Heterocyclic PAD4 inhibitors

Abstract

This disclosure generally relates to compounds represented by formula I that are inhibitors of PAD4, methods for producing these compounds, pharmaceutical compositions containing these compounds, and the use of these compounds in the treatment of diseases or disorders related to PAD4 enzyme activity. TIFF2026524962000140.tif8088

Description

[Technical Field]

[0001] (cross reference) This application claims priority to U.S. Provisional Application No. 63 / 514,934, filed July 21, 2023, which is incorporated herein by reference in its entirety.

[0002] (Field) This disclosure generally relates to substituted heterocyclic compounds, methods for producing these compounds, pharmaceutical compositions containing these compounds, and the use of these compounds in the treatment of diseases or disorders related to PAD4 enzyme activity.

[0003] (Imported by referencing the sequence list) This application includes a sequence listing submitted via EFS-WEB in XML format, all of which are incorporated herein by reference. The name of the XML file copy created on June 19, 2023, is "055920-606P01US_SeqList_ST26.xml" and its size is 3 kilobytes. [Background technology]

[0004] PAD4 (SEQ ID NO: 1) is a member of the peptidylarginine deiminase (PAD) family and is an enzyme that can catalyze the citrullination of arginine within peptide sequences. PAD4 deiminates or citrullines various proteins in vitro and in vivo, resulting in diverse functional responses in various diseases (Jones JE et al, Curr. Opin. Drug Discov. Devel., 12(5), (2009), 616-627). Examples of diseases or disorders include cancer symptoms, as well as rheumatoid arthritis and neutrophil-mediated diseases (e.g., vasculitis, systemic lupus erythematosus, ulcerative colitis). PAD4 inhibitors also have the potential for broader application as means and treatments for human diseases and disorders mediated by epigenetic mechanisms.

[0005] PAD4 inhibitors are effective against rheumatoid arthritis (RA). RA is an autoimmune disease affecting approximately 1% of the population (Wegner N. et al, Immunol. Rev., 233(1), (2010), 34-54). It is characterized by joint inflammation that weakens and destroys bone and cartilage. Numerous population studies have suggested a slight, albeit inconsistent, genetic association between PAD4 polymorphism and RA susceptibility (Kochi Y. et al, Ann. Rheum. Dis., 70, (2011), 512-515). PAD4 (along with its family member PAD2) is found in synovial tissue and is responsible for the deiminolysis of various joint proteins. This process is thought to lead to a loss of resistance to citrullinated substrates (e.g., fibrinogen, vimentin, and collagen) in RA joints, or to initiate an immune response. These anti-citrullinated protein antibodies (ACPAs) are associated with disease development and are used in diagnostic tests for rheumatoid arthritis (RA), such as commercially available tests using CCP2 or cyclic citrullinated protein 2. Furthermore, increased citrullination can directly affect the function of multiple joints and inflammatory mediators (e.g., fibrinogen, antithrombin, and several chemokines), and may therefore be directly involved in the pathogenesis of the disease. Anti-PAD4 antibodies are measurable in some RA patients and may correlate with more erosive disease forms.

[0006] PAD4 inhibitors are also useful in reducing pathological neutrophil activity in various diseases. Several studies have suggested that the formation of neutrophil extracellular traps (NETs), an innate defense mechanism in which neutrophils capture and kill pathogens, is related to histone citrullination, and that this process is deficient in PAD4 knockout mice (Neeli I. et al, J. Immunol., 180, (2008), 1895-1902, and Li P. et al, J. Exp. Med., 207(9), (2010), 1853-1862). Therefore, PAD4 inhibitors may be applicable to diseases in which NET formation in tissues contributes to local injury or pathological conditions. Such diseases include, but are not limited to, miniature vasculitis (Kessenbrock K. et al, Nat. Med., 15(6), (2009), 623-625), systemic lupus erythematosus (Hakkim A. et al, Proc. Natl. Acad. Sci. USA, 107(21), (2010), 9813-9818, and Villanueva E. et al, J. Immunol., 187(1), (2011), 538-52), ulcerative colitis (Savchenko A. et al, Pathol. Int., 61(5), (2011), 290-7), cystic fibrosis, and asthma (Dworski R. et al, J. Allergy Clin. Immunol., 127(5), (2011)). These include 1260-6), deep vein thrombosis (Fuchs T. et al, Proc. Natl. Acad. Sci. USA, 107(36), (2010), 15880-5), periodontitis (Vitkov L. et al, Ultrastructural Pathol., 34(1), (2010), 25-30), sepsis (Clark SR et al, Nat. Med., 13(4), (2007), 463-9), appendicitis (Brinkmann V. et al, Science, 303, (2004), 1532-5), and stroke.Furthermore, there is evidence suggesting that NETs may be involved in the pathogenesis of skin diseases such as cutaneous lupus erythematosus (Villanueva E. et al, J. Immunol., 187(1), (2011), 538-52) and psoriasis (Lin AM et al., J. Immunol., 187(1), (2011), 490-500), suggesting that systemic or transdermal administration of PAD4 inhibitors may be effective in treating NET skin diseases. PAD4 inhibitors may also act on other neutrophil functions and may therefore have broad applicability to neutrophil-related diseases.

[0007] Multiple studies have suggested the efficacy of PAD inhibitors (e.g., chloroamidine) in many animal model diseases, including collagen-induced arthritis (Willis VC et al, J. Immunol., 186(7), (2011), 4396-4404), dextran sulfate sodium (DSS)-induced experimental colitis (Chumanevich AA et al, Am. J. Physiol. Gastrointest. Liver Physiol., 300(6), (2011), G929-G938), spinal cord repair (Lange S. et al, Dev. Biol., 355(2), (2011), 205-14), and experimental autoimmune encephalomyelitis (EAE). Reports on DSS colitis have also shown that chloroamidine promotes apoptosis of inflammatory cells both in vitro and in vivo, suggesting that PAD4 inhibitors may be more generally effective against a wide range of inflammatory diseases.

[0008] PAD4 inhibitors are also useful in the treatment of cancer (Slack JL et al, Cell. Mol. Life Sci., 68(4), (2011), 709-720). Overexpression of PAD4 is observed in many cancers (Chang X. et al, BMC Cancer, 9, (2009), 40). The observation that PAD4 citrullines arginine residues of histones in the promoters of p53 target genes such as p21, and that this is involved in cell cycle inhibition and induction of apoptosis, suggests an antiproliferative role for PAD4 inhibitors (Li P. et al, Mol. Cell Biol., 28(15), (2008), 4745-4758).

[0009] The aforementioned role of PAD4 in deiminating histone arginine residues may indicate a role for PAD4 in the epigenetic regulation of gene expression. PAD4 is a major member of the PAD family, observed to be present in both the nucleus and cytoplasm. Early evidence that PAD4 acts as a histone demethyliminase and deiminase is inconsistent and has not yet been proven. However, by reducing arginine residues through conversion to citrulline, PAD4 may indirectly reduce histone arginine methylation (and the associated epigenetic regulation). PAD4 inhibitors may be useful as epigenetic means and therapeutic agents that influence the expression of diverse target genes in diseases under yet another condition. Through such mechanisms, PAD4 inhibitors may be effective in controlling citrullination levels in stem cells and therefore may therapeutically influence the pluripotency and differentiation potential of a variety of stem cells, including, but not limited to, embryonic stem cells, neural stem cells, hematopoietic stem cells, and cancer stem cells. Therefore, there is a need to identify and develop PAD4 inhibitors to treat diseases or disorders mediated by PAD4. [Prior art documents] [Non-patent literature]

[0010] [Non-licensed document 1] Jones JE et al, Curr. Opin. Drug Discov. Devel., 12(5), (2009), 616-627 [Non-licensed document 2] Wegner N. et al, Immunol. Rev., 233(1), (2010), 34-54 [Non-licensed document 3] Kochi Y. et al, Ann. Rheum. Dis., 70, (2011), 512-515

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Summary of the Invention

[0011] The present disclosure relates to Formula I:

Chemical Formula

[0012] In another embodiment, the disclosure provides a pharmaceutical composition comprising at least one compound represented by Formula I, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof, and one or more pharmaceutically acceptable carriers, excipients, or vehicles. In some embodiments, pharmaceutical compositions suitable for oral, parenteral, mucosal, transdermal, or topical administration are provided.

[0013] In another embodiment, the present disclosure provides a method for treating a disease or disorder related to PAD4 enzyme activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound represented by formula I, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

[0014] In another embodiment, the present disclosure provides a method for treating a disease or disorder related to PAD4 enzyme activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound represented by formula I, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof. Such disorders or conditions include, in particular, rheumatoid arthritis, vasculitis, systemic lupus erythematosus, and ulcerative colitis.

