Benzamide derivatives as CGAS-STING pathway agonists

Abstract

The pharmaceutical compositions of the present invention include functionalized benzamide derivatives that are used as cyclic GMP-AMP synthase-interferon gene stimulator (cGAS-STING) pathway agonists and are used to treat viral diseases and enhance anti-tumor immunity.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 740,210, filed on October 2, 2018; the entire contents of which are incorporated herein by reference. Background Art

[0003] The genome of vertebrates encodes an array of proteins called pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns upon infection with microorganisms, thereby activating a pro-inflammatory cytokine response (Akira et al., 2006). This innate cytokine response not only inhibits microbial proliferation and limits its spread, but also simultaneously induces a more robust adaptive immune response that ultimately controls microbial infection (Chang et al., 2012; Iwasaki and Medzhitov, 2015). Stimulator of interferon genes (STING) is a transmembrane protein located on the endoplasmic reticulum (ER) membrane and serves as a PRR for cyclic dinucleotides produced by intracellular bacteria or synthesized by the cytoplasmic DNA sensor, cyclic GMP-AMP synthase (cGAS) (Sun et al., 2013; Wu et al., 2013). The binding of cyclic dinucleotides to STING induces its dimerization and translocation from the ER membrane to perinuclear vesicles, and subsequently activates NFkB and TBK-1 / IRF3 (Burdette et al., 2011; Yin et al., 2012). Activation of these signaling pathways induces the expression of type I and type III interferons and other inflammatory cytokines (Tanaka and Chen, 2012). In addition, STING is a molecular hub for DNA-activated innate immune responses and plays an important role in host defense against DNA viruses, retroviruses, intracellular bacteria, and protozoa infections (Chen et al., 2016; Kondo et al., 2013). Therefore, STING is a molecular hub for DNA activation of innate immune responses and has been shown to play a crucial role in host defense against DNA viruses, retroviruses, intracellular bacteria, and protozoa infections (Cai et al., 2014). In addition, increasing evidence suggests that STING also plays an important role in host anti-tumor immunity (Corralesetal et al., 2016).

[0004] Due to its critical role in host immune responses, pharmacological modulation of STING activity has been considered a viable broad-spectrum immunotherapeutic approach for the treatment of pathogen infections and tumors. Indeed, recent studies have shown that intratumoral administration of 2'3'-cGAMP induces profound regression of established tumors in mice and generates a substantial systemic immune response capable of rejecting distant metastases and providing long-term immune memory (Corrales et al., 2015; Iurescia et al., 2018). STING agonists have also been shown to enhance the efficacy of immune checkpoint blockade therapy (Ghaffari et al., 2018; Wang et al., 2017) and enhance the immunogenicity of vaccines (Fu et al., 2015; Hanson et al., 2015). Furthermore, we and others have demonstrated that STING agonist therapy is able to induce host immune responses to control influenza A virus (Shirey et al., 2011), hepatitis B virus (HBV) (Guo et al., 2015; Hou et al., 2015; Guo et al., 2017), herpes simplex virus (HSV) (Skouboe et al., 2018), and human immunodeficiency virus (HIV) (Aroh et al., 2017). These studies provide proof of concept that pharmacological activation of STING is a compelling immunotherapeutic approach for the treatment of viral infections and cancer.

[0005] Other chronic viral infections that may be treated by activating STING include hepatitis C virus (HCV), as well as DNA and RNA viruses that cause acute infections, such as influenza virus and other virus families that cause the common cold and upper respiratory tract infections including, but not limited to, paramyxoviruses, rhinoviruses, adenoviruses, human coronaviruses (including coronavirus associated with severe respiratory syndrome; Middle East respiratory syndrome coronavirus, and human coronavirus OC43), virus families that cause hemorrhagic fevers (including, but not limited to, viruses belonging to the families Flaviviridae, Filoviridae, Arenaviridae, and Bunyaviridae), and viruses that cause encephalitis (including, but not limited to, West Nile virus, La Crosse virus, California encephalitis virus, Venezuelan equine encephalitis virus, Western equine encephalitis, Japanese encephalitis virus, Kwasana Forest virus, tick-borne encephalitis virus, rabies virus, chikungunya virus).

[0006] Cancers that could be treated by activating STING include bladder cancer, breast cancer, colorectal cancer, kidney cancer, liver cancer, lung cancer, melanoma, oral and oropharyngeal cancer, pancreatic cancer, prostate cancer, thyroid cancer, uterine cancer, leukemia, and lymphoma.

[0007] Currently, there are two classes of STING agonists: cyclic dinucleotides (CDNs) and non-nucleotide small molecules. Cyclic di-GMP and cyclic di-AMP produced by bacteria were the first identified STING agonists (Burdette et al., 2011). With the discovery of the cytosolic DNA sensor cGAS, its catalytic product 2′,3′-cGAMP was identified as a more potent STING agonist (Zhang et al., 2013). Although various formulations of CDNs have been shown to promote the activation of antitumor immune responses in mouse models (Fu et al., 2015), their poor cell membrane permeability and metabolic instability may limit their biological activity and medical applications. Therefore, medicinal chemistry efforts have been made to generate novel CDNs that are resistant to degradation by cellular extracellular nucleotide pyrophosphatase / phosphodiesterase (ENPP1) (Li et al., 2014; Lioux et al., 2016). In addition, delivery of CDNs with nanoparticles or liposomes improves their antitumor activity in vivo (Hanson et al., 2015). To date, there are only four chemical types of non-nucleotide small molecule STING agonists: DMXAA, G10, C11, and DSDP. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) was originally discovered and developed as a vascular disruptor with antitumor activity in various mouse models, but failed in a phase III clinical trial for the treatment of lung cancer (Conlon et al., 2013). It was recently identified as a specific agonist of mouse STING and can induce interferon (IFN)-dominated cytokine responses, thereby effectively inhibiting the replication of influenza A virus, hepatitis B virus, and type A virus in mice (Cavlar et al., 2013; Conlon et al., 2013; Guo et al., 2015). Interestingly, a genetic study showed that a single amino acid substitution (S162A) in human STING confers DMXAA sensitivity, which provides a clue for the synthesis of DMXAA analogs as human STING agonists (Gao et al., 2013). G10 or 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][l,4]thiazine-6-carboxamide and C11 or N-(methylcarbamoyl)-2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]sulfonyl}-2-phenylacetamide) are two human thorn-specific agonists recently identified by high-throughput screening by the group of Victor R. DeFilippis. Both G10 and C11 have been shown to induce antiviral responses against alphaviruses in human fibroblasts.DSDP or dispirodiketopiperazine compound, 2,7,2″,2″′-dispiro[indene-1″,3″-dione]-tetrahydrodithiazolo[3,2-a:3′,2′-d]pyrazine-5,10(5aH,10aH)-dione is another human SITNG-specific agonist identified by the inventor group as having antiviral activity against several flaviviruses, including dengue virus, yellow fever virus, and Zika virus. However, the in vivo biological activities and pharmacological properties of these three small molecule human STING agonists remain to be determined (Liu et al., 2017)(Sali et al., 2015).

[0008] Therefore, there is still a need for more effective small molecule STING agonists with better pharmacological properties as candidate drugs for immunotherapy of viral diseases and cancer. The present invention provides compounds as cGAS-STING pathway agonists that can induce proinflammatory cytokine responses in a human STING-dependent manner. Summary of the invention

[0009] The present invention relates to functionalized benzamide derivatives of formula (I):

[0010]

[0011] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0012] G, Y and Z are selected from CR 6 and N; or one of G, Y and Z is absent, and the adjacent atoms are linked together to form a 5-membered ring.

[0013] R is selected from hydrogen and C 1-6 A group consisting of alkyl groups;

[0014] R 1 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7 ,CONHR 8 、NHR 9 NR 9 R 10 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl and N-containing monocyclic heterocycloalkyl;

[0015] R 2 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C1-6 Alkenyl, CO 2 R 7 ,CONHR 8 、NHR 9 NR 9 R 10 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl and N-containing monocyclic heterocycloalkyl;

[0016] R 3 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7 ,CONHR 8 、NHR 9 NR 9 R 10 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl and N-containing monocyclic heterocycloalkyl;

[0017] R 4 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7 ,CONHR 8 、NHR 9 NR 9 R 10 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl and N-containing monocyclic heterocycloalkyl;

[0018] R and R 4 Together with the atoms to which they are bonded, they form a ring having 5 to 8 members, the ring optionally including a member selected from oxygen, C=O and SO 2 the parts of the group that make up it;

[0019] R 5 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7,CONHR 8 、NHR 9 NR 9 R 10 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl and N-containing monocyclic heterocycloalkyl;

[0020] R 6 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7 ,CONHR 8 、NHR 9 NR 9 R 10 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl and N-containing monocyclic heterocycloalkyl;

[0021] R and R 6 Together with the atoms to which they are bonded, they form rings having 5-8 members;

[0022] R 1 and R 6 together with the atoms to which they are bound, form an optionally substituted ring having 5 to 7 ring atoms;

[0023] R 2 and R 6 together with the atoms to which they are bound, form an optionally substituted ring having 5 to 7 ring atoms;

[0024] R 2 and R 6 together with the atoms to which they are bound, form an optionally substituted aromatic ring having 5 to 7 ring atoms, optionally including a moiety selected from oxygen, sulfur, nitrogen and NH;

[0025] R 4 and R 5 together with the atoms to which they are bound, form an optionally substituted ring having 5-7 ring atoms optionally including a moiety selected from oxygen, sulfur, nitrogen and NH;

[0026] R 4 and R 5together with the atoms to which they are bound, form an optionally substituted aromatic ring having 5-6 ring atoms, optionally including zero to three moieties selected from oxygen, sulfur, nitrogen and NH;

[0027] R 7 Selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3 -C 7 the group consisting of a cycloalkyl group and an optionally substituted phenyl group;

[0028] R 8 Selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3 -C 7 the group consisting of a cycloalkyl group and an optionally substituted phenyl group;

[0029] R 9 Selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3 -C 7 Cycloalkyl and optionally substituted phenyl, optionally substituted heteroaryl, COR 10 、SO 2 R 10 The group composed of;

[0030] R 10 Selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3 -C 7 the group consisting of a cycloalkyl group and an optionally substituted phenyl group;

[0031] R 9 and R 10 The units, together with the atoms to which they are bonded, form a ring having 5 to 8 ring atoms;

[0032] Two R's 10 The units, together with the atoms to which they are bonded, form a ring having 5-8 ring atoms;

[0033] R 11 Selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3 -C 7 The group consisting of a cycloalkyl group and an optionally substituted phenyl group.

[0034] In some embodiments, the compounds are useful as cyclic GMP-AMP synthase stimulators of the interferon gene (cGAS-STING) pathway agonists, for the treatment of viral diseases and for enhancing anti-tumor immunity.

[0035] The compounds of the present invention include compounds having formula (II):

[0036]

[0037] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0038] n is 1 or 2 or 3; and

[0039] R 1 , R 3 , R 4 and R 5 As defined elsewhere herein.

[0040] The compounds of the present invention include compounds having formula (III):

[0041]

[0042] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0043] R 12 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7 ,CONHR 8 、NHCOR 9 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl and N-containing monocyclic heterocycloalkyl;

[0044] R 13 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7 ,CONHR 8 、NHCOR 9 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl, and N-containing monocyclic heterocycloalkyl; and

[0045] M is selected from the group consisting of O, S and NH.

[0046] The compounds of the present invention include compounds having formula (IV):

[0047]

[0048] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes, wherein:

[0049] R 12 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7 ,CONHR 8 、NHCOR 9 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl and N-containing monocyclic heterocycloalkyl;

[0050] R 13 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7 ,CONHR 8 、NHCOR 9 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl, and N-containing monocyclic heterocycloalkyl; and

[0051] M is selected from the group consisting of O, S and NH.

[0052] The compounds of the present invention include compounds having formula (V):

[0053]

[0054] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0055] m is 1, 2 or 3; and

[0056] R 1 , R 2 and R 3 As defined elsewhere herein.

[0057] The compounds of the present invention include compounds having formula (VI):

[0058]

[0059] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein R 1 , R 2 and R 3 As defined elsewhere herein.

[0060] The compounds of the present invention include compounds having formula (VII):

[0061]

[0062] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0063] p is 0, 1, 2 or 3;

[0064] Q choose free CH 2 ,O,C=O,SO 2 The group formed; and

[0065] R 1 , R 2 and R 3 As defined elsewhere herein.

[0066] The compounds of the present invention include compounds having formula (VIII):

[0067]

[0068] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0069] r is 0, 1, 2, or 3; and

[0070] R 1 , R 2 , R 3 , R 4 and R 5 As defined elsewhere herein.

[0071] The compounds of the present invention include compounds having the formula (IX):

[0072]

[0073] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0074] Y, Z, R 1 , R 2 , R 3 , R 4 and R 5 As defined elsewhere herein.

[0075] The compounds of the present invention include compounds having formula (X): Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0076] Y, Z, R, R 1 , R 2 , R 3 , R 4 and R 5 As defined elsewhere herein.

[0077] The compounds of the present invention include compounds having the formula (XI):

[0078]

[0079] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0080] Y, Z, R, R 1 , R 2 , R 3 , R 4 and R 5 As defined elsewhere herein.

[0081] The compounds of the present invention include compounds having formula (XII):

[0082]

[0083] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0084] Y, Z, R, R 1 , R 2 , R 3 , R 4 and R 5 As defined elsewhere herein.

[0085] The compounds of the present invention include compounds having the formula (XIII):

[0086]

[0087] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0088] X, Y, R, R 1 , R 2 , R 3 , R 4 and R 5 As defined elsewhere herein.

[0089] In a preferred embodiment, the N-containing monocyclic heterocycloalkyl group is selected from

[0090] The group composed of;

[0091] Embodiments of the present invention also relate to compositions comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0092] The present invention also relates to a method for treating or preventing diseases involving cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway agonists, which can be used to treat viral diseases and enhance anti-tumor immunity, including, for example, HBV infection, the method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0093] The present invention also relates to methods for treating or preventing diseases involving cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway agonists, which can be used to treat viral diseases and enhance anti-tumor immunity, including, for example, HBV infection, wherein the method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0094] The present invention also relates to a method for treating or preventing diseases or conditions associated with HBV infection and diseases involving cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway agonists, and can be used for treating viral diseases and enhancing anti-tumor immunity, the method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0095] The present invention also relates to a method for treating or preventing diseases or conditions associated with HBV infection and diseases involving cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway agonists, and can be used to treat viral diseases and enhance anti-tumor immunity, wherein the method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0096] The present invention also relates to a method for treating or preventing chronic viral infections caused by hepatitis C virus (HCV), herpes simplex virus (HSV), human immunodeficiency virus (HIV), and acute infections caused by DNA and RNA viruses, such as influenza virus and other virus families that cause the common cold and upper respiratory tract infections, including but not limited to paramyxoviruses, rhinoviruses, adenoviruses, human coronaviruses (including coronavirus associated with severe respiratory syndrome; Middle East respiratory syndrome coronavirus and human coronavirus OC43), virus families that cause hemorrhagic fever (including but not limited to viruses belonging to the Flaviviridae, Filoviridae, Arenaviridae and Bunyaviridae families), and viruses that cause encephalitis (including but not limited to West Nile virus, La Crosse virus, California encephalitis virus, Venezuelan equine encephalitis virus, Western equine encephalitis, Japanese encephalitis virus, Kwasana Forest virus, tick-borne encephalitis virus, rabies virus, chikungunya virus), the method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0097] The present invention further relates to a method for treating or preventing diseases or conditions associated with chronic viral infections by hepatitis C virus (HCV), herpes simplex virus (HSV), and acute infections caused by DNA and RNA viruses, methods for treating or preventing diseases or conditions associated with DNA and RNA viruses that cause acute infections, DNA and RNA viruses such as influenza viruses and other virus families that cause the common cold and upper respiratory tract infections, including but not limited to paramyxoviruses, rhinoviruses, adenoviruses, human coronaviruses (including coronaviruses associated with severe respiratory syndrome; Middle East respiratory syndrome coronavirus and human coronavirus OC43), virus families that cause hemorrhagic fever (including but not limited to viruses belonging to the Flaviviridae, Filoviridae, Arenaviridae and Bunyaviridae families), and viruses that cause encephalitis (including but not limited to West Nile virus, La Crosse virus, California encephalitis virus, Venezuelan equine encephalitis virus, Western equine encephalitis, Japanese encephalitis virus, Kwasana Forest virus, tick-borne encephalitis virus, rabies virus, chikungunya virus), the method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0098] The present invention also relates to a method for treating or preventing cancer, including bladder cancer, breast cancer, colorectal cancer, kidney cancer, liver cancer, lung cancer, melanoma, oral and oropharyngeal cancer, pancreatic cancer, prostate cancer, thyroid cancer, uterine cancer, leukemia and lymphoma, comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0099] The present invention also relates to a method for treating or preventing a disease or condition associated with cancer, including bladder cancer, breast cancer, colorectal cancer, kidney cancer, liver cancer, lung cancer, melanoma, oral and oropharyngeal cancer, pancreatic cancer, prostate cancer, thyroid cancer, uterine cancer, leukemia and lymphoma, comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0100] These and other objects, features and advantages will become apparent to those of ordinary skill in the art by reading the following detailed description and the appended claims. Unless otherwise indicated, all percentages, ratios and proportions in the present invention are by weight. Unless otherwise indicated, all temperatures are in degrees Celsius (° C.). All documents cited are, in relevant parts, incorporated herein by reference. Any document cited herein should not be construed as prior art against the present invention. DETAILED DESCRIPTION

[0101] Throughout this specification, when compositions are described as having, including, or comprising particular components, or where methods are described as having, including, or comprising particular process steps, it is contemplated that the compositions of the invention also consist essentially of or consist of the following: and the methods of the invention also consist essentially of or consist of the recited process steps.

