,6H). Synthesis of (S)-2-amino-3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propionamide hydrochloride (P3.3)

[0985] Preparation 26. (S)-2-((tert-Butoxycarbonyl)amino)-3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propanoic acid (P3.1). To a solution of 2-hydroxybenzimidazole (750 mg, 5.59 mmol, 1.0 equiv) in DMSO (12 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.0 mL, 6.71 mmol, 1.2 equiv), and the mixture was then stirred at room temperature for 15 minutes. DMSO (12 mL) containing N-Boc-L-serine β-lactone (1.26 g, 6.71 mmol, 1.2 equiv) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for another 16 hours. The mixture was concentrated, treated with water, and purified by HCl. (水溶液) The pH value was adjusted to 6 and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and purified by Na2SO 4(s) The mixture was dried, filtered and concentrated in vacuo. The residue was purified by C-18 reverse phase column chromatography (mobile phase A: water, mobile phase B: methanol, UV: 214 nm and 254 nm, flow rate: 35 ml / min, gradient: 0-90% (B%)) to afford P3.1 (300 mg, 17% yield) as a white solid. 1H NMR(400MHz,DMSO-d6),δ:10.85(s,1H),7.17–7.10(m,2H),7.00–6.93(m, 3H),4.31–4.24(m,1H),4.19–4.10(m,1H),4.02–3.99(m,1H),1.22(s,9H). ...

Claims

1. A compound, characterized in that include: Formula (A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug or tautomer thereof, in: C is a heterocyclic ring selected from: Wherein: 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; Among them: key 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 is a single bond, p is 1 and E is C(O), and when the bond When is a double bond, p is 0 and E is N; m is an integer selected from 0, 1, 2; Where: Each key and is a single bond or a double bond; when When it is a double bond, each bond is a single bond, when When it is a single key, each key is independently selected from a single bond or a double bond; each p is an integer independently selected from 0 and 1; provided that when is a single bond, then p is 1, and when is a double bond, then p is 0; k is an integer selected from 0 and 1; provided that when the bond is a single bond and the bond is a single bond, then k is 1, and when the bond or the key When it is a double bond, k is 0; as well as in: R N Selected from H, C1-C6 alkyl, cycloalkyl; R 1 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 replaced by one or more R 16 replace; R 2 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 replaced by one or more R 16 replace; or R 1 and R 2 Together is the oxygen; or R 2 and R 3 together to form a bond; 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 replaced by one or more R 16 replace; R 4 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 replaced by one or more R 16 replace; or R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 16 replace; R 5 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, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 16 replace; R 5 '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, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 16 replace; or R 5 and R 5 'Forming oxo; R 6 Selected from H, C1-C6 alkyl, cycloalkyl, halogen, -CN, -OH; R 7 , R 8 , R 9 and R 10 Each is independently selected from H, alkyl; or R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; or R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; R 11 , R 12 , R 13 Each is independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R 15 Each independently selected from H, C1-C6 alkyl; or R 14 and R 15 Together with the atoms to which it is attached and any intermediate atoms, it forms a heterocyclic group optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; R 16 are independently selected from halogen, –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 alkyl is optionally substituted by cycloalkyl, heterocyclyl, aryl and heteroaryl; Y is selected from C1-C6 alkyl-S(O) u -, C1-C6 alkyl-C(O)-, heteroaryl-C(O)-, wherein the alkyl or heteroaryl is optionally substituted with one or more halogen, -OH, -CN; n is an integer selected from 0, 1, 2; u is an integer selected from 0, 1, 2; in, Cycloalkyl is a monocyclic or polycyclic saturated carbocyclic 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 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged or spiro) or 11-14 membered tricyclic ring system (fused, bridged or spiro) having one or more heteroatoms selected from O, N, S, P, Se or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic group having 5 to 24 ring atoms, the monovalent monocyclic or polycyclic aromatic group containing one or more ring heteroatoms selected from N, O, S, P or B, the remaining ring atoms being C; Provided that when in heterocycle (A-II), m is 0; A and B are CH; R 1 and R 2 is CH3, H, deuterium, or R 1 It is OH, or R 1 and R 2 Together they are oxo; n is 1; R 8 and R 9 is a C1-C6 alkyl group, or R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclopropyl or cyclohexyl group, or R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclobutyl group, a cyclohexyl group, or R 9 is cyclopentyl; R 11 , R 12 , R 13 Each is CH3; and when X is CN, Y is not CF3C(O)-, (CH3)3CS(O)2-, ClCH2C(O)-, (CH3)2CHC(O)-, CH3CH2C(O)-, CH3C(O)-; Provided that when in heterocycle (A-II), m is 1; A and B are CH; R 1 and R 2 is CH3 or H; n is 1; R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclopropyl, cyclopentyl or cyclohexyl group, or R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclobutyl group, a cyclohexyl group, or R 9 When it is cyclopentyl, Y is not CF3C(O)-; and provided that when in heterocycle (A-II), m is 0; A and B are CH; R 1 and R 2 Both are H; n is 2; R 9 or R 10 When it is a C1-C6 alkyl group, Y is not CF3C(O)- or CH3S(O)2.