[0015] Another aspect of the present disclosure relates to a method for treating or preventing a medical condition of the present disclosure in a subject requiring treatment. The method involves administering to a subject requiring treatment an effective amount of the compound represented by formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0016] Another aspect of the present disclosure relates to a compound represented by formula (I), as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, and pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing the medical conditions of the present disclosure.

[0017] Another aspect of the present disclosure relates to the use of a compound represented by formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of the medical conditions of the present disclosure.

[0018] In some embodiments, the Disclosure provides intermediates described herein that are suitable for use in the methods for producing the compounds described herein (for example, the intermediates are selected from the intermediates described in Examples 1 to 44).

[0019] In some embodiments, the Disclosure provides a method for producing the compounds of the Disclosure.

[0020] In some embodiments, this disclosure provides a method for producing a compound, comprising one or more steps described herein. [Modes for carrying out the invention]

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure belongs. In this specification, the singular form includes the plural form unless the context clearly indicates otherwise. Methods and substances similar to or equivalent to those described herein may be used in the implementation or testing of this disclosure, but suitable methods and substances are listed below. All publications, patent applications, patents, and other references referenced herein are incorporated by reference. References cited herein do not constitute prior art to the claimed disclosure. In case of any conflict, including definitions, this specification shall prevail. Furthermore, substances, methods, and examples are illustrative and not intended to limit the scope. In case of any conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

[0022] (definition) The compounds of the present disclosure generally include the above-mentioned compounds, and further include the compounds represented by the classes, subclasses, and species of the present disclosure. The following definitions used herein shall apply unless otherwise specified. For the purposes of the present disclosure, chemical elements are identified according to the CAS version of the periodic table of the elements in the Handbook of Chemistry and Physics, 75th Ed. Further, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March’s Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, all of which are incorporated herein by reference.

[0023] As used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched chain) or branched-chain, substituted or unsubstituted hydrocarbon chain containing one or more fully saturated or unsaturated moieties, or a monocyclic or bicyclic hydrocarbon (also referred to as "carbocycle", "carbocyclic", "alicyclic" or "cycloalkyl") having a single point of attachment to the remainder of the molecule and containing one or more fully saturated or unsaturated moieties but not being aromatic. Unless otherwise specified, aliphatic groups contain from 1 to 6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain from 1 to 5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain from 1 to 4 aliphatic carbon atoms. In yet other embodiments, aliphatic groups contain from 1 to 3 aliphatic carbon atoms, and in still other embodiments, aliphatic groups contain from 1 to 2 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.

[0024] In some embodiments, "carbocyclic" (or "alicyclic" or "carbocycle" or "cycloalkyl") refers to a C3-C8 hydrocarbon, which may be monocyclic or polycyclic, contain one or more fully saturated or unsaturated moieties but is not aromatic, and has a single point of attachment to the remainder of the molecule. The rings of a polycyclic carbocycle may be connected to one or two aromatic cycloalkyls or heterocycles via fusion, bridging, and / or one or more spiro bonds. Examples of typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, and the like.

[0025] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of basic nitrogen; or a replaceable nitrogen of a heterocycle such as, for example, N(3,4-dihydro-2H-pyrrolyl) as seen in, NH (seen in pyrrolidinyl), or NR + (seen in N-substituted pyrrolidinyl), etc.). In some embodiments, oxidized forms of sulfur include S=O and S(=O)2.

[0026] As used herein, the term "unsaturated" means a moiety having one or more unsaturated units.

[0027] The term "halogen" means F, Cl, Br, or I.

[0028] The term “aryl,” used alone or as part of a larger term, such as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to a monocyclic or dicyclic ring having a total of 5 to 14 ring members, at least one of which is aromatic, and each ring having 3 to 7 ring members. The term “aryl” may also be used synonymously with the term “aryl ring.” In certain embodiments of this disclosure, “aryl” refers to an aromatic ring, such as phenyl, biphenyl, naphthyl, and anthrasyl groups, which may have one or more substituents. The scope of the term “aryl” as used herein also includes groups in which an aromatic ring is condensed with one or more non-aromatic rings (e.g., indanyl, phthalimidyl, naphthimidyl, phenantridinyl, or tetrahydronaphthyl).

[0029] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger term such as "heteroaralkyl" or "heteroaralkoxy", refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, sharing 6, 10, or 14 π electrons in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" include groups in which a heteroaromatic ring is condensed with one or more aryl, cycloaliphatic, or heterocyclyl groups, where the group or binding site is located on the heteroaromatic ring. Examples of such groups include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, synnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxadinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. The heteroaryl group may be monocyclic or bicyclic. The term "heteroaryl" may be used synonymously with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," and any of these terms may include a ring that is appropriately substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, and the alkyl and heteroaryl portions may be independently substituted as appropriate.

[0030] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic group,” and “heterocyclic ring” are synonymous and refer to a stable 5-7 member monocyclic or 7-10 member bicyclic heterocyclic portion that is either saturated or partially unsaturated, having one or more, preferably 1-4, heteroatoms as defined above, in addition to a carbon atom. When referring to the ring atoms of a heterocycle, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (found in 3,4-dihydro-2H-pyrrolyl), NH (found in pyrrolidinyl), or + It may be NR (as seen in N-substituted pyrrolidinyl).

[0031] A heterocyclic group can be bonded to its pendant group with any heteroatom or carbon atom to form a stable structure, and any ring atom may be substituted as appropriate. Examples of such saturated or partially unsaturated heterocyclic groups include tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocyclic group,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic group” are used synonymously herein and include groups in which the heterocyclyl is condensed with one or more aryl, heteroaryl, or cycloaliphatic groups (e.g., indolinyl, 3H-indolyl, chromanyl, phenantridinyl, or tetrahydroquinolinyl), wherein the group or bond is located on the heterocyclyl. The heterocyclyl group may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, and the alkyl and heterocyclyl portions may be independently substituted as appropriate.

[0032] As used herein, the term “partially unsaturated” refers to a portion of a ring containing at least one double or triple bond. The term “partially unsaturated” is intended to include rings having multiple unsaturated moieties, but not to include aryl or heteroaryl moieties as defined herein.

[0033] As described herein, the compounds of this disclosure may include parts that are "may be substituted as appropriate." In general, the term "substituted" means that one or more hydrogens of the designated part are substituted with appropriate substituents, whether or not the term "may be substituted as appropriate" precedes them. "Substitution" applies to one or more hydrogens that are directly or indirectly indicated by the structure. (e.g., [ka] At least [ka] Show, [ka] At least [ka] This indicates that.) Unless otherwise specified, groups that "may be substituted as appropriate" may have appropriate substituents at each substituted position of the group, and if two or more positions in any structure may be substituted with two or more substituents selected from a particular group, the substituents may be the same or different at each bond position. The substituent combinations envisioned in this disclosure preferably result in the formation of stable or chemically feasible compounds. As used herein, "stable" means a compound that remains substantially unchanged when manufactured, detected, and, in some embodiments, recovered, purified, and used for one or more purposes of this disclosure.