[0102] In the present application, when an element or component is described as being included in a list of and / or selected from the listed elements or components, it should be understood that the element or component can be any one of the listed elements or components and can be selected from a group consisting of two or more of the elements or components.

[0103] Unless otherwise expressly stated, the singular forms in the present invention include the plural forms (and vice versa). In addition, unless otherwise specifically stated, in the case of a quantitative value preceded by the term "about", the present invention also includes the specific quantitative value itself.

[0104] It should be understood that the order of steps or the order in which certain actions are performed is not important, as long as the present invention remains operable. Furthermore, two or more steps or actions may be performed simultaneously.

[0105] As used herein, the term "halogen" refers to chlorine, bromine, fluorine and iodine.

[0106] As used herein, unless otherwise specified, "alkyl" and / or "aliphatic", whether used alone or as part of a substituent group, refers to straight and branched carbon chains having 1 to 20 carbon atoms or any number within this range, such as 1 to 6 carbon atoms or 1 to 4 carbon atoms. 1-6) shall independently refer to the number of carbon atoms in the alkyl portion or the alkyl portion of the larger alkyl substituent. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like. The alkyl group may be optionally substituted. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, 3-carboxypropyl, and the like. In substituents having multiple alkyl groups such as (C 1-6 alkyl) 2 In the amino group, the alkyl groups may be the same or different.

[0107] As used in the present invention, the term "alkenyl" and "alkynyl" groups, whether used alone or as part of a substituent, refer to straight and branched carbon chains with 2 or more carbon atoms, preferably 2 to 20 carbon atoms, wherein the alkenyl chain has at least one double bond and the alkynyl chain has at least one triple bond in the chain. Alkenyl and alkynyl can be optionally substituted. Non-limiting examples of alkenyl include vinyl, 3-propenyl, 1-propenyl (also 2-methylvinyl), isopropenyl (also 2-methylvinyl-2-yl), butene-4-yl, etc. Non-limiting examples of substituted alkenyl include 2-chlorovinyl (also 2-chlorovinyl), 4-hydroxybutene-1-yl, 7-hydroxy-7-methyloctyl-4-ene-2-yl, 7-hydroxy-7-methyloctyl-3,5-diene-2-yl, etc. The non-limiting examples of alkynyl include ethynyl, prop-2-ynyl (also propargyl), propyn-1-yl and 2-methyl-hex-4-yn-1-yl. The non-limiting examples of substituted alkynyl include 5-hydroxy-5-methyl hex-3-ynyl, 6-hydroxy-6-methyl hept-3-yn-2-yl, 5-hydroxy-5-ethyl hept-3-yn-yl etc.

[0108] As used herein, "cycloalkyl", whether used alone or as part of another group, refers to non-aromatic carbon-containing rings including cyclized alkyl, alkenyl and alkynyl groups, for example, having 3 to 14 ring carbon atoms, preferably 3 to 7 or 3 to 6 ring carbon atoms, or even 3 to 4 ring carbon atoms, and optionally including one or more (e.g., 1, 2 or 3) double bonds or triple bonds. The cycloalkyl group can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., including fused, bridged and / or spirocyclic systems), wherein carbon atoms are located inside or outside the ring system. Any suitable ring position of the cycloalkyl can be covalently attached to a defined chemical structure. The cycloalkyl ring can be optionally substituted. Non-limiting examples of cycloalkyl groups include: cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-4-yl, decahydroazainyl; bicyclo[6.2.0]decyl, decahydronaphthalenyl, and dodecahydro-1H-fluorenyl. The term "cycloalkyl" also includes carbocycles that are bicyclic hydrocarbon rings, non-limiting examples of which include bicyclo-[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, 1,3-dimethyl[2.2.1]hept-2-yl, bicyclo[2.2.2]octyl, and bicyclo[3.3.3]undecenyl.

[0109] "Haloalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogens. Haloalkyl includes perhaloalkyl groups, in which all hydrogen atoms of the alkyl group have been replaced with halogens (e.g., -CF 3 , -CF 2 CF 3 ). In addition to halogen, the haloalkyl group may be optionally substituted with one or more substituents. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

[0110] The term "alkoxy" refers to the group -O-alkyl, wherein alkyl is as defined above. Alkoxy may be optionally substituted. The term C 3 -C 6 Cycloalkoxy refers to a ring containing 3 to 6 carbon atoms and at least one oxygen atom (eg, tetrahydrofuran, tetrahydro-2H-pyran). 3 -C 6 A cycloalkoxy group may be optionally substituted.

[0111] The term "aryl" is defined as an unsaturated aromatic monocyclic ring of 6 carbon atoms or an unsaturated aromatic polycyclic ring of 10-14 carbon atoms when used alone or as a part of another group in the present invention. The aryl ring can be, for example, a phenyl or naphthyl ring, each of which is optionally substituted with one or more parts capable of replacing one or more hydrogen atoms. The non-limiting examples of aryl include: phenyl, naphthyl-1-yl, naphthyl-2-yl, 4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl, 2-(N,N--diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl, 3-methoxyphenyl, 8-hydroxynaphthyl-2-yl, 4,5-dimethoxynaphthyl-1-yl and 6-cyanonaphthyl-1-yl. Aryl also includes, for example, a phenyl or naphthyl ring fused to one or more saturated or partially saturated carbocyclic rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl, indanyl), which may be substituted on one or more carbon atoms of the aromatic and / or saturated or partially saturated rings.

[0112] The term "arylalkyl" or "aralkyl" refers to the radical -alkyl-aryl, wherein the alkyl and aryl groups are as defined herein. The aralkyl of the present invention is optionally substituted. Examples of arylalkyl include, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl, etc.

[0113] The term "heterocyclic" and / or "heterocycle" and / or "heterocyclyl", whether used alone or as part of another group, is defined in the present invention as one or more rings having 3 to 20 atoms, wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O) or sulfur (S), and wherein the ring further comprising the heteroatom is non-aromatic. In a heterocyclyl comprising 2 or more fused rings, the non-heteroatom bearing ring can be an aryl (e.g., indolyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclyls have 3 to 14 ring atoms, of which 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O) or sulfur (S). One or more N or S atoms in a heterocyclic group may be oxidized. A heterocyclic group may be optionally substituted.

[0114] Non-limiting examples of heterocyclic units having a monocyclic ring include: diazido, aziridinyl, uracil, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxazolidinedione, oxazolidinedione, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-yl (valerolactam), 2,3,4,5-tetrahydro-1H-nonyl (azepinyl), 2,3-dihydro-1H-indole and 1,2,3,4-tetrahydroquinoline. Non-limiting examples of heterocyclic units having 2 or more rings include hexahydro-1H-pyrrolazinyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolyl, and decahydro-1H-cyclooctylpyrrolyl.

[0115] The term "heteroaryl", whether used alone or as part of another group, is defined in the present invention as one or more rings having 5 to 20 atoms, wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O) or sulfur (S), and wherein at least one of the rings further comprising heteroatoms is aromatic. In heteroaryl groups comprising 2 or more fused rings, the non-heteroatom bearing ring can be a carbocycle (e.g., 6,7-dihydro-5H-cyclopentanepyrimidine) or an aryl (e.g., benzofuranyl, benzothienyl, indolyl). Exemplary heteroaryl groups have 5 to 14 ring atoms and contain 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O) or sulfur (S). One or more N or S atoms in the heteroaryl group may be oxidized. The heteroaryl group may be substituted. Non-limiting examples of heteroaryl rings comprising a single ring include: 1H-pyrrole, 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thienyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl and 4-dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings comprising 2 or more fused rings include benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolyl[3,2-d]pyrimidinyl, 7H-pyrrolyl|2,3-d]pyrimidinyl, pyridyl[2,3-d]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxyquinolinyl, and isoquinolinyl.

[0116] A non-limiting example of a heteroaryl group as described above is C 1 -C 5 Heteroaryl having 1 to 5 carbon ring atoms and at least one additional ring atom which is a heteroatom independently selected from nitrogen (N), oxygen (O) or sulfur (S) (preferably 1 to 4 additional ring atoms which are heteroatoms). 1 -C 5 Examples of heteroaryl groups include, but are not limited to, triazine, thiazol-2-yl, thiazol-4-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.

[0117] Unless otherwise indicated, when two substituents are joined together to form a ring having the indicated number of ring atoms (e.g., R 2 and R 3 Together with the nitrogen (N) to which they are attached, they form a ring with 3 to 7 ring members), the ring may have carbon atoms and optionally one or more (e.g. 1 to 3) additional heteroatoms independently selected from nitrogen (N), oxygen (O) or sulfur (S). The ring may be saturated or partially saturated and may be optionally substituted.

[0118] For the purposes of this invention, fused ring units including a single heteroatom as well as spirocycles, bicyclic rings, etc. will be considered to belong to the ring family corresponding to the heteroatom-containing ring. For example, 1,2,3,4-tetrahydroquinoline having the formula:

[0119]

[0120] For the purposes of the present invention, it is considered to be a heterocyclic unit. 6,7-dihydro-5H-cyclopentylpyrimidine having the following formula:

[0121]

[0122] For the purposes of the present invention, it is considered a heteroaryl unit. When the fused ring unit includes heteroatoms in both the saturated ring and the aryl ring, the aryl ring will dominate and determine the type of category to which the ring belongs. For example, 1,2,3,4-tetrahydro-[1,8]naphthyridine has the following formula:

[0123]

[0124] For the purposes of this invention, these are regarded as heteroaryl units.

[0125] Whenever any one of the term or its prefix root appears in the name of a substituent, the name should be interpreted as including those restrictions provided by the present invention. For example, whenever any one of the term "alkyl" or "aryl" or its prefix root appears in the name of a substituent (e.g., arylalkyl, alkylamino), the name should be interpreted as including the restrictions given above for "alkyl" and "aryl".

[0126] The term "substituted" is used throughout the specification. The term "substituted" is defined in the present invention as a moiety that has one or more hydrogen atoms replaced by a substituent or several (e.g., 1 to 10) substituents, whether acyclic or cyclic. A substituent is capable of replacing one or two hydrogen atoms of a single moiety at a time. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form the substituent, new moiety or unit. For example, a substitution unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, etc. Two hydrogen atom replacements include carbonyl, oxime, etc. Two hydrogen atom replacements from adjacent carbon atoms include epoxide, etc. Throughout the specification of the present invention, the term "substituted" is used to indicate that a moiety may have one or more hydrogen atoms replaced by a substituent. When a moiety is described as "substituted," any number of hydrogen atoms may be replaced. For example, difluoromethyl is a substituted C 1 Alkyl; trifluoromethyl is substituted C 1 Alkyl; 4-hydroxyphenyl is a substituted aromatic ring; (N,N-dimethyl-5-amino)octyl is a substituted C 8 Alkyl; 3-guanidinopropyl is a substituted C 3 Alkyl; 2-carboxypyridinyl is a substituted heteroaryl.

[0127] Variable groups defined herein, such as alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl, whether used alone or as part of another group, may be optionally substituted. Optionally substituted groups will be indicated as such.

[0128] The following are non-limiting examples of substituents that may replace a hydrogen atom on a moiety: halogens (chlorine (Cl), bromine (Br), fluorine (F), and iodine (I)), -CN, -NO 2 , oxo (=O), –OR 14 ,–SR 14 , –N(R 14 ) 2 ,–NR 14 C(O)R 14 ,–SO 2 R 14 ,–SO 2 OR 14 ,–SO 2 N(R 14 )2 , –C(O)R 14 , –C(O)OR 14 , –C(O)N(R 14 ) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-14 Cycloalkyl, aryl, heterocycle or heteroaryl, wherein each of alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocycle and heteroaryl is optionally substituted by 1-10 (e.g., 1-6 or 1-4) independently selected from halogen, -CN, -NO 2 , oxo and R 14 substituted by a group; wherein R 14 is independently hydrogen at each occurrence, –OR 15 ,–SR 15 , –C(O)R 15 , –C(O)OR 15 , –C(O)N(R 15 ) 2 ,–SO 2 R 15 、-S(O) 2 OR 15 , –N(R 15 ) 2 ,–NR 15 C(O)R 15 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, cycloalkyl (e.g. C 3-6 cycloalkyl), aryl, heterocyclic or heteroaryl, or two R 14 The units, together with the atoms to which they are bound, form an optionally substituted carbocyclic or heterocyclic ring having 3 to 7 ring atoms; wherein R 15 is independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, cycloalkyl (e.g., C 3-6 cycloalkyl), aryl, heterocyclic or heteroaryl, or two R 15 The units together with the atoms to which they are bonded form one or more substituted carbocyclic or heterocyclic rings, wherein the carbocyclic or heterocyclic rings preferably have 3 to 7 ring atoms.

[0129] In some embodiments, the substituents are selected from:

[0130] i)–OR 16 ; for example, –OH, –OCH 3 , –OCH 2 CH 3 , –OCH 2 CH 2 CH 3 ;

[0131] ii) – C(O)R 16 ; For example, –COCH 3 , –COCH 2 CH 3 , –COCH 2 CH 2 CH 3 ;

[0132] iii) –C(O)OR 16 ; For example, –CO 2 CH 3 , –CO 2 CH 2 CH 3 , –CO 2 CH 2 CH 2 CH 3 ;

[0133] iv)–C(O)N(R 16 ) 2 ; For example, –CONH 2 ,–CONHCH 3 、–CON(CH 3 ) 2 ;

[0134] v)–N(R 16 ) 2 ; For example, –NH 2 , –NHCH 3 、–N(CH 3 ) 2 、–NH(CH 2 CH 3 );

[0135] vi) Halogens: –F, –Cl, –Br and –I;

[0136] vii) – CH e X g ; wherein X is a halogen, m is 0 to 2, and e+g=3; for example, –CH 2 F, –CHF 2 , –CF 3 , –CCl3 , or –CBr 3 ;

[0137] viii) – SO 2 R 16 ; For example, –SO 2 H;–SO 2 CH 3 ; –SO 2 C 6 H 5 ;

[0138] ix) C 1 -C 6 Straight chain, branched chain or cyclic alkyl;

[0139] x) Cyano

[0140] xi) nitro;

[0141] xii)N(R 16 )C(O)R 16 ;

[0142] xiii) oxo (=O);

[0143] xiv) heterocyclic ring; and

[0144] xv) heteroaryl.

[0145] Each R 16 are independently hydrogen, optionally substituted C 1 -C 6 Straight or branched chain alkyl (e.g., optionally substituted C 1 -C 4 Straight chain or branched chain alkyl) or optionally substituted C 3 -C 6 Cycloalkyl (eg, optionally substituted C 3 -C 4 cycloalkyl); or two R 16 The units can be taken together to form a ring comprising 3-7 ring atoms. 16 are independently hydrogen, optionally substituted with halogen or C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkyl substituted C 1 -C 6 Straight chain or branched chain alkyl.

[0146] At various places in this specification, substituents of compounds are disclosed in groups or ranges. It is specifically intended that the description includes each and every individual subcombination of the members of these groups and ranges. For example, the term "C 1-6"alkyl" is specifically intended to disclose C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 and C 5 -C 6 alkyl.