2. The compound according to claim 1, characterized in that The compound comprises formula (II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug or tautomer thereof, in: A is selected from CR 4 and N; B is selected from CR 6 and N; R N Selected from H, C1-C6 alkyl, cycloalkyl; R 1 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 replaced by one or more R 16 replace; R 2 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 replaced by one or more R 16 replace; or R 1 and R 2 Together is the oxygen; or R 2 and R 3 together to form a bond; 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 replaced by one or more R 16 replace; R 4 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 replaced by one or more R 16 replace; or R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 16 replace; or R 3 and R 4 Together is the oxygen; R 6 Selected from H, C1-C6 alkyl, cycloalkyl, halogen, -CN, -OH; R 7 , R 8 , R 9 and R 10 Each is independently selected from H, C1-C6 alkyl, cycloalkyl; or R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; or R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; R 11 , R 12 , R 13 Each is independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R 15 Each independently selected from H, C1-C6 alkyl; or R 14 and R 15 Together with the atoms to which it is attached and any intermediate atoms, it forms a heterocyclic group optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; R 16 Independently selected from 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; 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 alkyl is optionally substituted by cycloalkyl, heterocyclyl, aryl and heteroaryl; Y is selected from C1-C6 alkyl-S(O) u -, C1-C6 alkyl-C(O)-, heteroaryl-C(O)-, wherein the alkyl or heteroaryl is optionally substituted with one or more halogen, -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; in, Cycloalkyl is a monocyclic or polycyclic saturated carbocyclic 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 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged or spiro) or 11-14 membered tricyclic ring system (fused, bridged or spiro) having one or more heteroatoms selected from O, N, S, P, Se or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic group having 5 to 24 ring atoms, the monovalent monocyclic or polycyclic aromatic group containing one or more ring heteroatoms selected from N, O, S, P or B, the remaining ring atoms being C; The conditions are when m is 0; A and B are CH; R 1 and R 2 is CH3, H, deuterium, or R 1 It is OH, or R 1 and R 2 Together they are oxo; n is 1; R 8 and R 9 is a C1-C6 alkyl group, or R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclopropyl or cyclohexyl group, or R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclobutyl group, a cyclohexyl group, or R 9 is cyclopentyl; R 11 , R 12 , R 13 Each is CH3; and when X is CN, Y is not CF3C(O)-, (CH3)3CS(O)2-, ClCH2C(O)-, (CH3)2CHC(O)-, CH3CH2C(O)-, CH3C(O)-; The conditions are when m is 1; A and B are CH; R 1 and R 2 is CH3 or H; n is 1; R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclopropyl, cyclopentyl or cyclohexyl group, or R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cyclobutyl group, a cyclohexyl group, or R 9 When it is cyclopentyl, Y is not CF3C(O)-; And the conditions are when m is 0; A and B are CH; R 1 and R 2 Both are H; n is 2; R 9 or R 10 When it is a C1-C6 alkyl group, Y is not CF3C(O)- or CH3S(O)2.