[0034] Suitable monovalent substituents on the substitutable carbon atoms of the group "may be substituted as appropriate" are, independently, halogens;-(CH2) 0-4 R ○ ;-(CH2) 0-4 Ure ○ ;-O(CH2) 0-4 R ○ -O-(CH2) 0-4 C(O)OR ○ ;-(CH2) 0-4 CH(OR ○ )2;-(CH2) 0-4 SR ○ ;R ○ (CH2) may be substituted with 0-4 Ph;R ○ (CH2) may be substituted with 0-4 O(CH2) 0-1 Ph;R ○ -CH=CHPh;R may be substituted. ○ (CH2) may be substituted with 0-4 O(CH2) 0-1 -Pyridyl;-NO2;-CN;-N3;-(CH2) 0-4 N(R ○ )2;-(CH2) 0-4 N(R ○ )C(O)R ○ ;-N(R ○ )C(S)R ○ ;-(CH2) 0-4 N(R ○ )C(O)NR ○ 2;-N(R ○ )C(S)NR ○ 2;-(CH2) 0-4 N(R ○ )C(O)OR ○ ;-N(R ○ )N(R ○ )C(O)R ○ ;-N(R ○ )N(R ○ )C(O)NR ○ 2;-N(R ○ )N(R ○ )C(O)OR ○ ;-(CH2) 0-4 C(O)R ○ ;-C(S)R ○ ;-(CH2)0-4 C(O)OR ○ ;-(CH2) 0-4 C(O)SR ○ ;-(CH2) 0-4 C(O)OSiR ○ 3;-(CH2) 0-4 OC(O)R ○ ;-OC(O)(CH2) 0-4 SR ○ ;-(CH2) 0-4 SC(O)R ○ ;-(CH2) 0-4 C(O)NR ○ 2;-C(S)NR ○ 2;-C(S)SR ○ ;-SC(S)SR ○ -(CH2) 0-4 OC(O)NR ○ 2;-C(O)N(OR ○ )R ○ ;-C(O)C(O)R ○ ;-C(O)CH2C(O)R ○ ;-C(NOR ○ )R ○ ;-(CH2) 0-4 SSR ○ ;-(CH2) 0-4 S(O)2R ○ ;-(CH2) 0-4 S(O)2OR ○ ;-(CH2) 0-4 OS(O)2R ○ ;-S(O)2NR ○ 2;-(CH2) 0-4 S(O)R ○ ;-N(R ○ )S(O)2NR ○ 2;-N(R ○ )S(O)2R ○ ;-N(OR ○ )R ○ ;-C(NH)NR ○ 2;-P(O)2R ○ ;-P(O)R ○ 2;-OP(O)R ○ 2;-OP(O)(OR ○ )2;SiR ○ 3;-(C 1-4 Straight lock または bifurcated lock アルキレン)ON(R○ )2; or -(C 1-4 Linear or branched alkylene)C(O)ON(R ○ )2, where each R ○ These may be substituted as defined below, independently of hydrogen and C. 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 A 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent R ○ Together with the interposing atom, it forms a 3-12 member saturated, partially unsaturated, or aryl monocycle or dicycle having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0035] R ○ (or two independent R ○ A suitable monovalent substituent on the ring formed with the interposing atom is independently a halogen, -(CH2) 0-2 R ● ,-(HaroR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 Ure ● ,-(CH2) 0-2 CH(OR ● )2, -O(HaroR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● ,-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● ,-(CH2) 0-2 SR ● ,-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● ,-(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ●3, -C(O)SR ● ,-(C 1-4 (Straight-chain or branched-chain alkylene) C(O)OR ● , or -SSR ● And here each R ● It is either unsubstituted, or if preceded by "halo", it is substituted with only one or more halogens, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 A 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from Ph, nitrogen, oxygen, or sulfur. ○ Suitable divalent substituents on the saturated carbon atom include =O and =S.

[0036] Appropriate divalent substituents on the saturated carbon atom of the group "may be substituted as appropriate" include: =O (oxo), =S, =NNR * 2. =NNHC(O)R * ,=NNHC(O)OR * ,=NNHS(O)2R * ,=NR * 、=NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S- is included, and here R * Each of these can be independently substituted with hydrogen, or C as defined below. 1-6 Selected from an aliphatic, or unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. A suitable divalent substituent bonded to an adjacent substituted carbon of the group "may be substituted as appropriate" is -O(CR * 2) 2-3 O- is included, and here R * Each of these can be independently substituted with hydrogen, or C as defined below. 1-6The elements are selected from unsubstituted 5-6 member saturated, partially unsaturated, or aryl rings having aliphatic or 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] R * Suitable substituents on the aliphatic are halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● It is either unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 It is a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, or sulfur.

[0038] A suitable substituent on the nitrogen of the group that "may be substituted as appropriate" is -R + , -NR + 2, -C(O)R + , -C(O)OR + ,-C(O)C(O)R + -C(O)CH2C(O)R + -S(O)2R + -S(O)2NR + 2, -C(S)NR + 2. -C(NH)NR + 2, or -N(R + )S(O)2R + This includes, and here each R + C can be substituted independently of hydrogen, as defined below. 1-6An aliphatic, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or regardless of the above definition, two independent Rs + together with the intervening atoms form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0039] R + Suitable substituents on the aliphatic group of R are independently halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if "halo" is pre-modified, is substituted only with one or more halogens and is independently C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0040] As used herein, the term "subject" refers to any human or non-human organism for which an effect can be obtained by treatment with a PAD4 inhibitor. Examples of subjects include humans and animals.

[0041] As used herein, the term "treating" or "treatment" refers to treating a disease state of a subject (e.g., a human or an animal) and includes (a) suppressing the disease state, i.e., blocking its progression; (b) alleviating the disease state, i.e., reducing the disease state; and / or (c) preventing the occurrence of the disease state in the subject.

[0042] As used herein, the terms “preventing” or “prevention” refer to preventive treatment (i.e., prevention and / or risk reduction) of an asymptomatic disease state in a subject (e.g., human or animal) aimed at reducing the probability of a clinical disease state occurring. Subjects may be selected for preventive treatment based on factors known to increase their risk of developing a clinical disease state compared to the population. “Preventive” therapies can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment in subjects that do not yet present with a clinical disease state, while secondary prevention is defined as prevention of the secondary onset of the same or similar clinical disease state.

[0043] As used herein, “therapeutic dose” means the amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits the desired biological response. In some embodiments, the therapeutic dose of a substance is an amount sufficient to treat, diagnose, prevent, and / or delay the onset of a disease, disorder, and / or condition when administered as part of a treatment plan to a subject suffering from or susceptible to the disease, disorder, and / or condition. As will be understood by those skilled in the art, the effective dose of a substance may vary depending on factors such as the desired biological endpoint, the substance being delivered, and the target cells or tissues. For example, the effective dose of a compound provided in a formulation for treating a disease, disorder, and / or condition is an amount that reduces, improves, alleviates, suppresses, prevents, delays the onset, reduces the severity, and / or reduces the incidence of one or more symptoms or characteristics of the disease, disorder, and / or condition. In some embodiments, the “therapeutic dose” is at least a minimum amount of the compound provided, or a composition containing the compound provided, sufficient to treat one or more symptoms of an MK2-mediated disease or disorder. The term "therapeutic effective dose" means, and includes, the amount of any compound or composition described herein that is effective when administered alone or in combination to prevent or treat a disease or disorder related to PAD4 enzyme activity. Where applicable to combination therapy, the term means the combined amount of active ingredients that produce a prophylactic or therapeutic effect, whether administered concomitantly, sequentially, or concurrently.

[0044] A "pharmaceutically acceptable carrier" refers to a medium generally accepted in the field for delivering biological agents to humans and / or animals. pharmaceutically acceptable carriers are formulated according to many factors that are well within the scope of the expertise of those skilled in the art. These factors include, but are not limited to, the type and nature of the agent being formulated, the patient to whom the composition containing the agent will be administered, the intended route of administration of the compound or composition, and the target therapeutic indicator. pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media. Such carriers may contain, in addition to the agent, many different components and additives, and such added components may be included in the formulation for a variety of reasons (e.g., stabilization of activators, binders, etc., known to those skilled in the art). Typical examples of such carriers include, but are not limited to, diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antimicrobial agents, antifungal agents, lubricants, dispersants, and coatings. A description of suitable pharmaceutically acceptable carriers and the factors involved in their selection is available in various readily accessible publications, such as Allen, LV, Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0045] This disclosure includes all isotopes of the atoms contained in the compounds of the present invention. Isotopes include atoms that have the same atomic number but different mass numbers. As a general example, but not limited to the following, isotopes of hydrogen include deutherium (symbolized D or 2 H) and tritium (symbol T or 3 It contains H). For example, the methyl group may be represented as CH3 or CD3. The carbon isotopes include 13 C and 14 It contains C. The isotope-labeled compounds disclosed herein can be prepared by conventional techniques generally known to those skilled in the art, or by methods similar to those described herein, using a suitable isotope-labeling reagent instead of other unlabeled reagents.

[0046] Compounds represented by Formula I form salts, and these salts are also within the scope of this disclosure. Unless otherwise specified, references to compounds represented by Formula I in this specification are understood to include references to their salts. As used herein, the term “salt” refers to acid salts and / or base salts formed by inorganic and / or organic acids and bases. Furthermore, if the compound represented by Formula I has both a basic and an acidic moiety, zwitterions ("intramolecular salts") may be formed, which are included in the term “salt” as used herein. Medicinally acceptable salts include salts that are generally acceptable in the pharmaceutical field for administration to subjects including humans and animals. Generally, a medicamentally acceptable salt is a salt that is non-toxic and physiologically acceptable. Salts of the compounds described herein may be formed, for example, by reacting the compound with a certain amount of acid or base (e.g., 1 equivalent), precipitating the salt in a solvent, or by subsequently freeze-drying an aqueous solution.