[0147] For the purposes of the present invention, the terms "compound", "analog" and "composition of matter" are also applicable to the cyclic GMP-AMP synthase-interferon gene stimulator (cGAS-STING) pathway agonists described in the present invention, including all enantiomeric forms, diastereomeric forms, salts, etc., and throughout this specification, the terms "compound", "analog" and "composition of matter" can be used interchangeably.

[0148] The compounds described in the present invention may include asymmetric atoms (also referred to as chiral centers), and some compounds may include one or more asymmetric atoms or centers, thus producing optical isomers (enantiomers) and diastereomers. The present invention and compounds disclosed in the present invention include such enantiomers and diastereomers, as well as racemization and resolution, enantiomerically pure R and S stereoisomers, and other mixtures of R and S stereoisomers and pharmaceutically acceptable salts thereof. Optical isomers can be obtained in pure form by standard methods known to those skilled in the art, including but not limited to the formation of diastereomeric salts, kinetic resolution and asymmetric synthesis. The present invention also includes cis and trans isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). It should also be understood that the present invention encompasses all possible positional isomers and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, including but not limited to column chromatography, thin layer chromatography and high performance liquid chromatography.

[0149] Pharmaceutically acceptable salts of the compounds of the present invention which may have an acidic moiety may be formed using organic and inorganic bases. Depending on the number of acidic hydrogens available for deprotonation, monoanionic salts and polyanionic salts may be considered. Suitable salts formed with bases include: metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts; ammonium salts and organic amine salts, such as with morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di- or tri-basic lower alkylamines (e.g., tert-butyl ethyl, diethyl, diisopropyl, triethyl, tributyl or dimethylpropylamine), or mono-, di- or tri-basic hydroxy lower alkylamines (e.g., mono-, di- or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCO 3 、Na 2 CO 3 , KHCO 3 , K 2 CO 3 , Cs 2 CO 3 , LiOH, NaOH, KOH, NaH 2 PO 4 、Na 2 HPO 4 and Na 3 PO 4. Internal salts may also be formed. Similarly, when the compounds disclosed herein include a basic moiety, organic and inorganic acids may be used to form salts. For example, salts may be formed from acetic acid, propionic acid, lactic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, tartaric acid, succinic acid, dichloroacetic acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hippocampal, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, phthalic acid, propionic acid, succinic acid, sulfuric acid, tartaric acid, toluenesulfonic acid and camphorsulfonic acid, as well as other known pharmaceutically acceptable acids.

[0150] As used herein, the terms "treat," "treating," and "treatment" refer to the partial or complete alleviation, suppression, amelioration and / or alleviation of a disease from which a patient is suspected to be suffering.

[0151] As used herein, "therapeutically effective" and "effective dose" refer to a substance or amount that induces a desired biological activity or effect.

[0152] Unless otherwise indicated, the terms "subject" or "patient" are used interchangeably and refer to mammals, such as human patients and non-human primates, and experimental animals, such as rabbits, rats and mice, and other animals. Therefore, the terms "subject" or "patient" used in the present invention refer to any mammalian patient or subject to which the compounds of the present invention can be administered. In an exemplary embodiment of the present invention, in order to identify the subject patient to be treated according to the method of the present invention, an acceptable screening method is used to determine the risk factors associated with the target or suspected disease or condition or to determine the subject's existing disease or condition. These screening methods include, for example, routine examinations to determine the risk factors that may be associated with the target or suspected disease or condition. These and other conventional methods allow clinicians to select patients in need of treatment using the methods and compounds of the present invention.

[0153] The cyclic GMP-AMP synthase-interferon gene stimulator (cGAS-STING) pathway agonist of the present invention is a functionalized benzamide derivative of formula (I):

[0154]

[0155] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0156] G, Y and Z are selected from CR 6 and N; or none of G, Y and Z is present, and the adjacent atoms are linked together to form a 5-membered ring; or

[0157] R is selected from hydrogen and C 1-6 A group consisting of alkyl groups;

[0158] R 1 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7 ,CONHR 8 、NHR 9 NR 9 R 10 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl and N-containing monocyclic heterocycloalkyl;

[0159] R 2 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7 ,CONHR 8 、NHR 9 NR 9 R 10 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl and N-containing monocyclic heterocycloalkyl;

[0160] R 3 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7 ,CONHR 8 、NHR 9 NR 9 R 10 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl and N-containing monocyclic heterocycloalkyl;

[0161] R 4 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7,CONHR 8 、NHR 9 NR 9 R 10 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl and N-containing monocyclic heterocycloalkyl;

[0162] R and R 4 Together with the atoms to which they are bonded, they form a ring having 5 to 8 members, the ring optionally including a member selected from oxygen, C=O and SO 2 the parts of the group that make up it;

[0163] R 5 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7 ,CONHR 8 、NHR 9 NR 9 R 10 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl and N-containing monocyclic heterocycloalkyl;

[0164] R 6 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7 ,CONHR 8 、NHR 9 NR 9 R 10 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl and N-containing monocyclic heterocycloalkyl;

[0165] R and R 6 Together with the atoms to which they are bonded, they form rings having 5-8 members;

[0166] R 1 and R 6 together with the atoms to which they are bound, form an optionally substituted ring having 5 to 7 ring atoms;

[0167] R 2 and R 6 together with the atoms to which they are bound, form an optionally substituted ring having 5 to 7 ring atoms;

[0168] R 2 and R 6 together with the atoms to which they are bound, form an optionally substituted aromatic ring having 5 to 7 ring atoms, optionally including a moiety selected from oxygen, sulfur, nitrogen and NH;

[0169] R 4 and R 5 together with the atoms to which they are bound, form an optionally substituted ring having 5-7 ring atoms optionally including a moiety selected from oxygen, sulfur, nitrogen and NH;

[0170] R 4 and R 5 together with the atoms to which they are bound, form an optionally substituted, optionally aromatic ring having 5-6 ring atoms, optionally including zero to three moieties selected from oxygen, sulfur, nitrogen and NH;

[0171] R 7 Selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3 -C 7 the group consisting of a cycloalkyl group and an optionally substituted phenyl group;

[0172] R 8 Selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3 -C 7 the group consisting of a cycloalkyl group and an optionally substituted phenyl group;

[0173] R 9 Selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3 -C 7 Cycloalkyl and optionally substituted phenyl, optionally substituted heteroaryl, COR 10 and SO 2 R 10 The group composed of;

[0174] R 10 Selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3 -C 7 the group consisting of a cycloalkyl group and an optionally substituted phenyl group;

[0175] R 9 and R 10 The units, together with the atoms to which they are bonded, form a ring having 5 to 8 ring atoms;

[0176] Two R's 10 The units, together with the atoms to which they are bonded, form a ring having 5-8 ring atoms;

[0177] R 11 Selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3 -C 7 The group consisting of a cycloalkyl group and an optionally substituted phenyl group.

[0178] The compounds of the present invention include compounds having formula (II):

[0179]

[0180] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0181] n is 1 or 2 or 3; and

[0182] R 1 , R 3 , R 4 and R 5 As defined elsewhere herein.

[0183] The compounds of the present invention include compounds having formula (III):

[0184]

[0185] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0186] R 12 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7 ,CONHR 8 、NHCOR 9 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl and N-containing monocyclic heterocycloalkyl;

[0187] R 13 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7 ,CONHR 8、NHCOR 9 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl, and N-containing monocyclic heterocycloalkyl; and

[0188] M is selected from the group consisting of O, S and NH.

[0189] R 1 , R 3 , R 4 and R 5 As defined elsewhere herein.

[0190] The compounds of the present invention include compounds having formula (IV):

[0191]

[0192] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0193] R 12 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7 ,CONHR 8 、NHCOR 9 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl and N-containing monocyclic heterocycloalkyl;

[0194] R 13 Selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 Alkenyl, CO 2 R 7 ,CONHR 8 、NHCOR 9 , OR 10 , cyano, N 3 、SO 2 R 11 , the group consisting of optionally substituted phenyl, optionally substituted heteroaryl, and N-containing monocyclic heterocycloalkyl; and

[0195] M is selected from the group consisting of O, S and NH.

[0196] R 1 , R3 , R 4 and R 5 as defined elsewhere herein.

[0197] The compounds of the present invention include compounds having formula (V):

[0198]

[0199] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0200] m is 1-3; and

[0201] R 1 , R 2 and R 3 As defined elsewhere herein.

[0202] The compounds of the present invention include compounds having formula (VI):

[0203] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0204] Y, Z, R 1 , R 2 and R 3 As defined elsewhere herein.

[0205] The compounds of the present invention include compounds having formula (VII):

[0206]

[0207] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0208] p is 0, 1, 2 or 3;

[0209] Q choose free CH 2 ,O,C=O,SO 2 The group formed; and

[0210] Y, Z, R 1 , R 2 and R 3 As defined elsewhere in this invention

[0211] The compounds of the present invention include compounds having formula (VIII):

[0212]

[0213] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0214] r is 0, 1, 2, or 3; and

[0215] G, Y, R 1 , R 2 , R 3 , R 4 and R 5 As defined elsewhere in this invention

[0216] The compounds of the present invention include compounds having the formula (IX):

[0217]

[0218] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0219] Y, Z, R 1 , R 2 , R 3 , R 4 and R 5 As defined elsewhere herein.

[0220] The compounds of the present invention include compounds having formula (X):

[0221]

[0222] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0223] Y, Z, R, R 1 , R 2 , R 3 , R 4 and R 5 As defined elsewhere herein.

[0224] The compounds of the present invention include compounds having the formula (XI):

[0225]

[0226] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0227] Y, Z, R, R 1 , R 2 , R 3 , R 4 and R 5 As defined elsewhere herein.

[0228] The compounds of the present invention include compounds having formula (XII):

[0229]

[0230] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0231] Y, Z, R, R 1 , R 2 , R 3 , R 4 and R 5 As defined elsewhere herein.

[0232] The compounds of the present invention include compounds having formula (XII):

[0233]

[0234] Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

[0235] X, Y, R, R 1 , R 2 , R 3 , R 4 and R 5 As defined elsewhere herein.

[0236] In a preferred embodiment, the N-containing monocyclic heterocycloalkyl group is selected from

[0237] The group composed of;

[0238] In some embodiments, G is CR 6 .

[0239] In some embodiments, Y is CR 6 .

[0240] In some embodiments, Z is CR 6 .

[0241] In some embodiments, G is N.

[0242] In some embodiments, Y is N.

[0243] In some embodiments, Z is N.

[0244] In some embodiments, G is absent and the adjacent atoms are joined together to form a 5-membered ring.

[0245] In some embodiments, Y is not present and the adjacent atoms are linked together to form a 5-membered ring.

[0246] In some embodiments, Z is not present and the adjacent atoms are linked together to form a 5-membered ring.

[0247] In some embodiments, Y is N.

[0248] In some embodiments, Z is N.

[0249] In some embodiments, R is hydrogen.

[0250] In some embodiments, R is C 1-6 alkyl.

[0251] In some embodiments, R 1 For hydrogen.

[0252] In some embodiments, R 1 It is a halogen.

[0253] In some embodiments, R 1 is an optionally substituted C 1-6 Halogenated alkyl.

[0254] In some embodiments, R 1 is an optionally substituted C 1-6 Alkenyl.

[0255] In some embodiments, R 1 For CO 2 R 7 .

[0256] In some embodiments, R 1 For CONHR 8 .

[0257] In some embodiments, R 1 NHR 9 .

[0258] In some embodiments, R 1 NR 9 R 10 .

[0259] In some embodiments, R 1 OR 10 .

[0260] In some embodiments, R 1 It is cyano.

[0261] In some embodiments, R 1 N 3 .

[0262] In some embodiments, R 1 For SO 2 R 11 .

[0263] In some embodiments, R 1 is optionally substituted phenyl.

[0264] In some embodiments, R 1 is an optionally substituted heteroaryl group.

[0265] In some embodiments, R 1 It is a monocyclic heterocycloalkyl group containing N.

[0266] In some embodiments, R 1 Freedom to choose Composed of groups.

[0267] In some embodiments, R 2 For hydrogen.

[0268] In some embodiments, R 2 It is a halogen.

[0269] In some embodiments, R 2 is an optionally substituted C 1-6 Halogenated alkyl.

[0270] In some embodiments, R 2 is an optionally substituted C 1-6 Alkenyl.

[0271] In some embodiments, R 2 For CO 2 R 7 .

[0272] In some embodiments, R 2 For CONHR 8 .

[0273] In some embodiments, R 2 NHR 9 .

[0274] In some embodiments, R 2 NR 9 R 10 .

[0275] In some embodiments, R 2 OR 10 .

[0276] In some embodiments, R 2 It is cyano.

[0277] In some embodiments, R 2 N 3 .

[0278] In some embodiments, R 2 For SO 2 R 11 .

[0279] In some embodiments, R 2 is optionally substituted phenyl.

[0280] In some embodiments, R 2 is an optionally substituted heteroaryl group.

[0281] In some embodiments, R 2 It is a monocyclic heterocycloalkyl group containing N.

[0282] In some embodiments, R 2 Freedom to choose Composed of groups.

[0283] In some embodiments, R 3 For hydrogen.

[0284] In some embodiments, R 3 It is a halogen.

[0285] In some embodiments, R 3 is an optionally substituted C 1-6 Halogenated alkyl.

[0286] In some embodiments, R 3 is an optionally substituted C 1-6 Alkenyl.

[0287] In some embodiments, R 3 For CO 2 R 7 .

[0288] In some embodiments, R 3 For CONHR 8 .

[0289] In some embodiments, R 3 NHR 9 .

[0290] In some embodiments, R 3 NR 9 R 10 .

[0291] In some embodiments, R 3 OR 10 .

[0292] In some embodiments, R 3 It is cyano.

[0293] In some embodiments, R3 N 3 .

[0294] In some embodiments, R 3 For SO 2 R 11 .

[0295] In some embodiments, R 3 is optionally substituted phenyl.

[0296] In some embodiments, R 3 is an optionally substituted heteroaryl group.

[0297] In some embodiments, R 3 It is a monocyclic heterocycloalkyl group containing N.

[0298] In some embodiments, R 3 Freedom to choose Composed of groups.

[0299] In some embodiments, R 4 For hydrogen.

[0300] In some embodiments, R 4 It is a halogen.

[0301] In some embodiments, R 4 is an optionally substituted C 1-6 Halogenated alkyl.

[0302] In some embodiments, R 4 is an optionally substituted C 1-6 Alkenyl.

[0303] In some embodiments, R 4 For CO 2 R 7 .

[0304] In some embodiments, R 4 For CONHR 8 .

[0305] In some embodiments, R 4 NHR 9 .

[0306] In some embodiments, R 4 NR 9 R 10 .

[0307] In some embodiments, R 4 OR 10 .

[0308] In some embodiments, R4 It is cyano.

[0309] In some embodiments, R 4 N 3 .

[0310] In some embodiments, R 4 For SO 2 R 11 .

[0311] In some embodiments, R 4 is optionally substituted phenyl.

[0312] In some embodiments, R 4 is an optionally substituted heteroaryl group.

[0313] In some embodiments, R 4 It is a monocyclic heterocycloalkyl group containing N.

[0314] In some embodiments, R 4 Freedom to choose Composed of groups.

[0315] In some embodiments, R and R 4 Together with the atoms to which they are bonded they form a ring having 5 members.

[0316] In some embodiments, R and R 4 Together with the atoms to which they are bonded they form a ring with 5 members containing oxygen.

[0317] In some embodiments, R and R 4 Together with the atoms to which they are bonded they form a ring having 5 members containing C=O.

[0318] In some embodiments, R and R 4 Together with the atoms to which they are bonded, they form a 5-carbon ring containing SO 2 members of the ring.

[0319] In some embodiments, R and R 4 Together with the atoms to which they are bonded they form a ring having 6 members.

[0320] In some embodiments, R and R 4 Together with the atoms to which they are bonded they form a ring having 6 members containing oxygen.

[0321] In some embodiments, R and R 4 Together with the atoms to which they are bonded they form a ring having 6 members containing C=O.

[0322] In some embodiments, R and R4 Together with the atoms to which they are bonded, they form a 6-carbon ring containing SO 2 members of the ring.

[0323] In some embodiments, R and R 4 Together with the atoms to which they are bonded they form a ring having 7 members.

[0324] In some embodiments, R and R 4 Together with the atoms to which they are bonded they form a ring having 7 members containing oxygen.

[0325] In some embodiments, R and R 4 Together with the atoms to which they are bonded they form a ring having 7 members containing C=O.

[0326] In some embodiments, R and R 4 Together with the atoms to which they are bonded, they form a 7-carbon ring containing SO 2 members of the ring.

[0327] In some embodiments, R and R 4 Together with the atoms to which they are bonded they form a ring having 8 members.