3. The compound according to claim 1, characterized in that The compound comprises formula (III): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug or tautomer thereof, in: The key 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; The condition is that when the key is a single bond, p is 1, E is C(O), and when the bond When it is a double bond, p is 0 and E is N; R N Selected from H, C1-C6 alkyl, cycloalkyl; R 1 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 replaced by one or more R 16 replace; R 4 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 replaced by one or more R 16 replace; or R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 16 replace; R 7 , R 8 , R 9 and R 10 Each is independently selected from H, C1-C6 alkyl, cycloalkyl; or R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; or R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; R 11 , R 12 , R 13 Each is independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R 15 Each independently selected from H, C1-C6 alkyl; or R 14 and R 15 Together with the atoms to which it is attached and any intermediate atoms, it forms a heterocyclic group optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; R 16 Independently selected from 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; 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 alkyl is optionally substituted by cycloalkyl, heterocyclyl, aryl and heteroaryl; Y is selected from C1-C6 alkyl-S(O) u -, C1-C6 alkyl-C(O)-, heteroaryl-C(O)-, wherein the alkyl or heteroaryl is optionally substituted with one or more halogen, -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; in, Cycloalkyl is a monocyclic or polycyclic saturated carbocyclic 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 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged or spiro) or 11-14 membered tricyclic ring system (fused, bridged or spiro) having one or more heteroatoms selected from O, N, S, P, Se or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic group having 5 to 24 ring atoms, which contains one or more ring heteroatoms selected from N, O, S, P or B, and the remaining ring atoms are C.

4. The compound according to claim 1, characterized in that The compound comprises formula (IV): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug or tautomer thereof, in: Each key and is a single bond or a double bond; when When it is a double bond, each bond is a single bond, when When it is a single key, each key are independently selected from single bonds or double bonds; Each p is an integer independently selected from 0 and 1; The condition is when is a single bond, then p is 1, and when When it is a double bond, p is 0; k is an integer selected from 0 and 1; The condition is that when the key is a single bond and the bond is a single bond, k is 1, and when the bond or the key When it is a double bond, k is 0; Each R N Independently selected from H, C1-C6 alkyl, cycloalkyl; R 5 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, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 16 replace; R 5 '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, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally replaced by one or more R 16 replace; or R 5 and R 5 'Forming oxo; R 7 , R 8 , R 9 and R 10 Each is independently selected from H, C1-C6 alkyl, cycloalkyl; or R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; or R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; R 11 , R 12 , R 13 Each is independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R 15 Each independently selected from H, C1-C6 alkyl; or R 14 and R 15 Together with the atoms to which it is attached and any intermediate atoms, it forms a heterocyclic group optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; R 16 Independently selected from 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; 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 alkyl is optionally substituted by cycloalkyl, heterocyclyl, aryl and heteroaryl; Y is selected from C1-C6 alkyl-S(O) u -, C1-C6 alkyl-C(O)-, heteroaryl-C(O)-, wherein the alkyl or heteroaryl is optionally substituted with one or more halogen, -OH, -CN; n is an integer selected from 0, 1, 2; u is an integer selected from 0, 1, 2; in, Cycloalkyl is a monocyclic or polycyclic saturated carbocyclic 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 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged or spiro) or 11-14 membered tricyclic ring system (fused, bridged or spiro) having one or more heteroatoms selected from O, N, S, P, Se or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic group having 5 to 24 ring atoms, which contains one or more ring heteroatoms selected from N, O, S, P or B, and the remaining ring atoms are C.