[0047] Compounds represented by formula I, which contain a basic moiety, can form salts with a variety of organic and inorganic acids. Examples of acid addition salts include acetates (e.g., salts formed with acetic acid or trihaloacetic acid (e.g., trifluoroacetic acid)), adipines, alginates, ascorbicates, aspartates, benzoates, benzenesulfons, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfons, cyclopentanepropionates, diglucons, dodecyl sulfates, ethanesulfons, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), and hydrobroms (formed with hydrogen bromide). Examples include hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate (formed with maleic acid), methanesulfonate (formed with methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., formed with sulfuric acid), sulfonate (e.g., those described herein), tartrate, thiocyanate, toluenesulfonate (e.g., tosylate), and undecanoate.

[0048] Compounds represented by formula I, which include an acidic moiety, can form salts with a variety of organic and inorganic bases. Examples of base addition salts include salts with ammonium salts, alkali metal salts (e.g., sodium, lithium, and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), salts with organic bases (e.g., organic amines (e.g., benzathine, dicyclohexylamine, hydravamin (formed with N,N-bis(dehydroabiethyl)-ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine)), and salts with amino acids (e.g., arginine, lysine, etc.)). The basic nitrogen-containing group may be quaternized by a reagent (e.g., lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long-chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others).

[0049] This disclosure includes compounds represented by Formula I, or pharmaceutically acceptable salts thereof, methods for producing these compounds, pharmaceutical compositions comprising these compounds, and the use of these compounds in the treatment of diseases or disorders related to PAD4 enzyme activity.

[0050] In some embodiments, this disclosure uses formula I: [ka] (In the formula, L, X1, X2, Y, R1, R2, R3, R4, R5, R6, and R7 are as defined and described herein.) The present invention provides the compound represented by or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, this disclosure relates to formulas Ia, Ia-1, Ia-2, Ia-3, Ia-4, and Ia-5: [ka] (In the formula, A is a C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl; X3 is CH2, NH, O, or S; and (r is an integer between 1 and 3) The present invention provides compounds selected from those represented by any of the following, or pharmaceutically acceptable salts, isomers, enantiomers, or tautomers thereof.

[0052] In some embodiments, formulas Ib, Ib-1, Ib-2, Ib-3, Ib-4, and Ib-5: [ka] [ka] (In the formula, A is a C3-C8 cycloalkyl, a 3- to 8-membered heterocyclyl, aryl, or heteroaryl.) The present invention provides compounds selected from those represented by any of the following, or pharmaceutically acceptable salts, isomers, enantiomers, or tautomers thereof.

[0053] In some embodiments, this disclosure relates to formulas Ic, Ic-1, Ic-2, Ic-3, Ic-4, and Ic-5: [ka] (In the formula, A is a C3-C8 cycloalkyl, a 3- to 8-membered heterocyclyl, aryl, or heteroaryl.) The present invention provides compounds selected from those represented by any of the following, or pharmaceutically acceptable salts, isomers, enantiomers, or tautomers thereof.

[0054] In some embodiments, this disclosure uses formulas Id, Ie, and If: [ka] (wherein A is a C3-C8 cycloalkyl, 3-8 member heterocyclyl, aryl, or heteroaryl; X3 is CH2, NH, O, or S; and (r is an integer between 1 and 3) The present invention provides compounds selected from those represented by any of the following, or pharmaceutically acceptable salts, isomers, enantiomers, or tautomers thereof.

[0055] In some embodiments, X1 is selected from CR8 or N. In some embodiments represented by any of the formulas described herein, X1 is CR8. In some embodiments represented by any of the formulas described herein, X1 is N.

[0056] In some embodiments, X2 is selected from CR8 or N. In some embodiments represented by any of the formulas described herein, X2 is CR8. In some embodiments represented by any of the formulas described herein, X2 is N.

[0057] In some embodiments, Y is -(CR9R 10 ) p -,-O-(CR9R 10 ) p -,-(CR9R 10 ) p -O-(CH2) m -,-(CR9R 10 ) p -O-(CH2) m -O-CH2-, and -(CR9R 10 ) p -O-(CH2) m -O- is selected. In some embodiments shown by any of the formulas described herein, Y is -(CR9R 10 ) p -. In some embodiments represented by any of the formulas described herein, Y is -O-(CR9R 10 ) p -. In some embodiments represented by any of the formulas described herein, Y is -(CR9R 10 )p -O-(CH2) m -. In some embodiments represented by any of the formulas described herein, Y is -(CR9R 10 ) p -O-(CH2) m -O-CH2-. In some embodiments represented by any of the formulas described herein, Y is -(CR9R 10 ) p -O-(CH2) m It is -O-.

[0058] In some embodiments, R1 is a 4- to 8-membered heterocycle containing at least one heteroatom selected from the group consisting of -CH(NHR7)-(C1-C3 alkyl) or N, O, or S, and the alkyl or heterocycle contains one or more R 11 It may be appropriately substituted with. In some embodiments represented by any of the formulas described herein, R1 is -CH(NHR7)-(C1-C3 alkyl). In some embodiments represented by any of the formulas described herein, where R1 is CH(NHR7)-(C1-C3 alkyl), C1-C3 alkyl is 1 or more R 11 It is substituted with. In some embodiments represented by any of the formulas described herein, R1 is a 4- to 8-membered heteroring containing at least one heteroatom. In some embodiments represented by any of the formulas described herein, the heteroatom is selected from the group consisting of N, O, or S. In some embodiments represented by any of the formulas described herein, the heteroatom is N. In some embodiments represented by any of the formulas described herein, the heteroatom is O. In some embodiments represented by any of the formulas described herein, the heteroatom is S. In some embodiments represented by any of the formulas described herein, the 4- to 8-membered heteroring containing at least one heteroatom has one or more R 11 It has been replaced with.

[0059] In some embodiments, R2 is selected from H and C1-C4 alkyl. In some embodiments represented by any of the formulas described herein, R2 is H. In some embodiments represented by any of the formulas described herein, R2 is C1-C4 alkyl. In some embodiments represented by any of the formulas described herein, R2 is C1-C3 alkyl. In some embodiments represented by any of the formulas described herein, R2 is C1-C2 alkyl. In some embodiments represented by any of the formulas described herein, R2 is C1 alkyl.

[0060] Generally, as defined above, R3 is selected from H, halogens, and C1-C4 alkyls. In some embodiments represented by any of the formulas described herein, R3 is H. In some embodiments represented by any of the formulas described herein, R3 is a halogen. In some embodiments represented by any of the formulas described herein, R3 is a C1-C4 alkyl. In some embodiments represented by any of the formulas described herein, R3 is a C1-C3 alkyl. In some embodiments represented by any of the formulas described herein, R3 is a C1-C2 alkyl. In some embodiments represented by any of the formulas described herein, R3 is a C1 alkyl.

[0061] In some embodiments, R4 is selected from hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl. In some embodiments represented by any of the formulas described herein, R4 is hydrogen. In some embodiments represented by any of the formulas described herein, R4 is C1-C4 alkyl. In some embodiments represented by any of the formulas described herein, R4 is C1-C3 alkyl. In some embodiments represented by any of the formulas described herein, R4 is C1-C2 alkyl. In some embodiments represented by any of the formulas described herein, R4 is C1 alkyl. In some embodiments represented by any of the formulas described herein, R4 is C2 alkyl. In some embodiments represented by any of the formulas described herein, R4 is C3 alkyl. In some embodiments represented by any of the formulas described herein, R4 is C4 alkyl. In some embodiments represented by any of the formulas described herein, R4 is C1-C4 haloalkyl. In some embodiments represented by any of the formulas described herein, R4 is C1-C3 haloalkyl. In some embodiments represented by any of the formulas described herein, R4 is a C1-C2 haloalkyl. In some embodiments represented by any of the formulas described herein, R4 is a C1 haloalkyl. In some embodiments represented by any of the formulas described herein, R4 is a C2 haloalkyl. In some embodiments represented by any of the formulas described herein, R4 is a C3 haloalkyl. In some embodiments represented by any of the formulas described herein, R4 is a C4 haloalkyl.