[0328] In some embodiments, R and R 4 Together with the atoms to which they are bonded they form a ring with 8 members containing oxygen.

[0329] In some embodiments, R and R 4 Together with the atoms to which they are bonded they form a ring having 8 members containing C=O.

[0330] In some embodiments, R and R 4 Together with the atoms to which they are bonded, they form a network with 8 SO 2 Ring of ring.

[0331] In some embodiments, R 5 For hydrogen.

[0332] In some embodiments, R 5 It is a halogen.

[0333] In some embodiments R 5 is an optionally substituted C 1-6 Halogenated alkyl.

[0334] In some embodiments, R 5 is an optionally substituted C 1-6 Alkenyl.

[0335] In some embodiments, R 5 For CO 2 R7 .

[0336] In some embodiments, R 5 For CONHR 8 .

[0337] In some embodiments, R 5 NHR 9 .

[0338] In some embodiments, R 5 NR 9 R 10 .

[0339] In some embodiments, R 5 OR 10 .

[0340] In some embodiments, R 5 It is cyano.

[0341] In some embodiments, R 5 N 3 .

[0342] In some embodiments, R 5 For SO 2 R 11 .

[0343] In some embodiments, R 5 is optionally substituted phenyl.

[0344] In some embodiments, R 5 is an optionally substituted heteroaryl.

[0345] In some embodiments, R 5 It is a monocyclic heterocycloalkyl group containing N.

[0346] In some embodiments, R 5 Freedom to choose Composed of groups.

[0347] In some embodiments, R 6 For hydrogen.

[0348] In some embodiments, R 6 It is a halogen.

[0349] In some embodiments, R 6 is an optionally substituted C 1-6 Halogenated alkyl.

[0350] In some embodiments, R 6 is an optionally substituted C 1-6 Alkenyl.

[0351] In some embodiments, R 6 For CO 2 R 7 .

[0352] In some embodiments, R 6 For CONHR 8 .

[0353] In some embodiments, R 6 NHR 9 .

[0354] In some embodiments, R 6 NR 9 R 10 .

[0355] In some embodiments, R 6 OR 10 .

[0356] In some embodiments, R 6 It is cyano.

[0357] In some embodiments, R 6 N 3 .

[0358] In some embodiments, R 6 For SO 2 R 11 .

[0359] In some embodiments, R 6 is optionally substituted phenyl.

[0360] In some embodiments, R 6 is an optionally substituted heteroaryl.

[0361] In some embodiments, R 6 It is a monocyclic heterocycloalkyl group containing N.

[0362] In some embodiments, R 6 Freedom to choose Composed of groups.

[0363] In some embodiments, R and R 6 Together with the atoms to which they are bonded they form a ring having 5 members.

[0364] In some embodiments, R and R 6 Together with the atoms to which they are bonded they form a ring having 6 members.

[0365] In some embodiments, R and R 6Together with the atoms to which they are bonded they form a ring having 7 members.

[0366] In some embodiments, R and R 6 Together with the atoms to which they are bonded they form a ring having 8 members.

[0367] In some embodiments, R 1 and R 6 Together with the atoms to which they are bonded they form an optionally substituted ring having 5 members.

[0368] In some embodiments, R 1 and R 6 Together with the atoms to which they are bonded they form an optionally substituted ring having 6 members.

[0369] In some embodiments, R 1 and R 6 Together with the atoms to which they are bonded they form an optionally substituted ring having 7 members.

[0370] In some embodiments, R 2 and R 6 Together with the atoms to which they are bonded they form an optionally substituted ring having 5 members.

[0371] In some embodiments, R 2 and R 6 Together with the atoms to which they are bonded they form an optionally substituted ring having 6 members.

[0372] In some embodiments, R 2 and R 6 Together with the atoms to which they are bonded they form an optionally substituted ring having 7 members.

[0373] In some embodiments, R 2 and R 6 Together with the atoms to which they are bound they form an optionally substituted aromatic ring having 5 ring atoms, optionally containing oxygen.

[0374] In some embodiments, R 2 and R 6 Together with the atoms to which they are bonded they form an optionally substituted aromatic ring having 5 ring atoms, optionally containing sulfur.

[0375] In some embodiments, R 2 and R 6 Together with the atoms to which they are bound they form an optionally substituted aromatic ring having 5 ring atoms, optionally containing nitrogen.

[0376] In some embodiments, R 2 and R 6Together with the atoms to which they are bound they form an optionally substituted aromatic ring having 5 ring atoms, optionally including NH.

[0377] In some embodiments, R 2 and R 6 Together with the atoms to which they are bound they form an optionally substituted aromatic ring having 6 ring atoms, optionally containing oxygen.

[0378] In some embodiments, R 2 and R 6 Together with the atoms to which they are bound they form an optionally substituted aromatic ring having 6 ring atoms, optionally containing sulfur.

[0379] In some embodiments, R 2 and R 6 Together with the atoms to which they are bound they form an optionally substituted aromatic ring having 6 ring atoms, optionally including nitrogen.

[0380] In some embodiments, R 2 and R 6 Together with the atoms to which they are bound they form an optionally substituted aromatic ring having 6 ring atoms, optionally including NH.

[0381] In some embodiments, R 4 and R 5 Together with the atoms to which they are bound they form an optionally substituted ring having 5 ring atoms optionally including a moiety selected from oxygen, sulfur, nitrogen and NH.

[0382] In some embodiments, R 4 and R 5 Together with the atoms to which they are bound they form an optionally substituted ring having 6 ring atoms optionally including a moiety selected from oxygen, sulfur, nitrogen and NH.

[0383] In some embodiments, R 4 and R 5 Together with the atoms to which they are bound they form an optionally substituted ring having 7 ring atoms optionally including a moiety selected from oxygen, sulfur, nitrogen and NH.

[0384] In some embodiments, R 4 and R 5 Together with the atoms to which they are bound they form an optionally substituted aromatic ring having 5 ring atoms optionally including zero to three moieties selected from oxygen, sulfur, nitrogen and NH.

[0385] In some embodiments, R 4 and R 5Together with the atoms to which they are bound they form an optionally substituted aromatic ring having 6 ring atoms optionally including zero to three moieties selected from oxygen, sulfur, nitrogen and NH.

[0386] In some embodiments, R 7 For hydrogen.

[0387] In some embodiments, R 7 is an optionally substituted C 1-4 alkyl.

[0388] In some embodiments, R 7 is an optionally substituted C 3 -C 7 Cycloalkyl.

[0389] In some embodiments, R 7 is optionally substituted phenyl.

[0390] In some embodiments, R 8 For hydrogen.

[0391] In some embodiments, R 8 is an optionally substituted C 1-4 alkyl.

[0392] In some embodiments, R 8 is an optionally substituted C 3 -C 7 Cycloalkyl.

[0393] In some embodiments, R 8 is an optionally substituted phenyl group.

[0394] In some embodiments, R 9 For hydrogen.

[0395] In some embodiments, R 9 is an optionally substituted C 1-4 alkyl.

[0396] In some embodiments, R 9 is an optionally substituted C 3 -C 7 Cycloalkyl.

[0397] In some embodiments, R 9 is an optionally substituted phenyl group.

[0398] In some embodiments, R 9 is an optionally substituted heteroaryl group.

[0399] In some embodiments, R 9 COR 10 .

[0400] In some embodiments, R 9 For SO 2 R 10 .

[0401] In some embodiments, R 10 For hydrogen.

[0402] In some embodiments, R 10 is an optionally substituted C 1-4 alkyl.

[0403] In some embodiments, R 10 is an optionally substituted C 3 -C 7 Cycloalkyl.

[0404] In some embodiments, R 10 is an optionally substituted phenyl group.

[0405] In some embodiments, R 9 and R 10 The units, together with the atoms to which they are bonded, form a ring having 5 ring atoms.

[0406] In some embodiments, R 9 and R 10 The units, together with the atoms to which they are bonded, form a ring having 6 ring atoms.

[0407] In some embodiments, R 9 and R 10 The units, together with the atoms to which they are bonded, form a ring having 7 ring atoms.

[0408] In some embodiments, R 9 and R 10 The units, together with the atoms to which they are bonded, form a ring having 8 ring atoms.

[0409] In some embodiments, two R 10 The units, together with the atoms to which they are bonded, form a ring having 5 ring atoms.

[0410] In some embodiments, two R 10 The units, together with the atoms to which they are bonded, form a ring having 6 ring atoms.

[0411] In some embodiments, two R 10 The units, together with the atoms to which they are bonded, form a ring having 7 ring atoms.

[0412] In some embodiments, two R 10 The units, together with the atoms to which they are bonded, form a ring having 8 ring atoms.

[0413] In some embodiments, R 11 For hydrogen.

[0414] In some embodiments, R 11 is an optionally substituted C 1-4 alkyl.

[0415] In some embodiments, R 11 is an optionally substituted C 3 -C 7 Cycloalkyl.

[0416] In some embodiments, R 11 is an optionally substituted phenyl group.

[0417] In some embodiments, n is 1.

[0418] In some embodiments, n is 2.

[0419] In some embodiments, n is 3.

[0420] In some embodiments, R 12 For hydrogen.

[0421] In some embodiments, R 12 It is a halogen.

[0422] In some embodiments, R 12 is an optionally substituted C 1-6 Halogenated alkyl.

[0423] In some embodiments, R 12 is an optionally substituted C 1-6 Alkenyl.

[0424] In some embodiments, R 12 For CO 2 R 7 .

[0425] In some embodiments, R 12 For CONHR 8 .

[0426] In some embodiments, R 12 For NHCOR 9 .

[0427] In some embodiments, R 12 OR 10 .

[0428] In some embodiments, R 12 It is cyano.

[0429] In some embodiments, R 12 N3 .

[0430] In some embodiments, R 12 For SO 2 R 11 .

[0431] In some embodiments, R 12 is an optionally substituted phenyl group.

[0432] In some embodiments, R 12 is an optionally substituted heteroaryl group.

[0433] In some embodiments, R 12 It is a monocyclic heterocycloalkyl group containing N.

[0434] In some embodiments, R 12 Freedom to choose Composed of groups.

[0435] In some embodiments, R 13 For hydrogen.

[0436] In some embodiments, R 13 It is a halogen.

[0437] In some embodiments, R 13 is an optionally substituted C 1-6 Halogenated alkyl.

[0438] In some embodiments, R 13 is an optionally substituted C 1-6 Alkenyl.

[0439] In some embodiments, R 13 For CO 2 R 7 .

[0440] In some embodiments, R 13 For CONHR 8 .

[0441] In some embodiments, R 13 For NHCOR 9 .

[0442] In some embodiments, R 13 OR 10 .

[0443] In some embodiments, R 13 It is cyano.

[0444] In some embodiments, R 13 N 3 .

[0445] In some embodiments, R 13 For SO 2 R 11 .

[0446] In some embodiments, R 13 is an optionally substituted phenyl group.

[0447] In some embodiments, R 13 is an optionally substituted heteroaryl group.

[0448] In some embodiments, R 13 It is a monocyclic heterocycloalkyl group containing N.

[0449] In some embodiments, R 13 Freedom to choose Composed of groups.

[0450] In some embodiments, M is O.

[0451] In some embodiments, M is S.

[0452] In some embodiments, M is NH.

[0453] In some embodiments, m is 1.

[0454] In some embodiments, m is 2.

[0455] In some embodiments, m is 3.

[0456] In some embodiments, p is 0.

[0457] In some embodiments, p is 1.

[0458] In some embodiments, p is 2.

[0459] In some embodiments, p is 3.

[0460] In some embodiments, r is 0.

[0461] In some embodiments, r is 1. In some embodiments, r is 2.

[0462] In some embodiments, r is 3.

[0463] In some embodiments, Q is CH 2 .

[0464] In some embodiments, Q is O.

[0465] In some embodiments, Q is C=O.

[0466] In some embodiments, Q is SO2 .

[0467] Exemplary embodiments include compounds having formula (II) or pharmaceutically acceptable salt forms thereof:

[0468]

[0469] Where n, R 1 , R 3 , R 4 and R 5 Non-limiting examples of are defined in Table 1 below.

[0470] Table 1

[0471]

[0472]

[0473] Exemplary embodiments include compounds having Formula (V) or pharmaceutically acceptable salt forms thereof:

[0474]

[0475] Where m, R 1 , R 2 , R 3 Non-limiting examples of non-limiting examples of A, G, Y and Z are defined in Table 2 below.

[0476] Table 2

[0477]

[0478]

[0479] Exemplary embodiments include compounds having Formula (VI) or pharmaceutically acceptable salt forms thereof:

[0480]

[0481] Where R 1 , R 2 , R 3 Non-limiting examples of A, G, Y and Z are defined in Table 3 below.

[0482] Table 3

[0483]

[0484]

[0485] Exemplary embodiments include compounds having Formula (VII) or pharmaceutically acceptable salt forms thereof:

[0486]

[0487] Where p, Q, R 1 , R 2 , R 3 Non-limiting examples of A, G, Y and Z are defined in Table 4 below.

[0488] Table 4

[0489]

[0490]

[0491] Exemplary embodiments include compounds having formula (IX) or pharmaceutically acceptable salt forms thereof:

[0492]

[0493] Where R 1 , R 2 , R 3 , R 4 , R 5 Non-limiting examples of A, Y and Z are defined in Table 5 below.

[0494] Table 5

[0495]

[0496]

[0497] Exemplary embodiments include compounds having formula (X) or pharmaceutically acceptable salt forms thereof:

[0498]

[0499] Among them, R 1 , R 2 , R 3 , R 4 , R 5 Non-limiting examples of A, Y and Z are defined in Table 6 below.

[0500] Table 6

[0501]

[0502]

[0503] Exemplary embodiments include compounds having formula (XII) or pharmaceutically acceptable salt forms thereof:

[0504]

[0505] Among them, R 1 , R 2 , R 3 , R 4 , R 5 Non-limiting examples of A, X, and Z are defined below in Table 7.

[0506] Table 7

[0507]

[0508]

[0509] To illustrate the manner in which compounds of the present invention are named and referred to herein, a compound having the formula:

[0510]

[0511] Has the chemical name 3,4-dimethoxy-N-(naphthalen-1-yl)benzamide.

[0512] To illustrate the manner in which compounds of the present invention are named and referred to herein, a compound having the formula:

[0513]

[0514] It has the chemical name N-(naphthalen-1-yl)benzo[d][1,3]dioxetan-5-carboxamide.

[0515] To illustrate the manner in which compounds of the present invention are named and referred to herein, a compound having the formula:

[0516]

[0517] Has the chemical name 2-chloro-N-(naphthalen-1-yl)nicotinamide.

[0518] Technology

[0519] The present invention further relates to a process for preparing the novel cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway agonist of the present invention.

[0520] The compounds of the present invention can be prepared by commercially available starting materials, compounds known in the literature or easily prepared intermediates using standard synthetic methods and procedures known to those skilled in the art, according to the methods outlined in the present invention. Standard synthetic methods and procedures for preparing organic molecules and functional group transformations and manipulations can be easily obtained from relevant scientific literature or standard textbooks in the field. It should be understood that, in the case of typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may also be used unless otherwise indicated. Optimal reaction conditions may vary with the specific reactants or solvents used, but such conditions may be determined by conventional optimization procedures by those skilled in the art. Those skilled in the art of organic synthesis will recognize that, in order to optimize the formation of the compounds described in the present invention, the nature and order of the synthetic steps presented may be changed.

[0521] The processes described herein can be monitored by any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic methods such as nuclear magnetic resonance spectroscopy (e.g., 'H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, chromatography such as high performance liquid chromatography (HPLC), gas chromatography (GC), gel permeation chromatography (GPC), or thin layer chromatography (TLC).

[0522] The preparation of compounds may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be easily determined by those skilled in the art. The chemical properties of protecting groups can be found in, for example, Greene et al., Protective Groups in Organic Synthesis, 2nd edition (Wiley & Sons, 1991). For all purposes, the entire disclosure is incorporated into the present invention by reference.

[0523] Reaction of the present invention or method can be carried out in the suitable solvent that the technician in the field of organic synthesis can easily select.Suitable solvent is usually at the temperature of carrying out reaction, that is, can be at the temperature within the range of the freezing temperature of solvent to the boiling temperature of solvent, and reactant, intermediate and / or product do not react substantially.Given reaction can be carried out in a mixture of a solvent or more than one solvent.Depending on specific reactions steps, suitable solvent for specific reactions steps can be selected.