5. The compound according to claim 1, characterized in that The compound comprises formula (V): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug or tautomer thereof, in: R 1 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 replaced by one or more R 16 replace; R 4 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 replaced by one or more R 16 replace; or R 1 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 3-14 membered heterocycle, or a 5-6 membered heteroaryl, wherein the cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted by one or more R 16 replace; R 7 , R 8 , R 9 and R 10 Each is independently selected from H, C1-C6 alkyl, cycloalkyl; or R 8 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; or R 9 and R 10 Together with the atoms to which it is attached and any intervening atoms, it forms a cycloalkyl group optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; R 11 , R 12 , R 13 Each is independently selected from C1-C6 alkyl, cycloalkyl, halogen, -CN; R 14 and R 15 Each independently selected from H, C1-C6 alkyl; or R 14 and R 15 Together with the atoms to which it is attached and any intermediate atoms, it forms a heterocyclic group optionally substituted with one or more halogen, -OH, -CN, C1-C6 alkyl; R 16 Independently selected from halogen, –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 alkyl is optionally substituted by cycloalkyl, heterocyclyl, aryl and heteroaryl; Y is selected from C1-C6 alkyl-S(O) u -, C1-C6 alkyl-C(O)-, heteroaryl-C(O)-, wherein the alkyl or heteroaryl is optionally substituted with one or more halogen, -OH, -CN; n is an integer selected from 0, 1, 2; u is an integer selected from 0, 1, 2; in, Cycloalkyl is a monocyclic or polycyclic saturated carbocyclic 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 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged or spiro) or 11-14 membered tricyclic ring system (fused, bridged or spiro) having one or more heteroatoms selected from O, N, S, P, Se or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic group having 5 to 24 ring atoms, which contains one or more ring heteroatoms selected from N, O, S, P or B, and the remaining ring atoms are C.

6. The compound according to claim 2, characterized in that The compounds include formulas (II-IAAAI), (II-IAAA-II), (II-IAAA-III), (II-IAABI), (II-IAACI), (II-IAADI), (II-IABAI), (II-IBAAI), (II-II-AAAI), (II-II-ABAI) or (II-II-ACAI): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

7. The compound according to claim 2, characterized in that The compound comprises formula (II-IAAAIA) or (II-IAAAIB): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, wherein w is an integer selected from 0, 1, 2, 3 and 4.

8. The compound according to claim 2, characterized in that The compounds include formula (II-IW): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein ring W is selected from 3-10 membered cycloalkyl, 6-10 membered aryl, 3-14 membered heterocycle or 5-6 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 according to claim 3, characterized in that The compounds include formula (III-IIAAAI) or (III-II-IAAI): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

10. The compound according to claim 4, characterized in that The compounds include formula (IV-IAAI), (IV-II-AAI) or (IV-III-AAI): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

11. The compound according to claim 5, characterized in that The compounds include formula (VIAAI): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, wherein w is an integer selected from 0, 1, 2, 3, 4.

12. A compound, characterized in that Selected from: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

13. A pharmaceutical composition, characterized in that The invention comprises a 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, characterized in that Further included are additional pharmaceutically active agents.

15. A method for inhibiting coronavirus replication, characterized in that: The method comprises administering to a subject a compound according to any one of claims 1 to 12 or a pharmaceutical composition according to any one of claims 13 or 14.

16. A method for treating a disease or condition associated with coronavirus infection, characterized in that: The method comprises administering to a subject a compound according to any one of claims 1 to 12 or a pharmaceutical composition according to any one of claims 13 or 14.

17. A method for treating coronavirus infection, characterized in that: The method comprises administering a compound according to any one of claims 1 to 12 or a pharmaceutical composition according to any one of claims 13 or 14 to a subject in need of treatment.

18. The method according to claim 17, characterized in that The coronavirus infection is COVID-19.

19. The method according to any one of claims 15 to 18, characterized in that The subject is a mammal.

20. The method according to claim 19, characterized in that The subject is a human.

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