[0062] In some embodiments, R5 is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, heteroaryl, or aryl; the heteroaryl or aryl may be appropriately substituted with one or more halogens or C1-C6 alkoxy. In some embodiments represented by any of the formulas described herein, R5 is H. In some embodiments represented by any of the formulas described herein, R5 is a halogen. In some embodiments represented by any of the formulas described herein, R5 is a C1-C4 alkyl. In some embodiments represented by any of the formulas described herein, R5 is a C1-C3 alkyl. In some embodiments represented by any of the formulas described herein, R5 is a C1-C2 alkyl. In some embodiments represented by any of the formulas described herein, R5 is a C1 alkyl. In some embodiments represented by any of the formulas described herein, R5 is a C2 alkyl. In some embodiments represented by any of the formulas described herein, R5 is a C3 alkyl. In some embodiments represented by any of the formulas described herein, R5 is a C4 alkyl. In some embodiments represented by any of the formulas described herein, R5 is a C1-C4 alkoxy. In some embodiments represented by any of the formulas described herein, R5 is a C1-C3 alkoxy. In some embodiments represented by any of the formulas described herein, R5 is a C1-C2 alkoxy. In some embodiments represented by any of the formulas described herein, R5 is a C1 alkoxy. In some embodiments represented by any of the formulas described herein, R5 is a C1-C4 haloalkyl. In some embodiments represented by any of the formulas described herein, R5 is a C1-C3 haloalkyl. In some embodiments represented by any of the formulas described herein, R5 is a C1-C2 haloalkyl. In some embodiments represented by any of the formulas described herein, R5 is a C1 haloalkyl. In some embodiments represented by any of the formulas described herein, R5 is a C2 haloalkyl.In some embodiments represented by any of the formulas described herein, R5 is a C3 haloalkyl. In some embodiments represented by any of the formulas described herein, R5 is a C4 haloalkyl. In some embodiments represented by any of the formulas described herein, R5 is a heteroaryl. In some embodiments represented by any of the formulas described herein, R5 is an aryl. In some embodiments represented by any of the formulas described herein, where R5 is a heteroaryl or aryl, the heteroaryl or aryl is substituted with one or more halogens. In some embodiments represented by any of the formulas described herein, where R5 is a heteroaryl or aryl, the heteroaryl or aryl is substituted with one or more C1-C6 alkoxys. In some embodiments represented by any of the formulas described herein, R5 is a heteroaryl, and the heteroaryl is substituted with one or more halogens. In some embodiments represented by any of the formulas described herein, R5 is a heteroaryl, and the heteroaryl is substituted with one or more C1-C6 alkoxys. In some embodiments represented by any of the formulas described herein, R5 is a heteroaryl, and the heteroaryl is substituted with one or more C1-C5 alkoxys. In some embodiments represented by any of the formulas described herein, R5 is a heteroaryl molecule, and the heteroaryl molecule is substituted with one or more C1-C4 alkoxy molecules. In some embodiments represented by any of the formulas described herein, R5 is a heteroaryl molecule, and the heteroaryl molecule is substituted with one or more C1-C3 alkoxy molecules. In some embodiments represented by any of the formulas described herein, R5 is a heteroaryl molecule, and the heteroaryl molecule is substituted with one or more C1-C2 alkoxy molecules. In some embodiments represented by any of the formulas described herein, R5 is a heteroaryl molecule, and the heteroaryl molecule is substituted with one or more C2 alkoxy molecules.In some embodiments represented by any of the formulas described herein, R5 is a heteroaryl, and the heteroaryl is substituted with one or more C3 alkoxy groups. In some embodiments represented by any of the formulas described herein, R5 is a heteroaryl, and the heteroaryl is substituted with one or more C4 alkoxy groups. In some embodiments represented by any of the formulas described herein, R5 is a heteroaryl, and the heteroaryl is substituted with one or more C5 alkoxy groups. In some embodiments represented by any of the formulas described herein, R5 is a heteroaryl, and the heteroaryl is substituted with one or more C6 alkoxy groups. In some embodiments represented by any of the formulas described herein, R5 is an aryl, and the aryl is substituted with one or more halogens. In some embodiments represented by any of the formulas described herein, R5 is an aryl, and the aryl is substituted with one or more C1-C6 alkoxy groups. In some embodiments represented by any of the formulas described herein, R5 is an aryl, and the aryl is substituted with one or more C1-C5 alkoxy groups. In some embodiments represented by any of the formulas described herein, R5 is an aryl, and the aryl is substituted with one or more C1-C4 alkoxy groups. In some embodiments represented by any of the formulas described herein, R5 is an aryl molecule, and the aryl molecule is substituted with one or more C1-C3 alkoxy molecules. In some embodiments represented by any of the formulas described herein, R5 is an aryl molecule, and the aryl molecule is substituted with one or more C1-C2 alkoxy molecules. In some embodiments represented by any of the formulas described herein, R5 is an aryl molecule, and the aryl molecule is substituted with one or more C1 alkoxy molecules. In some embodiments represented by any of the formulas described herein, R5 is an aryl molecule, and the aryl molecule is substituted with one or more C2 alkoxy molecules. In some embodiments represented by any of the formulas described herein, R5 is an aryl molecule, and the aryl molecule is substituted with one or more C3 alkoxy molecules.In some embodiments represented by any of the formulas described herein, R5 is an aryl molecule, and the aryl molecule is substituted with one or more C4 alkoxy molecules. In some embodiments represented by any of the formulas described herein, R5 is an aryl molecule, and the aryl molecule is substituted with one or more C5 alkoxy molecules. In some embodiments represented by any of the formulas described herein, R5 is an aryl molecule, and the aryl molecule is substituted with one or more C6 alkoxy molecules.

[0063] In some embodiments, R6 is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, heteroaryl, or aryl; the heteroaryl or aryl may be appropriately substituted with one or more halogens or C1-C6 alkoxy. In some embodiments represented by any of the formulas described herein, R6 is H. In some embodiments represented by any of the formulas described herein, R6 is a halogen. In some embodiments represented by any of the formulas described herein, R6 is a C1-C4 alkyl. In some embodiments represented by any of the formulas described herein, R6 is a C1-C3 alkyl. In some embodiments represented by any of the formulas described herein, R6 is a C1-C2 alkyl. In some embodiments represented by any of the formulas described herein, R6 is a C1 alkyl. In some embodiments represented by any of the formulas described herein, R6 is a C2 alkyl. In some embodiments represented by any of the formulas described herein, R6 is a C3 alkyl. In some embodiments represented by any of the formulas described herein, R6 is a C4 alkyl. In some embodiments represented by any of the formulas described herein, R6 is a C1-C4 alkoxy. In some embodiments represented by any of the formulas described herein, R6 is a C1-C3 alkoxy. In some embodiments represented by any of the formulas described herein, R6 is a C1-C2 alkoxy. In some embodiments represented by any of the formulas described herein, R6 is a C1 alkoxy. In some embodiments represented by any of the formulas described herein, R6 is a C1-C4 haloalkyl. In some embodiments represented by any of the formulas described herein, R6 is a C1-C3 haloalkyl. In some embodiments represented by any of the formulas described herein, R6 is a C1-C2 haloalkyl. In some embodiments represented by any of the formulas described herein, R6 is a C1 haloalkyl. In some embodiments represented by any of the formulas described herein, R6 is a C2 haloalkyl. In some embodiments represented by any of the formulas described herein, R6 is a C3 haloalkyl.In some embodiments represented by any of the formulas described herein, R6 is a C4 haloalkyl. In some embodiments represented by any of the formulas described herein, R6 is a heteroaryl. In some embodiments represented by any of the formulas described herein, R6 is an aryl. In some embodiments represented by any of the formulas described herein, where R6 is a heteroaryl or aryl, the heteroaryl or aryl is substituted with one or more halogens. In some embodiments represented by any of the formulas described herein, where R6 is a heteroaryl or aryl, the heteroaryl or aryl is substituted with one or more C1-C6 alkoxys. In some embodiments represented by any of the formulas described herein, R6 is a heteroaryl, and the heteroaryl is substituted with one or more halogens. In some embodiments represented by any of the formulas described herein, R6 is a heteroaryl, and the heteroaryl is substituted with one or more C1-C6 alkoxys. In some embodiments represented by any of the formulas described herein, R6 is a heteroaryl, and the heteroaryl is substituted with one or more C1-C5 alkoxys. In some embodiments represented by any of the formulas described herein, R6 is a heteroaryl molecule, and the heteroaryl molecule is substituted with one or more C1-C4 alkoxy molecules. In some embodiments represented by any of the formulas described herein, R6 is a heteroaryl molecule, and the heteroaryl molecule is substituted with one or more C1-C3 alkoxy molecules. In some embodiments represented by any of the formulas described herein, R6 is a heteroaryl molecule, and the heteroaryl molecule is substituted with one or more C1-C2 alkoxy molecules. In some embodiments represented by any of the formulas described herein, R6 is a heteroaryl molecule, and the heteroaryl molecule is substituted with one or more C2 alkoxy molecules. In some embodiments represented by any of the formulas described herein, R6 is a heteroaryl molecule, and the heteroaryl molecule is substituted with one or more C3 alkoxy molecules.In some embodiments represented by any of the formulas described herein, R6 is a heteroaryl, and the heteroaryl is substituted with one or more C4 alkoxy groups. In some embodiments represented by any of the formulas described herein, R6 is a heteroaryl, and the heteroaryl is substituted with one or more C5 alkoxy groups. In some embodiments represented by any of the formulas described herein, R6 is a heteroaryl, and the heteroaryl is substituted with one or more C6 alkoxy groups. In some embodiments represented by any of the formulas described herein, R6 is an aryl, and the aryl is substituted with one or more halogens. In some embodiments represented by any of the formulas described herein, R6 is an aryl, and the aryl is substituted with one or more C1-C6 alkoxy groups. In some embodiments represented by any of the formulas described herein, R6 is an aryl, and the aryl is substituted with one or more C1-C5 alkoxy groups. In some embodiments represented by any of the formulas described herein, R6 is an aryl, and the aryl is substituted with one or more C1-C4 alkoxy groups. In some embodiments represented by any of the formulas described herein, R6 is an aryl, and the aryl is substituted with one or more C1-C3 alkoxy groups. In some embodiments represented by any of the formulas described herein, R6 is an aryl molecule, and the aryl molecule is substituted with one or more C1-C2 alkoxy molecules. In some embodiments represented by any of the formulas described herein, R6 is an aryl molecule, and the aryl molecule is substituted with one or more C1 alkoxy molecules. In some embodiments represented by any of the formulas described herein, R6 is an aryl molecule, and the aryl molecule is substituted with one or more C2 alkoxy molecules. In some embodiments represented by any of the formulas described herein, R6 is an aryl molecule, and the aryl molecule is substituted with one or more C3 alkoxy molecules. In some embodiments represented by any of the formulas described herein, R6 is an aryl molecule, and the aryl molecule is substituted with one or more C4 alkoxy molecules. In some embodiments represented by any of the formulas described herein, R6 is an aryl molecule, and the aryl molecule is substituted with one or more C5 alkoxy molecules.In some embodiments represented by any of the formulas described herein, R6 is an aryl, and the aryl is substituted with one or more C6 alkoxys.