[0524] General synthetic method

[0525] General synthetic schemes for preparing compounds

[0526] The reagents used to prepare the compounds of the present invention are either commercially available or can be prepared by standard procedures described in the literature. According to the present invention, such compounds can be produced by one of the following reaction schemes.

[0527] The first aspect of the process of the present invention relates to a process for preparing benzamides having formula (I). Compounds of formula (I) can be prepared according to the processes outlined in Schemes 1-4.

[0528]

[0529] Thus, a suitably substituted compound of formula (XIV), a known compound or a compound prepared by a known method is reacted with thionyl chloride, optionally in the presence of an organic solvent such as dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethylformamide, optionally under heating, optionally under microwave irradiation, to give a compound of formula (XV). Alternatively, a compound of formula (XIV) is reacted with oxalyl chloride, optionally in the presence of dimethylformamide, optionally in an organic solvent such as dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethylformamide, etc., optionally under heating, optionally under microwave irradiation, to provide a compound of formula (XV). Then, the compound of formula (XV) is reacted with a compound of formula (XVI), a known compound or a compound prepared by a known method, optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, optionally in the presence of 4-N,N-dimethylaminopyridine, in an organic solvent such as dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethylformamide, etc., optionally under heating, optionally under microwave irradiation, to obtain a compound of formula (I).

[0530]

[0531] Alternatively, in the presence of a coupling agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N'-dicyclohexylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate, benzotriazol-1-yl-oxy-tris(dimethylamino)-hexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidino-hexafluorophosphate, in the presence of a coupling agent such as tetrahydrofuran, 1,4-dioxane, dioxane, etc. In an organic solvent such as methylformamide, dichloromethane, dichloroethane, methanol, ethanol, etc., optionally in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, optionally in the presence of 4-N,N-dimethylaminopyridine, optionally under heating, optionally with microwave irradiation, a suitably substituted compound of formula (XIV), a known compound or a compound prepared by a known method is reacted with a compound of formula (XVI), a known compound or a compound prepared by a known method to obtain a compound of formula (I).

[0532]

[0533] In the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), bis(acetonitrile)dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0), etc., in the presence of a base such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, triethylamine, diisopropylethylamine, pyridine, etc., optionally in the presence of water, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, 1,2-dichloroethane, etc., optionally under heating, optionally under microwave irradiation, a compound of formula (XVII), a known compound or a compound prepared by a known method (wherein X 1 The compound of formula (XIX) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, etc. in a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, optionally in the presence of water, optionally under heating, optionally under microwave irradiation, to obtain a compound of formula (XIV).

[0534]

[0535] In the presence of a palladium catalyst such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), bis(acetonitrile)dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0), or a copper catalyst such as copper iodide or copper acetate, in the presence of a base such as sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, pyridine, triethylamine, etc., optionally in the presence of (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, in the presence of a solvent such as toluene, benzene, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, methylene chloride, 1,2-dichloroethane, etc., optionally under heating, optionally under microwave irradiation, a compound of formula (XX), a known compound or a compound prepared by a known method with a compound of formula (XXI), a known compound or a compound prepared by a known method (wherein X 2 The compound of formula (XXII) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, etc. in a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, optionally in the presence of water, optionally under heating, optionally under microwave radiation, to obtain a compound of formula (XXIII).

[0536] Example

[0537] The following examples provide methods for preparing representative compounds of the present disclosure. One skilled in the art will know how to substitute appropriate reagents, starting materials, and purification methods known to those skilled in the art to prepare other compounds of the present invention.

[0538] 1 H NMR spectra were recorded on a 300 MHz INOVAVARIAN spectrometer. Chemical shift values ​​are given in ppm and are referred to as the internal standard of TMS (tetramethylsilane). The peak diagram is shown as follows: s, singlet; d, doublet; t, triplet; q, quadruple; m, multi-peak and dd, double doublet. The coupling constant (J) is expressed in Hertz (Hz). The mass spectrum was obtained on a 1200AligentLC-MS spectrometer (ES-API, positive ion). Silica gel column chromatography was performed on 100-200 mesh silica gel, and the eluent was a mixture of ethyl acetate and hexane, or a mixture of methanol and ethyl acetate. All tested compounds had a purity of at least 95%. Analytical HPLC (acetonitrile-water buffered with 0.1% formic acid) was run on an Agilent1100HPLC instrument equipped with an Agilent, ZORBAXSB-C18 column and UV detection at 210nm.

[0539]

[0540] Example 1: N-(Naphthalene-1-yl)benzo[d][1,3]dioxazole-5-carboxamide: Piperidinic acid (0.0829 g, 0.499 mmol), 1-aminonaphthalene (0.080 g, 0.5586 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.2068 g, 0.5453 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.26 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The mixture was washed with 4% paraformaldehyde and saturated brine, then concentrated under vacuum and purified using normal phase chromatography (12 g Isco silica gel column, ethyl acetate-hexane, 0-30%) to give a white solid (0.0562 g, 38.65%). 1 H NMR (300 MHz, CDCl 3 ): δ8.05-8.02 (m, 2H), 7.91-7.89 (m, 2H), 7.74 (d, J=7.5Hz, 1H), 7.55-7.48 (m, 5H), 6.94 (d, J=9Hz, 1H), 6.09 (s, 2H, OCH 2 O) C 18 H 13 NO 3 MS calculated value, 291.09; observed, (M+H) + 292.3.

[0541]

[0542] Example 2: N-(Naphthalen-1-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-carboxamide: 1,4-Benzyldioxane-6-carboxylic acid (0.0860 g, 0.4773 mmol), 1-aminonaphthalene (0.0752 g, 0.525 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.1991 g, 0.525 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.25 mL). The mixture was stirred at 22 °C for 18 h. Ethyl acetate (20 mL) was added to dilute the mixture and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (12 g Isco silica gel column, ethyl acetate-hexane, ) was purified to give a white solid (0.0737 g, 50.58%). 1 H NMR (300 MHz, CDCl 3 ): δ8.10-8.05 (m, 2H), 7.90-7.89 (m, 2H), 7.73 (d, J=6Hz, 1H), 7.54-7.52 (m, 5H), 7.00-6.98 (m, 1H), 4.34 (s, 4H, OCH 2 CH 2 O) C 19 H 15 NO 3 MS calculated value, 305.11; observed, (M+H) + 306.3.

[0543]

[0544] Example 3: 3-Methoxy-N-(naphthalen-1-yl)benzamide: 3-Methoxybenzoic acid (0.0796 g, 0.5231 mmol), 1-aminonaphthalene (0.0824 g, 0.5754 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.2182 g, 0.5754 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.27 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (12 g Isco silica gel column, ethyl acetate-hexane, ) was purified to give a white solid (0.0861 g, 59.34%). 1 H NMR (300 MHz, CDCl 3 ): δ8.19 (s, 1H), 8.09-8.07 (m, 2H), 7.92-7.91 (m, 2H), 7.76 (d, J=6Hz, 1H), 7.55-7.45 (m, 6H), 7.15-7.13 (m, 1H), 3.91 (s, 3H, OCH 3 ). C 18 H 15 NO 2 MS calculated value, 277.11; observed, (M+H) +278.4.

[0545]

[0546] Example 4: 2-Bromo-6-methoxy-N-(naphthalen-1-yl)benzamide: 2-Bromo-5-methoxybenzoic acid (0.0634 g, 0.2744 mmol), 1-aminonaphthalene (0.1145 g, 0.3018 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.1145 g, 0.3018 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.14 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (12 g Isco silica gel column, ethyl acetate-hexane, ) was purified to give a white solid (0.0604 g, 61.82%). 1 H NMR (300 MHz, CDCl 3 ): δ8.16-8.14(m, 2H), 8.03-8.01(m, 1H), 7.92-7.89(m, 1H), 7.77(d, J=9Hz, 1H), 7.54(br, 4H), 7.35(s, 1H), 6.95-6.92(m, 1H), 3.87(s, 3H, OCH 3 ). Calculated C 18 H 14 BrNO 2 MS calculated for 355.02; observed, (M+H) + 356.3.

[0547]

[0548] Example 5: 2-Bromo-N-(naphthalene-1-yl)benzamide: 2-Bromo-benzoic acid (0.0822 g, 0.4089 mmol), 1-aminonaphthalene (0.0644 g, 0.4497 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.1705 g, 0.4497 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.21 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (12 g Isco silica gel column, ethyl acetate-hexane, ) was purified to give a white solid (0.0296 g, 22.2%). 1 H NMR (300 MHz, CDCl 3 ): δ 8.16 (d, J = 6 Hz, 1H), 8.06-8.02 (m, 2H), 7.92 (s, 1H), 7.79-7.69 (m, 3H), 7.56-7.46 (m, 4H), 7.41-7.38 (m, 1H). Calculated C 17 H 12 MS calculated for BrNO is 325.01; observed, (M+H) + 326.3.

[0549]

[0550] Example 6: 6-Bromo-N-(naphthalen-1-yl)benzo[d][1,3]dioxazole-5-carboxamide: 6-Bromobenzo[d][1,3]dioxazole-5-carboxylic acid (0.0550 g, 0.2245 mmol), l-aminonaphthalene (0.0354 g, 0.2469 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.0936 g, 0.2469 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.12 mL). The mixture was stirred at 22 °C for 18 h. Ethyl acetate (20 mL) was added to dilute the mixture and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (12 g Isco silica gel column, ethyl acetate-hexane, ) was purified to give a white solid (6.97 mg, 8.39%).1 H NMR (300 MHz, CDCl 3 ): δ8.15-8.13 (m, 2H), 8.00 (d, J=6Hz, 1H), 7.91-7.89 (m, 1H), 7.76 (d, J=9Hz, 1H), 7.55-7.50 (m, 3H), 7.30 (s, 1H), 7.11 (s, 1H), 6.08 (s, 2H, OCH 2 O). Calculated C 18 H 12 BrNO 3 MS calculated for 369.00; observed (M+H) + 370.3.

[0551]

[0552] Example 7: N-(Naphthalen-1-yl)-3,4-dihydro-2H-benzo[b][1,4]dioxepane-7-carboxamide: 3,4-Dihydro-2H-1,5-benzodioxanone-7-carboxylic acid (0.0842 g, 0.4336 mmol), 1-aminonaphthalene (0.0683 g, 0.4769 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.1809 g, 0.4769 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.23 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum, and purified by normal phase chromatography (12 g Isco silica gel column, ethyl acetate-hexane, ) was purified to give a white solid (0.0175 g, 12.66%). 1 H NMR (300 MHz, CDCl 3 ): δ8.10(s, 1H), 8.05-8.02(m, 1H), 7.91-7.88(m, 2H), 7.75-7.73(m, 1H), 7 .62-7.49(m, 5H), 7.10-7.07(m, 1H), 4.36-4.29(m, 4H), 2.32-2.22(m, 2H). C 20 H 17 NO 3 MS calculated value, 319.12; observed, (M+H) + 320.4.

[0553]

[0554] Example 8: 3,4-Dimethoxy-N-(naphthalen-1-yl)benzamide: 3,4-Dimethoxybenzoic acid (0.0996 g, 0.5467 mmol), 1-aminonaphthalene (0.0861 g, 0.6013 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.2280 g, 0.6013 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.29 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (12 g Isco silica gel column, ethyl acetate-hexane, ) was purified to give a white solid (0.009 g). 1 H NMR (300 MHz, CDCl 3 ): δ8.17 (s, 1H), 8.03-8.00 (m, 1H), 7.92-7.89 (m, 2H), 7.77-7.74 (m, 1H), 7.59-7.50 (m, 4H), 6.98-6.95 (m, 1H), 3.98-3.94 (m, 6H). C 19 H 17 NO 3 MS calculated value, 307.12; observed, (M+H) + 308.4.

[0555]

[0556] Example 9: N-(Naphthalene-1-yl)benzamide: 1-Amino-naphthalene (0.0667 g, 0.4658 mmol) and N,N-dimethylpyridin-4-amine (DMAP, 0.0086 g, 0.0705 mmol) were dissolved in pyridine (1 mL) and treated with benzoyl chloride (0.059 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified using normal phase chromatography (12 g gold silica gel column, ethyl acetate-hexane, 0-20%) to give the desired product (white solid, 0.0374 g). 1 H NMR (300 MHz, CDCl 3): δ8.20 (s, 1H), 8.08-7.92 (m, 5H), 7.77-7.75 (m, 1H), 7.61-7.51 (m, 6H). C 17 H 13 MS calculated for NO, 247.10; observed, (M+H) + 248.4.

[0557]

[0558] Example 10: 2-Chloro-N-(naphthalen-1-yl)benzamide: 1-amino-naphthalene (0.0548 g, 0.3827 mmol) and triethylamine (NEt 3 , 0.16 mL, 1.1481 mmol) was dissolved in CH 2 Cl 2 (1 mL) and treated with 2-chlorobenzoyl chloride (0.049 mL, 0.3827 mmol). The mixture was stirred at 22 °C for 18 h. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The mixture was washed with saturated brine and then concentrated under vacuum and purified by normal phase chromatography (12 g gold silica gel column, ethyl acetate-hexane, 0-15%) to give a mixture. The mixture was purified by HPLC (CH 3 CN(0.1%TFA)-H 2 O (0.1% TFA), 30% ~ 90% (CH 3 CN %, 15 min) and further purification to give the title compound (white solid, 1.57 mg). 1 H NMR (300 MHz, CDCl 3 ): δ8.35 (s, 1H), 8.15-8.14 (m, 1H), 8.01-7.92 (m, 3H), 7.78-7.75 (m, 1H), 7.55-7.47 (m, 6H). C 17 H 12 MS calculated for ClNO 281.06; observed, (M+H) + 282.3.

[0559]

[0560] Example 11: 4-Fluoro-N-(naphthalen-1-yl)-2-(trifluoromethyl)benzamide: 1-aminonaphthalene (0.0567 g, 0.3959 mmol) and triethylamine (NEt 3 , 0.17 mL, 1.1877 mmol) was dissolved in CH 2 Cl2 (1 mL) and treated with 4-fluoro-2-(trifluoromethyl)-benzoyl chloride (0.0897 g, 0.3959 mmol). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum, and purified by normal phase chromatography (12 g gold silica gel column, ethyl acetate-hexane, 0-15%) to obtain a mixture, which was then purified by HPLC (CH 3 CN(0.1%TFA)-H 2 O (0.1% TFA), 30% ~ 90% (CH 3 CN %, 15 min) and further purification to give the title compound (white solid, 3.53 mg). 1 H NMR (300 MHz, CDCl 3 ): δ8.05-8.03 (m, 1H), 7.90-7.80 (m, 5H), 7.53 (s, 4H), 7.39 (s, 1H). C 18 H 11 F 4 MS calculated for NO, 333.08; observed, (M+H) + 334.4.

[0561]

[0562] Example 12: 2,4-difluoro-N-(naphthalen-1-yl)benzamide: 1-aminonaphthalene (0.0523 g, 0.3652 mmol) and triethylamine (NEt3, 0.15 mL, 1.0956 mmol) were dissolved in CH 2 Cl 2 (1 mL) and treated with 2,4-difluorobenzoyl chloride (0.045 mL, 0.3652 mmol). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified using normal phase chromatography (12 g gold silica gel column, ethyl acetate-hexane, 0-20%) to provide the title product (0.0531 g, white solid). 1 H NMR (300 MHz, CDCl 3): δ8.83 (d, J=15Hz, 1H), 8.32-8.27 (m, 1H), 8.17 (d, J=6Hz, 1H), 7.93-7.90 (m, 2H), 7.77-7.74 (m, 1H), 7.55 (s, 3H), 7.10-6.95 (m, 2H). C 17 H 11 F 2 MS calculated for NO, 283.08; observed, (M+H) + 284.4.

[0563]

[0564] Example 13: 2-Fluoro-N-(naphthalen-1-yl)-5-nitrobenzamide: 1-amino-naphthalene (0.0586 g, 0.4092 mmol) and N,N-diisopropylethylamine ((iPr) 2 NEt, 0.19 mL, 1.116 mmol) was dissolved in CH 2 Cl 2 (2 mL) and treated with 2-fluoro-5-nitrobenzoyl chloride (0.0787 g, 0.3866 mmol). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum, and first purified by normal phase chromatography (12 g gold silica gel column, ethyl acetate-hexane, 0-20%) to give a mixture, and then purified by HPLC (CH 3 CN(0.1%TFA)-H 2 O (0.1% TFA), 30% ~ 90% (CH 3 The mixture was further purified on 4% (CN), 15 min) to give the title compound (11.48 mg, white solid). 1 H NMR (300 MHz, CDCl 3 ): δ9.18 (s, 1H), 8.84 (d, J=15Hz, 1H), 8.46 (s, 1H), 8.18 (s, 1H), 7.93 (d, J=6Hz, 2H), 7.80 (d, J=6Hz, 1H), 7.58-7.43 (m, 4H). C 17 H 11 FN 2 O 3 MS calculated value, 310.08; observed, (M+H) + 311.3.