[0064] In some embodiments represented by any of the formulas described herein, R5 and R6, together with the intervening atom, form a C3-C6 cycloalkyl or a 4- to 8-membered heterocycline. In some embodiments represented by any of the formulas described herein, R5 and R6, together with the intervening atom, form a C3-C6 cycloalkyl. In some embodiments represented by any of the formulas described herein, R5 and R6, together with the intervening atom, form a C3-C5 cycloalkyl. In some embodiments represented by any of the formulas described herein, R5 and R6, together with the intervening atom, form a C3-C4 cycloalkyl. In some embodiments represented by any of the formulas described herein, R5 and R6, together with the intervening atom, form a C3 cycloalkyl. In some embodiments represented by any of the formulas described herein, R5 and R6, together with the intervening atom, form a 4- to 8-membered heterocycline. In some embodiments represented by any of the formulas described herein, R5 and R6, together with the intervening atom, form a 4- to 7-membered heterocycline. In some embodiments represented by any of the formulas described herein, R5 and R6, together with the intervening atom, form a 4- to 6-membered heterocycline. In some embodiments represented by any of the formulas described herein, R5 and R6, together with the intervening atom, form a 4- to 5-membered heterocycline. In some embodiments represented by any of the formulas described herein, R5 and R6, together with the intervening atom, form a 4-membered heterocycline.

[0065] In some embodiments, each R7 is independently selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl. In some embodiments represented by any of the formulas described herein, at least one R7 is H. In some embodiments represented by any of the formulas described herein, at least one R7 is C1-C4 alkyl. In some embodiments represented by any of the formulas described herein, at least one R7 is C1-C3 alkyl. In some embodiments represented by any of the formulas described herein, at least one R7 is C1-C2 alkyl. In some embodiments represented by any of the formulas described herein, at least one R7 is C1 alkyl. In some embodiments represented by any of the formulas described herein, at least one R7 is C2 alkyl. In some embodiments represented by any of the formulas described herein, at least one R7 is C3 alkyl. In some embodiments represented by any of the formulas described herein, at least one R7 is C3-C4 cycloalkyl. In some embodiments represented by any of the formulas described herein, at least one R7 is C3 cycloalkyl. In some embodiments represented by any of the formulas described herein, at least one R7 is a C4 cycloalkyl group. In some embodiments represented by any of the formulas described herein, at least one R7 is a cyclopropyl group.

[0066] Generally, as defined above, each R8 is independently selected from H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. In some embodiments represented by any of the formulas described herein, at least one R8 is independently selected from halogen, alkoxy, and alkyl. In some embodiments represented by any of the formulas described herein, at least one R8 is H. In some embodiments represented by any of the formulas described herein, at least one R8 is halogen. In some embodiments represented by any of the formulas described herein, at least one R8 is C1-C4 alkyl. In some embodiments represented by any of the formulas described herein, at least one R8 is C1-C3 alkyl. In some embodiments represented by any of the formulas described herein, at least one R8 is C1-C2 alkyl. In some embodiments represented by any of the formulas described herein, at least one R8 is C1 alkyl. In some embodiments represented by any of the formulas described herein, at least one R8 is C2 alkyl. In some embodiments represented by any of the formulas described herein, at least one R8 is C3 alkyl. In some embodiments represented by any of the formulas described herein, at least one R8 is a C4 alkyl. In some embodiments represented by any of the formulas described herein, at least one R8 is a C1-C4 haloalkyl. In some embodiments represented by any of the formulas described herein, at least one R8 is a C1-C3 haloalkyl. In some embodiments represented by any of the formulas described herein, at least one R8 is a C1-C2 haloalkyl. In some embodiments represented by any of the formulas described herein, at least one R8 is a C1 haloalkyl. In some embodiments represented by any of the formulas described herein, at least one R8 is a C2 haloalkyl. In some embodiments represented by any of the formulas described herein, at least one R8 is a C3 haloalkyl.In some embodiments represented by any of the formulas described herein, at least one R8 is a C4 haloalkyl. In some embodiments represented by any of the formulas described herein, at least one R8 is a C1-C4 alkoxy. In some embodiments represented by any of the formulas described herein, at least one R8 is a C1-C3 alkoxy. In some embodiments represented by any of the formulas described herein, at least one R8 is a C1-C2 alkoxy. In some embodiments represented by any of the formulas described herein, at least one R8 is a C1 alkoxy. In some embodiments represented by any of the formulas described herein, at least one R8 is a C2 alkoxy. In some embodiments represented by any of the formulas described herein, at least one R8 is a C3 alkoxy. In some embodiments represented by any of the formulas described herein, at least one R8 is a C4 alkoxy.

[0067] Generally, as defined above, each R9 is independently selected from H, halogen, C1-C4 alkyl, and C3-C4 carbocyric. In some embodiments represented by any of the formulas described herein, R9 is H. In some embodiments represented by any of the formulas described herein, R9 is a halogen. In some embodiments represented by any of the formulas described herein, R9 is a C1-C4 alkyl. In some embodiments represented by any of the formulas described herein, R9 is a C1-C3 alkyl. In some embodiments represented by any of the formulas described herein, R9 is a C1-C2 alkyl. In some embodiments represented by any of the formulas described herein, R9 is a C1 alkyl.

[0068] In some embodiments represented by any of the formulas described herein, R9 is a C2 alkyl group. In some embodiments represented by any of the formulas described herein, R9 is a C3 alkyl group. In some embodiments represented by any of the formulas described herein, R9 is a C4 alkyl group. In some embodiments represented by any of the formulas described herein, R9 is a C3-C4 carbocyacrylic group. In some embodiments represented by any of the formulas described herein, R9 is a C3 carbocyacrylic group. In some embodiments represented by any of the formulas described herein, R9 is a C4 carbocyacrylic group.

[0069] Generally as defined above, each R 10 R is independently selected from H, halogens, and C1-C4 alkyl groups. In some embodiments represented by any of the formulas described herein, R 10 is H. In some embodiments represented by any of the formulas described herein, R 10 is a halogen. In some embodiments represented by any of the formulas described herein, R 10 R is a C1-C4 alkyl group. In some embodiments represented by any of the formulas described herein, R 10 R is a C1-C3 alkyl group. In some embodiments represented by any of the formulas described herein, R 10 R is a C1-C2 alkyl group. In some embodiments represented by any of the formulas described herein, R 10 is a C1 alkyl group. In some embodiments represented by any of the formulas described herein, R 10 R is a C2 alkyl group. In some embodiments represented by any of the formulas described herein, R 10 R is a C3 alkyl group. In some embodiments represented by any of the formulas described herein, R 10 It is a C4 alkyl group.

[0070] In some embodiments represented by any of the formulas described herein, R5, R6, and R9 together with the intervening and adjacent atoms form a C3-C6 cycloalkyl, a 4- to 8-membered heterocyclyl, a heteroaryl, or an aryl, and the cycloalkyl, heterocyclyl, heteroaryl, or aryl is composed of one or more R 12They may be appropriately substituted with. In some embodiments represented by any of the formulas described herein, R5, R6, and R9, together with the intervening atom and adjacent atoms, form a C3-C6 cycloalkyl group. In some embodiments represented by any of the formulas described herein, R5, R6, and R9, together with the intervening atom and adjacent atoms, form a C3 cycloalkyl group. In some embodiments represented by any of the formulas described herein, R5, R6, and R9, together with the intervening atom and adjacent atoms, form a C4 cycloalkyl group. In some embodiments represented by any of the formulas described herein, R5, R6, and R9, together with the intervening atom and adjacent atoms, form a C5 cycloalkyl group. In some embodiments represented by any of the formulas described herein, R5, R6, and R9, together with the intervening atom and adjacent atoms, form a C6 cycloalkyl group. In some embodiments represented by any of the formulas described herein, R5, R6, and R9, together with the intervening atom and adjacent atoms, form a 4- to 8-membered heterocycline group. In some embodiments represented by any of the formulas described herein, R5, R6, and R9, together with the intervening atom and adjacent atoms, form a four-membered heterocycline. In some embodiments represented by any of the formulas described herein, R5, R6, and R9, together with the intervening atom and adjacent atoms, form a five-membered heterocycline. In some embodiments represented by any of the formulas described herein, R5, R6, and R9, together with the intervening atom and adjacent atoms, form a six-membered heterocycline. In some embodiments represented by any of the formulas described herein, R5, R6, and R9, together with the intervening atom and adjacent atoms, form a seven-membered heterocycline. In some embodiments represented by any of the formulas described herein, R5, R6, and R9, together with the intervening atom and adjacent atoms, form an eight-membered heterocycline. In some embodiments represented by any of the formulas described herein, R5, R6, and R9, together with the intervening atom and adjacent atoms, form a heteroaryl.In some embodiments represented by any of the formulas described herein, R5, R6, and R9, together with the intervening atom and adjacent atoms, form an aryl group. In some embodiments represented by any of the formulas described herein, R5, R6, and R9, together with the intervening atom and adjacent atoms, form a C3-C6 cycloalkyl group, the cycloalkyl group having 1 or more R atoms. 12 It is replaced by. In some embodiments represented by any of the formulas described herein, R5, R6, and R9 together with the intervening atom and adjacent atoms form a 4- to 8-membered heterocycline, and the heterocycline has one or more R 12 It is substituted with. In some embodiments represented by any of the formulas described herein, R5, R6, and R9 together with the intervening atom and adjacent atoms form a heteroaryl, and the heteroaryl is composed of one or more R 12 It is replaced by. In some embodiments represented by any of the formulas described herein, R5, R6, and R9 together with the intervening atom and adjacent atom form an aryl, and the aryl is one or more R 12 It has been replaced with.

[0071] Generally as defined above, each R 11 R is independently selected from H, halogens, C1-C6 alkyls, and C1-C6 alkoxys. In some embodiments represented by any of the formulas described herein, R 11 is H. In some embodiments represented by any of the formulas described herein, R 11 is a halogen. In some embodiments represented by any of the formulas described herein, R 11 R is a C1-C6 alkyl group. In some embodiments represented by any of the formulas described herein, R 11 R is a C1-C5 alkyl group. In some embodiments represented by any of the formulas described herein, R 11 R is a C1-C4 alkyl group. In some embodiments represented by any of the formulas described herein, R 11R is a C1-C3 alkyl group. In some embodiments represented by any of the formulas described herein, R 11 R is a C1-C2 alkyl group. In some embodiments represented by any of the formulas described herein, R 11 is a C1 alkyl group. In some embodiments represented by any of the formulas described herein, R 11 R is a C2 alkyl group. In some embodiments represented by any of the formulas described herein, R 11 R is a C3 alkyl group. In some embodiments represented by any of the formulas described herein, R 11 R is a C4 alkyl group. In some embodiments represented by any of the formulas described herein, R 11 R is a C5 alkyl group. In some embodiments represented by any of the formulas described herein, R 11 R is a C6 alkyl group. In some embodiments represented by any of the formulas described herein, R 11 R is a C1-C6 alkoxy. In some embodiments represented by any of the formulas described herein, R 11 R is a C1-C5 alkoxy. In some embodiments represented by any of the formulas described herein, R 11 R is a C1-C4 alkoxy. In some embodiments represented by any of the formulas described herein, R 11 R is a C1-C3 alkoxy. In some embodiments represented by any of the formulas described herein, R 11 R is a C1-C2 alkoxy. In some embodiments represented by any of the formulas described herein, R 11 is a C1 alkoxy. In some embodiments represented by any of the formulas described herein, R 11 is a C2 alkoxy. In some embodiments represented by any of the formulas described herein, R 11 R is a C3 alkoxy. In some embodiments represented by any of the formulas described herein, R 11 R is a C4 alkoxy. In some embodiments represented by any of the formulas described herein, R 11R is a C5 alkoxy. In some embodiments represented by any of the formulas described herein, R 11 It is a C6 alkoxy.

[0072] In some embodiments, each R 12 These are independently H, halogen, -OH, -NH2, -CN, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl, and C3-C4 cycloalkyl, 3-10 member heterocyclyl, heteroaryl, and C6-C 10 Selected from the aryl group. In some embodiments represented by any of the formulas described herein, at least one R 12 R is selected from H, halogen, C1-C4 alkoxy, or C1-C6 alkyl. In some embodiments represented by any of the formulas described herein, R 12 is H. In some embodiments represented by any of the formulas described herein, R 12 is a halogen. In some embodiments represented by any of the formulas described herein, R 12 is -OH. In some embodiments represented by any of the formulas described herein, R 12 R is -NH2. In some embodiments represented by any of the formulas described herein, R 12 is -CN. In some embodiments represented by any of the formulas described herein, R 12 R is a C1-C6 alkyl group. In some embodiments represented by any of the formulas described herein, R 12 R is a C1-C5 alkyl group. In some embodiments represented by any of the formulas described herein, R 12 R is a C1-C4 alkyl group. In some embodiments represented by any of the formulas described herein, R 12 R is a C1-C3 alkyl group. In some embodiments represented by any of the formulas described herein, R 12 R is a C1-C2 alkyl group. In some embodiments represented by any of the formulas described herein, R 12is a C1 alkyl group. In some embodiments represented by any of the formulas described herein, R 12 R is a C2 alkyl group. In some embodiments represented by any of the formulas described herein, R 12 R is a C3 alkyl group. In some embodiments represented by any of the formulas described herein, R 12 R is a C4 alkyl group. In some embodiments represented by any of the formulas described herein, R 12 R is a C5 alkyl group. In some embodiments represented by any of the formulas described herein, R 12 R is a C6 alkyl group. In some embodiments represented by any of the formulas described herein, R 12 R is a C1-C4 alkoxy. In some embodiments represented by any of the formulas described herein, R 12 R is a C1-C3 alkoxy. In some embodiments represented by any of the formulas described herein, R 12 R is a C1-C2 alkoxy. In some embodiments represented by any of the formulas described herein, R 12 is a C1 alkoxy. In some embodiments represented by any of the formulas described herein, R 12 is a C2 alkoxy. In some embodiments represented by any of the formulas described herein, R 12 R is a C3 alkoxy. In some embodiments represented by any of the formulas described herein, R 12 R is a C4 alkoxy. In some embodiments represented by any of the formulas described herein, R 12 R is a C1-C4 haloalkoxy. In some embodiments represented by any of the formulas described herein, R 12 R is a C1 haloalkoxy. In some embodiments represented by any of the formulas described herein, R 12 R is a C2 haloalkoxy. In some embodiments represented by any of the formulas described herein, R 12 R is a C3 haloalkoxy. In some embodiments represented by any of the formulas described herein, R 12R is a C4 haloalkoxy. In some embodiments represented by any of the formulas described herein, R 12 R is a C1-C4 haloalkyl. In some embodiments represented by any of the formulas described herein, R 12 R is a C1 haloalkyl. In some embodiments represented by any of the formulas described herein, R 12 R is a C2 haloalkyl. In some embodiments represented by any of the formulas described herein, R 12 R is a C3 haloalkyl. In some embodiments represented by any of the formulas described herein, R 12 R is a C4 haloalkyl. In some embodiments represented by any of the formulas described herein, R 12 R is a C3-C4 cycloalkyl. In some embodiments represented by any of the formulas described herein, R 12 R is a C3 cycloalkyl. In some embodiments represented by any of the formulas described herein, R 12 R is a C4 cycloalkyl. In some embodiments represented by any of the formulas described herein, R 12 R is a C5 cycloalkyl. In some embodiments represented by any of the formulas described herein, R 12 R is a C6 cycloalkyl. In some embodiments represented by any of the formulas described herein, R 12 R is a C7 cycloalkyl. In some embodiments represented by any of the formulas described herein, R 12 R is a C8 cycloalkyl. In some embodiments represented by any of the formulas described herein, R 12 R is a C9 cycloalkyl. In some embodiments represented by any of the formulas described herein, R 12 is C 10 It is cycloalkyl. In some embodiments represented by any of the formulas described herein, R 12 R is a 3- to 10-membered heterocycline. In some embodiments represented by any of the formulas described herein, R 12R is a three-membered heterocyclyl. In some embodiments represented by any of the formulas described herein, R 12 R is a four-membered heterocyclyl. In some embodiments represented by any of the formulas described herein, R 12 R is a 5-membered heterocycline. In some embodiments represented by any of the formulas described herein, R 12 R is a 6-membered heterocycline. In some embodiments represented by any of the formulas described herein, R 12 R is a 7-membered heterocycline. In some embodiments represented by any of the formulas described herein, R 12 R is an 8-membered heterocycline. In some embodiments represented by any of the formulas described herein, R 12 R is a 9-membered heterocycline. In some embodiments represented by any of the formulas described herein, R 12 R is a 10-membered heterocycline. In some embodiments represented by any of the formulas described herein, R 12 R is a heteroaryl compound. In some embodiments represented by any of the formulas described herein, R 12 is C6-C 10 It is an aryl. In some embodiments represented by any of the formulas described herein, R 12 R is a C6 aryl compound. In some embodiments represented by any of the formulas described herein, R 12 R is a C8 aryl. In some embodiments represented by any of the formulas described herein, R 12 is a C9 aryl. In some embodiments represented by any of the formulas described herein, R 12 is C 10 It is Ariel.