[0565]

[0566] Example 14: 2-Chloro-N-(naphthalen-1-yl)nicotinamide: 1-amino-naphthalene (0.0663 g, 0.4630 mmol) and N,N-diisopropylethylamine ((iPr) 2 NEt, 0.20 mL, 1.1616 mmol) was dissolved in CH 2 Cl 2 (2 mL) and treated with 2-chloronicotinoyl chloride (0.0681 g, 0.3872 mmol). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum, and purified using normal phase chromatography (12 g gold silica gel column, ethyl acetate-hexane, 0-50%) to give the title compound (0.0118 g, white solid). 1 H NMR (300 MHz, CDCl 3 ): δ8.66 (s, 1H), 8.56 (s, 1H), 8.35 (d, J = 6Hz, 1H), 8.11-7.77 (m, 4H), 7.56-7.45 (m, 4H). C 16 H 11 C1N 2 MS calculated for O, 282.06; observed, (M+H) + 283.3.

[0567]

[0568] Example 15: 4-Bromo-2-chloro-N-(naphthalen-1-yl)benzamide: 4-Bromo-2-chlorobenzoic acid (0.0706 g, 0.2781 mmol), 1-aminonaphthalene (0.0438 g, 0.3058 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.1160 g, 0.3058 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.15 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and first purified by normal phase chromatography (12 g Isco silica gel column, ethyl acetate-hexane, ) and then in HPLC (CH 3 CN(0.1%TFA)-H 2O (0.1% TFA), 30% ~ 90% (CH 3 CN %, 15 min) to give the title compound (white solid, 0.0229 g). 1 H NMR (300 MHz, CDCl 3 ): δ8.34 (s, 1H), 8.12 (d, J=9Hz, 1H), 7.97-7.72 (m, 5H), 7.57 (s, 4H). C 17 H 11 MS calculated for BrClNO, 358.97; observed, (M+H) + 360.3.

[0569]

[0570] Example 16: 2-Bromo-4,5-dimethoxy-N-(naphthalen-1-yl)benzamide: 2-Bromo-4,5-dimethoxybenzoic acid (0.0701 g, 0.2685 mmol), 1-aminonaphthalene (0.0423 g, 0.2953 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.1119 g, 0.2953 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.14 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and first purified by normal phase chromatography (12 g Isco silica gel column, ethyl acetate-hexane, ) and then in HPLC (CH 3 CN(0.1%TFA)-H 2 O (0.1% TFA), 30% ~ 90% (CH 3 CN %, 15 min) to give the title compound (white solid, 0.0198 g). 1 H NMR (300 MHz, CDCl 3 ): δ8.44 (s, 1H), 8.17 (d, J = 6Hz, 1H), 8.05 (d, J = 9Hz, 1H), 7.91 (d, J = 9Hz, 1H), 7.76 (d, J=9Hz, 1H), 7.57-7.52 (m, 3H), 7.48 (s, 1H), 7.11 (s, 1H), 3.96 (s, 6H). C 19 H 16 BrNO3 MS calculated value, 385.03; observed, (M+H) + 386.3.

[0571]

[0572] Example 17: 2-Bromo-4,5-difluoro-N-(naphthalen-1-yl)benzamide: 2-Bromo-4,5-difluorobenzoic acid (0.0885 g, 0.3734 mmol), 1-aminonaphthalene (0.0588 g, 0.4107 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.1558 g, 0.4107 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.20 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (12 g Isco silica gel column, ethyl acetate-hexane, ) gave the title compound (white solid, 0.0408 g). 1 H NMR (300 MHz, CDCl 3 ): δ8.14-8.10 (m, 2H), 7.99-7.91 (m, 2H), 7.81-7.69 (m, 2H), 7.57-7.52 (m, 4H). C 17 H 10 F 2 MS calculated for NO, 360.99; observed, (M+H) + 362.3.

[0573]

[0574] Example 18: 2-Bromo-4-methoxy-N-(naphthalen-1-yl)benzamide: 2-Bromo-4-methoxybenzoic acid (0.0677 g, 0.293 mmol), 1-aminonaphthalene (0.0462 g, 0.3223 mmol, 1.1 eq.) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.1222 g, 0.3223 mmol, 1.1 eq.) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.15 mL, 3 eq.). The mixture was stirred at 22 °C for 18 h. Ethyl acetate (20 mL) was added to dilute the mixture and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and first purified by normal phase chromatography (4 g Isco silica gel column, ethyl acetate-hexane, ethyl acetate %: ) and then in HPLC (H 2 O(0.1%TFA)-CH 3 CN (0.1% TFA), H 2 The product was further purified on the HPLC (0%: 90%-10%) to give a white solid (0.0116 g). 1 H NMR (300 MHz, CDCl 3 ): δ8.24-8.16 (m, 2H), 8.01 (s, 1H), 7.91-7.74 (m, 3H), 7.24 (s, 3H), 7.21 (s, 1H), 7.00 (s, 1H), 3.88 (s, 3H). C 18 H 14 BrNO 2 MS calculated value, 355.02; observed, (M+H) + 356.3.

[0575]

[0576] Example 19: 6-Bromo-N-(5,6,7,8-tetrahydronaphthalen-1-yl)benzo[d][l,3]dioxazole-5-carboxamide: 5,6,7,8-tetrahydronaphthalen-1-amine (0.021 g, 0.14 mmol, 1.1 eq) and N,N-diisopropylethylamine (0.07 mL, 0.39 mmol, 3 eq) were dissolved in dichloromethane (1 mL). 6-Bromo-1,3-benzaldehyde-5-carbonyl chloride (0.1349 mmol / mL prepared in situ in CH 2 Cl 2, 1 equivalent) was added to the above solution. The mixture was stirred at 22°C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and HCl (1 M, 5 mL, twice), saturated NaHCO 3 The solution was washed with saturated brine and then concentrated. Purification on ISCO (4 g silica gel column, ethyl acetate-hexane, ethyl acetate %: 0-20%) gave a white solid (0.0289 g). 1 H NMR (300 MHz, CDCl 3 ): δ7.84(s, 1H), 7.49(s, 1H), 7.18-7.15(m, 2H), 7.06(s, 1H), 6.97-6.94(m, 1H), 6.05(s, 2H, OCH 2 O), 2.80-2.78(m, 2H), 2.68-2.66(m, 2H), 1.84-1.79(m, 4H). C 18 H 16 BrNO 3 MS calculated value, 373.03; found value: 373.03. Observed, (M+H) + 374.3.

[0577]

[0578] Example 20: 6-Bromo-N-methyl-N-(naphthalen-1-yl)benzo[d][1,3]dioxazole-5-carboxamide: The method was the same as the synthesis method of Example 19. Purification on ISCO (4 g silica gel column, ethyl acetate-hexane, 0-25%) gave a white solid (0.035 g). 1 H NMR (300 MHz, CDCl 3 ): δ7.98 (d, J=9Hz, 1H), 7.85 (d, J=9Hz, 1H), 7.73 (d, J=9Hz, 1H), 7.65-7.50 (m, 4H), 6.79 (s, 1H), 6.39 (s, 1H), 5.76 (s, 1H, OCH 2 O), 5.71(s, 1H, OCH 2 O), 3.54 (s, 3H, NCH 3 ). 19 H 14 BrNO 3 MS calculated value, 383.02; observed, (M+H) + 384.4.

[0579]

[0580] Example 21: 6-Bromo-N-(2,3-dimethylphenyl)benzo[d][1,3]dioxazole-5-carboxamide: The method was the same as the synthesis method of Example 19. Purification on ISCO (4 g silica gel column, ethyl acetate-hexane, 0-25%) gave a white solid (0.0334 g). 1 H NMR (300 MHz, CDCl 3 ): δ7.65 (d, J=6Hz, 1H), 7.54 (s, 1H), 7.20-7.13 (m, 2H), 7.07 (s, 2H), 6.06 (s, 2H, OCH 2 O), 2.33 (s, 3H, CH 3 ), 2.25(s, 3H, CH 3 ). C 16 H 14 BrNO 3 MS calculated value, 347.02; observed, (M+H) + 348.3.

[0581]

[0582] Example 22: 6-Bromo-N-(3-cyano-2-fluorophenyl)benzo[d][1,3]dioxazole-5-carboxamide: The method was the same as the synthesis method of Example 19. Purification on ISCO (4 g silica gel column, ethyl acetate-hexane, 0-25%) gave a white solid (0.0334 g). 1 H NMR (300 MHz, CDCl 3 ): δ8.80-8.75(m, 1H), 8.17(s, 1H), 7.39-7.21(m, 4H), 6.09(s, 2H, OCH 2 O) C 15 H 8 BrFN 2 O 3 MS calculated value, 361.97; observed, (M+H) + 363.2.

[0583]

[0584] Example 23: 6-bromo-N-(2,3-dihydro-1H-indan-4-yl)benzo[d][1,3]dioxazole-5-carboxamide: The method was the same as the synthesis method of Example 19. Purification on ISCO (4 g silica gel column, ethyl acetate-hexane, ethyl acetate %: 0-20%) gave a white solid (0.0313 g). 1 H NMR (300 MHz, CDCl 3): δ7.94 (d, J=6Hz, 1H), 7.62 (s, 1H), 7.22-7.19 (m, 2H), 7.08-7.06 (m, 2H), 6.06 (s, 2H, OCH 2 O), 3.00-2.90(m, 4H), 2.16-2.09(m, 2H). C 17 H 14 BrNO 3 MS calculated value, 359.02; observed, (M+H) + 360.3.

[0585]

[0586] Example 24: 6-Bromo-N-(3-fluoro-2-methylphenyl)benzo[d][1,3]dioxazole-5-carboxamide: The method was the same as the synthesis method of Example 19. Purification on ISCO (4 g silica gel column, ethyl acetate-hexane, 0-20%) gave a white solid (0.0273 g). 1 H NMR (300 MHz, CDCl 3 ): δ7.79(s, 1H), 7.61(s, 1H), 7.26-7.21(m, 2H), 7.07(s, 1H), 6.94-6.89(m, 1H), 6.06(s, 2H, OCH 2 O), 2.25 (s, 3H, CH 3 ). 15 H 11 BrFNO 3 MS calculated value, 350.99; observed, (M+H) + 352.3.

[0587]

[0588] Example 25: 6-Bromo-N-(2-bromo-3-methylphenyl)benzo[d][1,3]dioxazole-5-carboxamide: The method was the same as the synthesis method of Example 19. Purification on ISCO (4 g silica gel column, ethyl acetate-hexane, 0-20%) gave a white solid (0.0273 g). 1 H NMR (300 MHz, CDCl 3 ): δ8.33-8.27(m, 2H), 7.16(s, 1H), 7.08-7.04(m, 2H), 6.07(s, 2H, OCH 2 O), 2.45 (s, 3H, CH 3 ). 15 H 11 Br 2 NO3 MS calculated value, 410.91; observed, (M+H) + 412.2.

[0589]

[0590] Example 26: 6-Bromo-N-(2,3-dichlorophenyl)benzo[d][1,3]dioxazole-5-carboxamide: The method was the same as the synthesis method of Example 19. Purification on ISCO (4 g silica gel column, ethyl acetate-hexane, 0-20%) gave a yellow solid (0.0363 g). 1 H NMR (300 MHz, CDCl 3 ): δ8.49(s, 1H), 8.32(s, 1H), 7.17(s, 1H), 7.08(s, 1H), 6.07(s, 2H, OCH 2 O) C 14 H 8 BrClNO 3 MS calculated value, 386.91; observed, (M+H) + 388.2.

[0591]

[0592] Example 27: 6-Bromo-N-(2-fluorophenyl)benzo[d][1,3]dioxazole-5-carboxamide: The method was the same as the synthesis method of Example 19. Purification on ISCO (4 g silica gel column, ethyl acetate-hexane, 0-20%) gave a white solid (0.024 g). 1 H NMR (300 MHz, CDCl 3 ): δ8.49-8.44(m, 1H), 8.02(s, 1H), 7.20-7.07(m, 5H), 6.07(s, 2H, OCH 2 O) C 14 H 9 BrFNO 3 MS calculated value, 336.97; observed, (M+H) + 338.3.

[0593]

[0594] Example 28: 6-Bromo-N-(3-bromo-2-methylphenyl)benzo[d][1,3]dioxazole-5-carboxamide: The method was the same as the synthesis method of Example 19. Purification on ISCO (4 g silica gel column, ethyl acetate-hexane, 0-20%) gave a white solid (0.0301 g). 1H NMR (300 MHz, CDCl 3 ): δ7.86-7.83 (m, 1H), 7.62 (s, 1H), 7.45 (d, J=6Hz, 1H), 7.19-7.06 (m, 3H), 6.06 (s, 2H, OCH 2 O), 2.44 (s, 3H, CH 3 ). 15 H 11 Br 2 NO 3 MS calculated value, 410.9. Observed, (M+H) + 412.2.

[0595]

[0596] Example 29: 6-Bromo-N-(quinolin-8-yl)benzo[d][1,3]dioxazole-5-carboxamide: The method was the same as the synthesis method of Example 19. Purification on ISCO (4 g silica gel column, ethyl acetate-hexane, 0-20%) gave a white solid (0.0386 g). 1 H NMR (300 MHz, CDCl 3 ): δ10.30 (s, 1H), 8.92-8.90 (m, 1H), 8.80 (s, 1H), 8.18 (d, J=6Hz, 1H), 7.59 -7.54(m,2H),7.48-7.44(m,1H),7.21(s,1H),7.11(s,1H),6.07(s,2H,OCH 2 O) C 17 H 11 Bn 2 O 3 MS calculated value, 370.00; observed, (M+H) + 371.3.

[0597]

[0598] Example 30: N-(3-(Benzyloxy)-2-methylphenyl)-6-bromobenzo[d][1,3]dioxazole-5-carboxamide: The method was the same as the synthesis method of Example 19. Purification on ISCO (4 g silica gel column, ethyl acetate-hexane, 0-20%) gave a white solid (0.0386 g). 1 H NMR (300 MHz, CDCl 3): δ7.62-7.56(m, 2H), 7.43-7.32(m, 5H), 7.20(s, 2H), 7.06(s, 1H), 6.83-6.80(m, 1H), 6.05(s, 2H, OCH 2 O), 5.10 (s, 2H, PhCH 2 ), 2.27(s, 3H, CH 3 ). 22 H 18 BrNO 4 MS calculated value, 439.04; observed, (M+H) + 440.4.

[0599]

[0600] Example 31: N-(2-(1-H-pyrrol-1-yl)phenyl)-6-bromobenzo[d][1,3]dioxazole-5-carboxamide: The method was the same as the synthesis method of Example 19. Purification on ISCO (4 g silica gel column, ethyl acetate-hexane, 0-20%) gave a white solid (0.0258 g). 1 H NMR (300 MHz, CDCl 3 ): δ8.57 (d, J=9Hz, 1H), 7.75 (s, 1H), 7.47-7.42 (m, 2H), 7.33-7.18 (m, 3H), 7.05 (s, 1H), 6.97 (s, 1H), 6.82 (s, 2H), 6.02 (s, 2H, OCH 2 O) C 18 H 13 Bn 2 O 3 MS calculated value, 384.01; observed, (M+H) + 385.3.

[0601]

[0602] Example 32: 4-Chloro-2-fluoro-N-(naphthalen-1-yl)benzamide: 4-Chloro-2-fluorobenzoic acid (0.0349 g, 0.20 mmol), 1-aminonaphthalene (0.037 g, 0.258 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.0874 g, 0.2305 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.38 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (4 g Isco silica gel column, ethyl acetate-hexane, ) was purified to give a white solid (0.0066 g, 11.0%). 1 H NMR (300 MHz, CDCl 3 ): δ8.34 (s, 1H), 8.12 (d, J=9Hz, 1H), 8.0-7.90 (m, 3H), 7.77 (d, J=9Hz, 1H), 7.59-7.51 (m, 3H), 7.28 (s, 1H), 7.20-7.13 (m, 1H). C 17 H 11 MS calculated for ClFNO, 299.05; observed, (M+H) + 300.3.

[0603]

[0604] Example 33: 4-Chloro-2,5-difluoro-N-(naphthalen-1-yl)benzamide: 4-Chloro-2,5-difluorobenzoic acid (0.0397 g, 0.20 mmol), 1-aminonaphthalene (0.037 g, 0.258 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.0841 g, 0.2218 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.04 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (4 g Isco silica gel column, ethyl acetate-hexane, ) was purified to give white needle crystals (0.0150 g, 22.9%).1 H NMR (300 MHz, CDCl 3 ): δ8.86 (d, J=15Hz, 1H), 8.16 (d, J=9Hz, 1H), 8.09-8.04 (m, 1H), 7.91 (d, J= 9Hz, 2H), 7.77 (d, J=9Hz, 1H), 7.61-7.52 (m, 3H), 7.38 (dd, J=12Hz, 6Hz, 1H). C 17 H 10 CIF 2 MS calculated for NO, 317.04; observed, (M+H) + 318.3.

[0605]

[0606] Example 34: 2-Bromo-5-fluoro-N-(naphthalen-1-yl)benzamide: 2-Bromo-5-fluorobenzoic acid (0.0375 g, 0.17 mmol), 1-aminonaphthalene (0.037 g, 0.258 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.0746 g, 0.1967 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.033 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (4 g Isco silica gel column, ethyl acetate-hexane, ) was purified to give white needle crystals (0.0492 g, 83.5%). 1 H NMR (300 MHz, CDCl 3 ): δ8.13-8.11(m, 2H), 7.99(d, J=9Hz, 1H), 7.93-7.90(m, 1H), 7.79(d, J=9Hz , 1H), 7.67 (dd, J=9Hz, 3Hz, 1H), 7.59-7.52 (m, 4H), 7.12 (dt, J=9Hz, 3Hz, 1H). C 17 H 11 MS calculated for BrFNO, 343.00; observed, (M+H) + 345.3.

[0607]

[0608] Example 35: 2,3-Dichloro-N-(naphthalen-1-yl)benzamide: 2,3-Dichlorobenzoic acid (0.0319 g, 0.167 mmol), 1-aminonaphthalene (0.037 g, 0.258 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.0759 g, 0.2000 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.032 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (4 g Isco silica gel column, ethyl acetate-hexane, ) was purified to give white needle-like crystals (0.0361 g, 68.4%). 1 H NMR (300 MHz, CDCl 3 ): δ8.14-8.07 (m, 2H), 7.95-7.90 (m, 2H), 7.79-7.71 (m, 2H), 7.65-7.51 (m, 4H), 7.38 (t, J=9Hz, 1H). C 17 H 11 Cl 2 MS calculated for NO, 315.02; observed, (M+H) + 316.3.

[0609]

[0610] Example 36: 2,4,5-Trifluoro-N-(naphthalen-1-yl)benzamide: 2,4,5-Trifluorobenzoic acid (0.0402 g, 0.2282 mmol), 1-aminonaphthalene (0.037 g, 0.258 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.0964 g, 0.2542 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.044 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (4 g Isco silica gel column, ethyl acetate-hexane, ) was purified to give a white solid (0.0094 g, 13.8%). 1H NMR (300 MHz, CDCl 3 ): δ8.84 (d, J=15Hz, 1H), 8.16-8.08 (m, 2H), 7.93-7.90 (m, 2H), 7.78-7.75 (m, 1H), 7.60-7.51 (m, 3H), 7.19-7.10 (m, 1H). C 17 H 10 F 3 MS calculated for NO 301.07; observed, (M+H) + 302.4.

[0611]

[0612] Example 37: 2,4,6-Trifluoro-N-(naphthalen-1-yl)benzamide: 2,4,6-Trifluorobenzoic acid (0.0421 g, 0.2390 mmol), 1-aminonaphthalene (0.037 g, 0.258 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.1019 g, 0.2687 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.046 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (4 g Isco silica gel column, ethyl acetate-hexane, ) was purified to give a white solid (0.025 g, 34.7%). 1 H NMR (300 MHz, CDCl 3 ): δ8.06 (d, J=9Hz, 1H), 7.94-7.90 (m, 3H), 7.79 (d, J=9Hz, 1H), 7.60-7.51 (m, 3H), 6.84 (t, J=9Hz, 2H). C 17 H 10 F 3 MS calculated for NO, 301.07; observed, (M+H) + 302.3.

[0613]

[0614] Example 38: 2-Bromo-4-fluoro-N-(naphthalen-1-yl)benzamide: 2-Bromo-4-fluorobenzoic acid (0.0314 g, 0.1433 mmol), 1-aminonaphthalene (0.037 g, 0.258 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.0605 g, 0.1595 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.027 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (4 g Isco silica gel column, ethyl acetate-hexane, ) was purified to give a white solid (0.0164 g, 33.3%). 1 H NMR (300 MHz, CDCl 3 ): δ8.14-8.07 (m, 2H), 7.98 (d, J=9Hz, 1H), 7.92-7.76 (m, 3H), 7.57-7.51 (m, 3H), 7.44 (d, J=9Hz, 1H), 7.22-7.17 (m, 1H). C 17 H 11 MS calculated for BrFNO, 343.0; observed, (M+H) + 344.3.

[0615]

[0616] Example 39: 2-Chloro-4-fluoro-N-(naphthalen-1-yl)benzamide: 2-Chloro-4-fluorobenzoic acid (0.0421 g, 0.2411 mmol), 1-aminonaphthalene (0.037 g, 0.258 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.1085 g, 0.2861 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.046 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (4 g Isco silica gel column, ethyl acetate-hexane, ) was purified to give a white solid (0.0473 g, 65.4%). 1H NMR (300 MHz, CDCl 3 ): δ8.85 (d, J=15Hz, 1H), 8.27-8.17 (m, 2H), 7.95-7.90 (m, 2H), 7.76-7.75 (m, 1H), 7.60-7.51 (m, 3H), 7.38-7.29 (m, 2H). C 17 H 11 MS calculated for ClFNO, 299.05; observed, (M+H) + 300.3.

[0617]

[0618] Example 40: 2-Fluoro-N-(naphthalen-1-yl)-4-(trifluoromethyl)benzamide: 2-Fluoro-3-(trifluoromethyl)benzoic acid (0.0357 g, 0.1715 mmol), 1-aminonaphthalene (0.037 g, 0.258 mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.0739 g, 0.1949 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.033 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (4 g Isco silica gel column, ethyl acetate-hexane, ) was purified to give a white solid (0.0483 g, 65.4%). 1 H NMR (300 MHz, CDCl 3 ): δ8.85 (d, J=15Hz, 1H), 8.27-8.17 (m, 2H), 7.95-7.90 (m, 2H), 7.76-7.75 (m, 1H), 7.60-7.51 (m, 3H), 7.38-7.29 (m, 2H). C 18 H 11 F 4 MS calculated for NO, 333.08; observed, (M+H) + 334.4.

[0619]

[0620] Example 41: 6-Bromo-N-phenylbenzo[d][1,3]dioxazole-5-carboxamide: Aniline (0.0776 g, 0.8332 mmol) and N,N-diisopropylethylamine (0.04 mL) were dissolved in dichloromethane (1 mL). 6-Bromo-1,3-benzodioxole-5-carbonyl chloride (1 mL, 0.0697 mmol / mL) was then added to the above solution. The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (4 g Isco silica gel column, ethyl acetate-hexane, ) was purified to give a white solid (0.0165 g). 1 H NMR (300 MHz, CDCl 3 ): δ7.67-7.61(m, 3H), 7.40-7.35(m, 2H), 7.19-7.14(m, 2H), 7.05(s, 1H), 6.05(s, 2H, OCH 2 O) C 14 H 10 BrNO 3 MS calculated value, 318.98, observed, (M+H) + 322.3.

[0621]

[0622] Example 42: 6-Bromo-N-(o-tolyl)benzo[d][1,3]dioxazole-5-carboxamide: The title compound was prepared according to the method of Example 41, except that aniline was replaced with 2-methylaniline. Purification on ISCO (4 g Isco silica gel column, ethyl acetate-hexanes, ethyl acetate %: 0-25%) gave a white solid (0.01436 g). 1 H NMR (300 MHz, CDCl 3 ): δ7.99 (d, J=6Hz, 1H), 7.57 (s, 1H), 7.29-7.21 (m, 3H), 7.15-7.10 (m, 1H), 7.07 (s, 1H), 6.06 (s, 2H, OCH 2 O), 2.35 (s, 3H, CH 3 ). C 15 H 12 BrNO 3 MS calculated value, ,333.00; observed, (M+H) + 334.3.

[0623]

[0624] Example 43: 6-Bromo-N-(2,6-dimethylphenyl)benzo[d][1,3]dioxazole-5-carboxamide: The title compound was prepared according to the method of Example 41, except that 2,6-dimethylaniline was used instead of aniline. Purification on ISCO (4g Isco silica gel column, ethyl acetate-hexanes, ethyl acetate %: 0-25%) gave a white solid (0.01725 g). 1 H NMR (300 MHz, CDCl 3 ): δ7.21(s, 1H), 7.15-7.10(m, 3H), 7.08(s, 1H), 6.06(s, 2H, OCH 2 O), 2.35(s, 2x3H, CH 3 ). C 16 H 14 BrNO 3 MS calculated value, 347.02; observed, (M+H) + 348.3.

[0625]

[0626] Example 44: 6-Bromo-N-(2-chlorophenyl)benzo[d][1,3]dioxazole-5-carboxamide: The title compound was prepared according to the method of Example 41, except that 2-chloroaniline was used instead of aniline. Purification on ISCO (4g Isco silica gel column, ethyl acetate-hexanes, ethyl acetate %: 0-25%) gave a white solid (0.0166 g). 1 H NMR (300 MHz, CDCl 3 ): δ8.53 (d, J=9Hz, 1H), 8.24 (s, 1H), 7.43-7.40 (m, 1H), 7.36-7.31 (m, 1H), 7.18 (s, 1H), 7.13-7.06 (m, 2H), 6.07 (s, 2H, OCH 2 O) C 14 H 9 BrClNO 3 MS calculated, 352.94; observed, (M+H) + 354.2.

[0627]

[0628] Example 45: 6-Bromo-N-(3-chlorophenyl)benzo[d][1,3]dioxazole-5-carboxamide: The title compound was prepared according to the method of Example 41, except that 3-chloroaniline was used instead of aniline. Purification on ISCO (4g Isco silica gel column, ethyl acetate-hexanes, ethyl acetate %: 0-25%) gave a white solid (0.0096 g). 1 H NMR (300 MHz, CDCl 3 ): δ7.76 (s, 1H), 7.69 (s, 1H), 7.46 (d, J=6Hz, 1H), 7.32-7.26 (m, 1H), 7.21-7.13 (m, 2H), 7.06 (s, 1H), 6.06 (s, 2H, OCH 2 O) C 14 H 9 BrClNO 3 MS calculated value, 352.94; observed, (M+H) + 354.3.

[0629]

[0630] Example 57: 6-Bromo-N-(2-morpholinylphenyl)benzo[d][1,3]dioxazole-5-carboxamide: The title compound was prepared according to the method of Example 41, except that aniline was replaced with 2-morpholinylaniline. Purification on ISCO (4g Isco silica gel column, ethyl acetate-hexanes, ethyl acetate %: 0-25%) gave a white solid (0.01896 g). 1 H NMR (300 MHz, CDCl 3 ): δ9.18 (s, 1H), 8.57-8.54 (m, 1H), 7.26-7.22 (m, 2H), 7.16-7.10 (m, 2H), 7.08 (s, 1H), 6.07 (s, 2H, OCH 2 O), 3.83 (t, J=6Hz, 4H, NCH 2 CH 2 O), 2.90 (t, J=6Hz, 4H, NCH 2 CH 2 O) C 18 H 17 Bn 2 O 4 MS calculated for, 404.04; observed, (M+H) + 405.4.

[0631]

[0632] Example 47: 2,4-Dichloro-N-(naphthalen-1-yl)benzamide: 2,4-Dichlorobenzoyl chloride (0.0446 g, 0.2129 mmol) and 1-aminonaphthalene (0.0842 g, 0.5880 mmol) were dissolved in dichloromethane (1 mL) and treated with N,N-diisopropylethylamine (0.11 mL). The mixture was stirred at 22 °C for 18 hours. A lot of white solid precipitated. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (4 g Isco silica gel column, ethyl acetate-hexane, ) and purified by HPLC ((CH 3 CN-H 2 The target compound (6.64 mg) as a light pink solid was further purified on 4% paraformaldehyde (0, 20% to 95%, 17 min, 15 mL / min). 1 H NMR (300 MHz, CDCl 3 ): δ8.34 (s, 1H), 8.12 (d, J=9Hz, 1H), 7.98-7.89 (m, 3H), 7.78 (d, J=6Hz, 1H), 7.61-7.51 (m, 4H), 7.43 (d, J=9Hz, 1H). C 17 H 11 Cl 2 MS calculated for NO, 315.02; observed, (M+H) + 316.3.

[0633]

[0634] Example 48: 6-Bromo-N-(2-(prop-1-en-2-yl)phenyl)benzo[d][1,3]dioxazole-5-carboxamide: 2-(prop-1-en-2-yl)aniline (0.0824 g, 0.6187 mmol) and N,N-diisopropylethylamine (0.04 mL) were dissolved in dichloromethane (1 mL). Then 6-bromo-1,3-benzodioxole-5-carbonyl chloride (1 mL, 0.0697 mmol / mL) was added to the above solution. The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine and then concentrated under vacuum and purified using normal phase chromatography (4 g Isco silica gel column, ethyl acetate-hexane, 0-25%) to give a pale yellow oil (0.0148 g). 1 H NMR (300 MHz, CDCl3 ): δ8.45 (d, J=9Hz, 1H), 8.07 (s, 1H), 7.35-7.30 (m, 1H), 7.20-7.10 (m, 3H), 7.05 (s, 1H), 6.05 (s, 2H, OCH 2 O), 5.37-5.35(m, 1H), 5.06-5.04(m, 1H), 2.08-2.07(m, 3H, CH 3 ). 17 H 14 BrNO 3 MS calculated value, 359.02; observed, (M+H) + 360.3.

[0635]

[0636] Example 49: N-([1,1'-biphenyl]-2-yl)-6-bromobenzo[d][1,3]dioxazole-5-carboxamide: The title compound was prepared according to the method of Example 48, except that 2-phenylaniline was used instead of aniline. Purification on ISCO (4 g silica gel column, ethyl acetate-hexanes, ethyl acetate %: 0-25%) gave a yellow solid (0.01149 g). 1 H NMR (300 MHz, CDCl 3 ): δ8.46 (d, J=6Hz, 1H), 7.72 (s, 1H), 7.48-7.36 (m, 6H), 7.20-7.10 (m, 2H), 7.02 (s, 1H), 6.93 (s, 1H), 6.00 (s, 2H, OCH 2 O) C 20 H 14 BrNO 3 MS calculated values, observed, (M+H) + 396.4.

[0637]

[0638] Example 50: N-(Benzo[c][l,2,5]thiadiazol-4-yl)-6-bromobenzo[d][l,3]dioxazole-5-carboxamide: 6-Bromo-l,3-benzodioxole-5-carboxylic acid (0.0352 g, 0.1436 mmol), 2,1,3-benzothiadiazol-4-amine (0.0265 g, 0.1753 mmol) and (2-(lH-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.0622 g, 0.1640 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.03 mL). The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified by normal phase chromatography (4 g Isco silica gel column, ethyl acetate-hexane, ) was purified to give a yellow solid (0.0191 g, 35.2%). 1 HNMR (300 MHz, CDCl 3 ): δ9.17 (s, 1H), 8.63 (d, J=6Hz, 1H), 7.75-7.63 (m, 2H), 7.11 (s, 1H), 6.09 (s, 2H, OCH 2 O) C 14 H 8 Bn 3 O 3 SMS calcd, 376.95; observed, (M+H) + 378.3.

[0639]

[0640] Example 51: 2-Bromo-4,5-difluoro-N-(5,6,7,8-tetrahydronaphthalen-1-yl)benzamide: 5,6,7,8-tetrahydronaphthalen-1-amine (0.0575 g, 0.3906 mmol) and N,N-diisopropylethylamine (0.08 mL) were dissolved in dichloromethane (1 mL). Then 2-bromo-4,5-difluorobenzoyl chloride (1 mL, 0.1476 mmol / mL) was added to the above solution. The mixture was stirred at 22 °C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was treated with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated under vacuum and purified using normal phase chromatography (4 g Isco silica gel column, ethyl acetate-hexane, 0-20%) to give a white solid (0.0235 g).1 H NMR (300 MHz, CDCl 3 ): δ7.78 (d, J=6Hz, 1H), 7.61 (t, J=9Hz, 1H), 7.52-7.47 (m, 2H), 7.19 (t, J=9Hz, 1H ), 7.00 (d, J=9Hz, 1H), 2.81 (t, J=6Hz, 2H), 2.68 (t, J=6Hz, 2H), 1.87-1.78 (m, 4H). C 17 H 14 F 2 MS calculated for NO, 365.02; observed, (M+H) + 366.3.

[0641]

[0642] Example 52: 2-Bromo-N-(2,3-dihydro-1H-indan-4-yl)-4,5-difluorobenzamide: The title compound was prepared according to the method of Example 51, except that 2,3-dihydro-1H-indan-4-amine was used instead of 5,6,7,8-tetrahydronaphthalen-1-amine. Purification on ISCO (4 g silica gel column, ethyl acetate-hexanes, ethyl acetate %: 0-20%) gave a white solid (0.0356 g). 1 HNMR (300 MHz, CDCl 3 ): δ7.89 (d, J=9Hz, 1H), 7.67-7.61 (m, 2H), 7.49 (dd, J=9Hz, 6Hz, 1H), 7.21 (d, J=6Hz, 1H), 7.10 (d, J=6Hz, 1H), 2.99 (t, J=6Hz, 2H), 2.91 (t, J=6Hz, 2H), 2.19-2.09 (m, 2H). C 16 H 12 F 2 MS calculated for NO, 351.01; observed, (M+H) + 352.3.

[0643]

[0644] Example 53: 2-Bromo-N-(2,3-dimethylphenyl)-4,5-difluorobenzamide: The title compound was prepared according to the method of Example 51, except that 2,3-dimethylaniline was used instead of 5,6,7,8-tetrahydronaphthalen-1-amine. Purification on ISCO (4 g silica gel column, ethyl acetate-hexane, ethyl acetate %: 0-20%) gave a white solid (0.0234 g). 1 H NMR (300 MHz, CDCl 3): δ7.64-7.47 (m, 4H), 7.17 (t, J=9Hz, 1H), 7.09 (d, J=6Hz, 1H), 2.33 (s, 3H, CH 3 ), 2.25(s, 3H, CH 3 ). 15 H 12 F 2 MS calculated for NO, 339.01; observed, (M+H) + 340.3.

[0645]

[0646] Example 54: 2-Bromo-N-(2,3-dichlorophenyl)-4,5-difluorobenzamide: The title compound was prepared according to the method of Example 51, except that naphthalene-1-amine was used instead of 5,6,7,8-tetrahydronaphthalene-1-amine. Purification on ISCO (4 g silica gel column, ethyl acetate-hexanes, ethyl acetate %: 0-20%) gave a white solid (0.0073 g). 1 H NMR (300 MHz, CDCl 3 ): δ8.46 (t, J=6Hz, 1H), 8.34 (s, 1H), 7.63-7.50 (m, 2H), 7.31-7.29 (m, 2H). C 13 H 6 BrCl 2 F 2 MS calculated for NO, 378.9; observed, (M+H) + 380.3.

[0647] Dosage form

[0648] The invention also relates to a composition or dosage form comprising a cyclic GMP-AMP synthase-interferon gene stimulator (cGAS-STING) pathway agonist according to the present invention. Generally, the composition of the present invention comprises: an effective amount of one or more alkylated imino sugars and salts thereof of the present invention, which effectively provide an inhibitory effect on glucosidase; and one or more excipients.

[0649] For the purpose of the present invention, the terms "excipient" and "carrier" are used interchangeably throughout the specification of the present invention, and the terms are defined in the present invention as "ingredients used in the practice of formulating safe and effective pharmaceutical compositions."

[0650] The formulator will appreciate that excipients are primarily used to provide a safe, stable and functional drug, not only as part of the overall vehicle, but also as a means for the active ingredient to be effectively absorbed by the recipient. Excipients can play a role as simple and direct as an inert filler, or the excipients used in the present invention can be part of a pH stabilizing system or coating to ensure safe delivery of the ingredient to the stomach. The formulator can also take advantage of the fact that the compounds of the present invention have improved cellular potency, pharmacokinetic properties, and improved oral bioavailability.

[0651] The present invention also provides a pharmaceutical composition, which includes at least one compound of the present invention and one or more pharmaceutically acceptable carriers, excipients or diluents. The embodiment of such a carrier is well known to those skilled in the art, and can be prepared according to acceptable pharmaceutical methods, such as those described in "Remington's Pharmaceutical Sciences" (17th edition), Alfonoso R. Gennaro, Mike Publishing House, PA (1985). For all purposes, the entire disclosure is incorporated into the present invention by reference. As used in the present invention, "pharmaceutically acceptable" refers to a substance that is acceptable for pharmaceutical application from a toxicological point of view and does not interact adversely with active ingredients. Therefore, pharmaceutically acceptable carriers are compatible with other ingredients in the dosage form and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical composition.

[0652] The compounds of the present invention may be administered orally or parenterally, either pure or in combination with conventional pharmaceutical carriers. Suitable solid carriers may include one or more substances that may also be used as flavoring agents, lubricants, solubilizers, suspending agents, fillers, solubilizers, compression aids, adhesives, or tablet disintegrating agents or encapsulating materials. The compounds may be formulated in a conventional manner, for example, in a manner similar to that used for known antiviral agents. Oral dosage forms including the compounds of the present disclosure may include any conventionally used oral form, including tablets, capsules, buccal forms, lozenges, lozenges, and oral liquids, suspensions, or solutions. In powders, the carrier may be a finely divided solid, which is a mixture with the finely divided compound. In tablets, the compounds disclosed in the present invention may be mixed with a carrier having the necessary compression properties in a suitable ratio and compressed into a desired shape and size. Powders and tablets may include up to 99% of the compound.

[0653] Capsules may include a mixture of one or more compounds disclosed herein with inert fillers and / or diluents such as pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweeteners, powdered cellulose (e.g., crystalline and microcrystalline cellulose), flours, gelatin, gums, and the like.

[0654] Useful tablets can be prepared by conventional tableting, wet granulation or dry granulation methods, and use pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (including surfactants), suspending agents or stabilizers, including but not limited to magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyvinyl pyrrolidine, alginic acid, gum arabic, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting wax and ion exchange resin. Surface modifiers include nonionic and anionic surface modifiers. Representative examples of surface modifiers include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetyl stearyl alcohol, cetomacrogole mulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium lauryl sulfate, magnesium aluminum silicate, and triethanolamine. The oral dosage form of the present invention can utilize standard delayed or extended release dosage forms to change the absorption of the compound. The oral dosage form can also include administering the compound disclosed in the present invention in water or juice, including suitable solubilizers or emulsifiers as needed.

[0655] Liquid carriers can be used to prepare solutions, suspensions, emulsions, syrups, elixirs, and for inhalation administration. The compounds of the present invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier, such as water, an organic solvent, or a mixture of the two, or a pharmaceutically acceptable oil or fat. The liquid carrier can include other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, pigments, viscosity modifiers, stabilizers, and osmotic regulators (osmo-regulators). Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly including additives described in the present invention, such as cellulose derivatives, such as sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyols, such as diols) and their derivatives, and oils (such as fractionated coconut oil and peanut oil). For parenteral administration, the carrier can be an oily ester, such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used for parenteral administration in the form of sterile liquid compositions. The liquid carrier for pressurized compositions can be halogenated hydrocarbons or other pharmaceutically acceptable propellants.

[0656] Liquid pharmaceutical compositions in the form of sterile solutions or suspensions can be used, for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in liquid or solid form.

[0657] Preferably, the pharmaceutical composition is a unit dosage form, such as a tablet, capsule, powder, solution, suspension, emulsion, granule or suppository. In this form, the pharmaceutical composition can be subdivided into a unit dose including an appropriate amount of compound. The unit dosage form can be a packaged composition, such as a packaged powder, vial, ampoule, pre-filled syringe or a pouch including a liquid. Alternatively, the unit dosage form can be a capsule or tablet itself, or can be a packaged form of any such composition of an appropriate number. Such a unit dosage form can include a compound of about 1 mg / kg to a compound of about 500 mg / kg, and can be given in a single dose or two or more doses. The compound can be guided to the blood of the recipient in any useful manner, including oral, implanted, parenteral (including intravenous, intraperitoneal and subcutaneous injections), rectal, vaginal and transdermal.

[0658] When administering for the treatment or suppression of a particular disease state or condition, it should be understood that the effective dose can vary according to the particular compound used, the mode of administration, the severity of the condition being treated, and various physical factors associated with the subject. In therapeutic applications, the compound of the present invention can be provided to a patient already suffering from the disease in an amount sufficient to cure or at least partially alleviate the symptoms of the disease and its complications. The dosage for treating a particular individual must usually be determined subjectively by the attending physician. The variables involved include the specific circumstances and their state, as well as the size, age, and reaction pattern of the patient.

[0659] In some cases, it may be necessary to use devices such as, but not limited to, metered dose inhalers, respirators, multi-dose dry powder inhalers, pumps, squeeze-actuated nebulizers, aerosol dispensers, and aerosol nebulizers to apply the compound directly to the patient's airway. In order to be administered by intranasal or intrabronchial inhalation, the compound of the present invention can be formulated into a liquid composition, a solid composition, or an aerosol composition. For example, the liquid composition may include one or more compounds of the present invention, one or more compounds of the present invention are dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents, and can be administered by, for example, a pump or an squeeze-actuated nebulizer. The solvent may be, for example, isotonic saline or antibacterial water. For example, the solid composition may be a powder dosage form, which includes one or more compounds of the present invention, one or more compounds of the present invention are mixed with acceptable lactose or other inert powders used in the bronchus and can be administered by, for example, an aerosol dispenser or a capsule that wraps the solid composition is broken or pierced and the solid composition is delivered to be administered by a device for inhalation. For example, the aerosol composition may include one or more compounds of the present invention, a propellant, a surfactant, and a cosolvent, and can be administered by, for example, a metering device. The propellant may be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other physiologically and environmentally acceptable propellant.

[0660] The compounds of the present invention can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or their pharmaceutically acceptable salts, hydrates or esters can be prepared in water by mixing with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol and mixtures thereof in oils. Under common storage and use conditions, these dosage forms usually contain preservatives to inhibit the growth of microorganisms.

[0661] The pharmaceutical form suitable for injection can include sterile aqueous solution or dispersion and sterile powder for temporary preparation of sterile injectable solution or dispersion. In certain embodiments, the form can be sterile, and its viscosity allows it to flow through the syringe. The form is preferably stable under manufacturing and storage conditions, and can be preserved to resist the contamination of microorganisms such as bacteria and fungi. Carrier can be a solvent or dispersion medium, which includes, for example, water, ethanol, polyol (such as glycerol, propylene glycol and liquid polyethylene glycol), its suitable mixture and vegetable oil.

[0662] The compounds of the present invention can be administered transdermally, i.e., across the surface of the body and the inner layers of body passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present invention, including pharmaceutically acceptable salts, hydrates or esters thereof, in the form of lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal).

[0663] Transdermal administration can be accomplished by using a transdermal patch containing a compound (e.g., a compound disclosed in the present invention that is absorbed systemically into the bloodstream through the skin) and a carrier that is inert to the compound, nontoxic to the skin, and allows the compound to be delivered to the bloodstream through the body. The carrier can take a variety of forms, such as creams and ointments, pastes, gels, and occlusive devices. Creams and ointments can be viscous liquids or semisolid emulsions of the oil-in-water or water-in-oil type. Pastes composed of absorbent powders dispersed in petroleum or hydrophilic petroleum containing the compound are also suitable. Various occlusive devices can be used to release the compound into the bloodstream, such as a reservoir covering the compound with or without a carrier or a semipermeable membrane comprising a matrix of the compound. Other occlusive devices are known in the literature.

[0664] The compounds of the present invention can be administered rectally or vaginally in the form of conventional suppositories. Suppository formulations can be made from conventional materials, including cocoa butter, with or without wax to change its melting point and glycerol. Water-soluble suppository bases can also be used, such as polyethylene glycols of various molecular weights.

[0665] Lipid dosage forms or nanocapsules can be used to introduce the compounds of the present invention into host cells in vitro or in vivo. Lipid dosage forms and nanocapsules can be prepared by methods known in the art.

[0666] In order to increase the effectiveness of the compounds of the present invention, it may be desirable to combine the compounds with other agents that are effective in treating the target disease. For example, other active compounds (i.e., other active ingredients or agents) that are effective in treating the target disease may be administered together with the compounds of the present invention. Other agents may be administered simultaneously or at different times with the compounds disclosed herein.

[0667] The compounds of the present invention can be used to treat or inhibit pathological conditions or disorders in mammals, such as human subjects. Therefore, the present invention provides a method for treating or inhibiting pathological conditions or disorders by providing a compound of the present invention (including a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising one or more compounds of the present invention in combination or in conjunction with a pharmaceutically acceptable carrier to a mammal. The compounds of the present invention can be administered alone or in combination with other therapeutically effective compounds or therapies to treat or inhibit pathological conditions or disorders.

[0668] Non-limiting examples of compositions according to the present invention include from about 0.001 mg to about 1000 mg of one or more cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway agonists according to the present invention and one or more excipients; from about 0.01 mg to about 100 mg of one or more cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway agonists according to the present invention and one or more excipients; and from about 0.1 mg to about 10 mg of one or more cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway agonists according to the present invention and one or more excipients.

[0669] Technology

[0670] Cell lines. The human hepatoblastoma cell line HepG2 was obtained from ATCC. Establishment of HepG2-derived cell lines stably expressing human STING: HepG2 cells stably expressing wild-type human STING (HepG2 / STING) were generated by transduction of the pCX4bsr retroviral vector (Addgene) including the corresponding STING cDNA and selection with 10 μg / ml blasticidin. HepG2 / STING cells were then transduced by the pGreenFireISRE lentiviral vector system (System Biosciences) to generate a reporter cell line HepG2 / STING / ISG54Luc expressing firefly luciferase under the control of the ISG54 promoter. The pGreenFireISRE reporter lentiviral vector includes four copies of the ISG54ISRE1-derived consensus interferon-stimulated response element (ISRE) sequence, which controls the expression of green fluorescent protein (GFP) and firefly luciferase in response to IRF3 activation and IFN stimulation. epG2 / STING / ISG54Luc cells were maintained in Dulbecco's modified minimal essential medium (DMEM) / F12 (Invitrogen) supplemented with 10% fetal bovine serum, 100 U / ml penicillin and 100 μg / ml streptomycin, as well as 400 μg / ml G418 and 2 μg / ml puromycin.

[0671] ISG54 luciferase reporter gene assay: HepG2 / STING / ISG54Luc reporter cells were cultured at 4 × 10 4 The cells were seeded at a density of 100 μg / well in a black wall / clear bottom 96-well plate and grown overnight in 1 mL of culture medium. Test compounds were dissolved in DMSO at a stock concentration of 100 mM and luciferase activity was dose-dependently assessed from 100 μM to 0.78 μM in 2-fold dilutions. Experiments were performed in triplicate wells.

[0672] Firefly luciferase activity was measured 4 hours after treatment with the test compounds by adding an equal volume (1 mL) of Steady-Glo to the culture medium (Promega) followed by photometric measurement using a TopCounter (PerkinElmer).

[0673] ISG54 promoter activation activity is reported. Luciferase activity is converted to induction fold relative to the mock-treated control. Dose-dependency curves of luciferase activity (induction fold) for each test compound are generated using the average values ​​from triplicate wells. The luciferase activity induced by the test compound is reported to be 5 times that of the mock-treated control group according to the minimum effective concentration (MinEC5X). Specifically, in HepG2 / STING / ISG54, compounds that induce a dose-dependent enhancement of luciferase expression equal to or greater than 5 times at a concentration of 50 μM are considered active compounds.

[0674] Table 8

[0675] The concentrations required for 5-fold IFN-induction (μM) of the present invention are: A≤50μM; 100≥B>50μM.

[0676]

[0677]

Claims

1. A compound having a formula selected from the following: or a pharmaceutically acceptable salt thereof.

2. A composition comprising an effective amount of at least one compound according to claim 1.

3. The composition according to claim 2, further comprising at least one excipient.

4. Use of an effective amount of at least one compound according to claim 1 in the preparation of a medicament for treating diseases associated with dysregulation of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway.

5. The use according to claim 4, in, The medicament further comprises at least one excipient.

6. The use according to claim 4 or 5, in, The disease associated with dysregulation of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway is a viral infection.

7. The use according to claim 4 or 5, in, The disease associated with dysregulation of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway is cancer.

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