[0073] In some embodiments, L is selected from covalent bonds and -CH2-. In some embodiments represented by any of the formulas described herein, L is a covalent bond. In some embodiments represented by any of the formulas described herein, L is -CH2-.

[0074] In some embodiments, m is an integer selected from 1, 2, and 3. In some embodiments shown by any of the formulas described herein, m is 1. In some embodiments shown by any of the formulas described herein, m is 2. In some embodiments shown by any of the formulas described herein, m is 3.

[0075] In some embodiments, p is an integer selected from 2, 3, 4, 5, and 6. In some embodiments shown by any of the formulas described herein, p is 2. In some embodiments shown by any of the formulas described herein, p is 3. In some embodiments shown by any of the formulas described herein, p is 4. In some embodiments shown by any of the formulas described herein, p is 5. In some embodiments shown by any of the formulas described herein, p is 6.

[0076] In some embodiments, X3 is selected from CH2, NH, O, and S. In some embodiments represented by any of the formulas described herein, X3 is CH2. In some embodiments represented by any of the formulas described herein, X3 is NH. In some embodiments represented by any of the formulas described herein, X3 is O. In some embodiments represented by any of the formulas described herein, X3 is S.

[0077] In some embodiments, A is selected from C3-C8 cycloalkyl, aryl, and heteroaryl compounds. In some embodiments represented by any of the formulas described herein, A is a C3-C8 cycloalkyl compound. In some embodiments represented by any of the formulas described herein, A is a C3 cycloalkyl compound. In some embodiments represented by any of the formulas described herein, A is a C4 cycloalkyl compound. In some embodiments represented by any of the formulas described herein, A is a C5 cycloalkyl compound. In some embodiments represented by any of the formulas described herein, A is a C6 cycloalkyl compound. In some embodiments represented by any of the formulas described herein, A is a C7 cycloalkyl compound. In some embodiments represented by any of the formulas described herein, A is a C8 cycloalkyl compound. In some embodiments represented by any of the formulas described herein, A is an aryl compound. In some embodiments represented by any of the formulas described herein, A is a heteroaryl compound.

[0078] In some embodiments, r is an integer between 0 and 3. In some embodiments represented by any of the formulas described herein, r is between 1 and 3. In some embodiments represented by any of the formulas described herein, r is between 0 and 2. In some embodiments represented by any of the formulas described herein, r is 0. In some embodiments represented by any of the formulas described herein, r is 1. In some embodiments represented by any of the formulas described herein, r is 2. In some embodiments represented by any of the formulas described herein, r is 3.

[0079] In some embodiments, the compound represented by formula I is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or selected from a pharmaceutically acceptable salt thereof.

[0080] It should be understood that all isomers, including mixtures thereof, are included in this disclosure. If a compound contains a double bond, the substituent may be in an E configuration or a Z configuration. If a compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may be in a cis configuration or a trans configuration. All tautomers are also intended to be included.

[0081] The compounds of this disclosure, as well as their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs, may exist as tautomers (e.g., as amides or iminoethers). In this specification, all such tautomers are considered as part of this disclosure.

[0082] The compounds of this disclosure may contain chiral or asymmetric centers and therefore may exist in various stereoisomers. All stereoisomers of the compounds of this disclosure and mixtures thereof (including racemic mixtures) are intended to be part of this disclosure. Furthermore, this disclosure includes all geometric and positional isomers. For example, if a compound of this disclosure contains a double bond or a fused ring, both cis and trans isomers, as well as mixtures thereof, are included in the scope of this disclosure. Each compound disclosed herein includes all enantiomers that conform to the general structure of the compound. Compounds may be in pure form as a racemate or enantiomer, or in any other form, from a stereochemical standpoint. Assay results may reflect data collected for racemates, pure enantiomers, or any other form, from a stereochemical standpoint.

[0083] Diastereomer mixtures can be separated into individual diastereomers based on physicochemical differences by methods well known to those skilled in the art, e.g., chromatography and / or fractional crystallization. Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral alcohol or an asymmetric additive such as Mosher's acid chloride) to convert it into a diastereomer mixture, separating the diastereomers, and converting the separated diastereomers back into their corresponding pure enantiomers (e.g., by hydrolysis). Some of the compounds of this disclosure may also be atropisomers (e.g., substituted biaryls) and may be considered part of this disclosure. Enantiomers can also be separated using a chiral HPLC column.

[0084] Furthermore, the compounds of this disclosure may exist in various tautomers, and all such forms are included within the scope of this disclosure. For example, all keto-enol and imine-enamine forms of the compounds are included within this disclosure.

[0085] All stereoisomers of the compound (e.g., geometric isomers, optical isomers, etc.) (including stereoisomers of salts, solvates, esters, and prodrugs of the compound, as well as stereoisomers of salts, solvates, and esters of prodrugs), for example, those that may exist due to chiral carbons on various substituents, including enantiomers (which may exist without chiral carbons), rotational isomers, atropisomers, and diastereomers, are considered to be included in the scope of this disclosure, as are positional isomers (e.g., 4-pyridyl and 3-pyridyl). (For example, if the compound represented by formula (I) incorporates a double bond or fused ring, both cis and trans forms, as well as mixtures thereof, are included in the scope of this disclosure. Also, for example, all keto-enol and imine-enamine forms of the compound are included in this disclosure.) The individual stereoisomers of the compounds of this disclosure may, for example, substantially contain no other isomers, or may be, for example, as a racemate, or mixed with all other stereoisomers or selected other stereoisomers. The chiral centers of this disclosure may be in an S configuration or an R configuration as defined by the recommendations of IUPAC 1974. The use of terms such as “salt,” “solvate,” “ester,” and “prodrug” is intended to apply equally to the salts, solvates, esters, and prodrugs of the enantiomers, stereoisomers, rotational isomers, tautomers, positional isomers, racemates, or prodrugs of the compounds of the present invention.

[0086] (Pharmaceutical composition) In some embodiments, the Disclosure provides compositions comprising the compounds provided herein, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, adjuvants, or vehicles. The amount of the compound in the compositions of the Disclosure is such that it is clearly effective in inhibiting PAD4 in a biological sample or patient. In certain embodiments, the amount of the compound in the compositions of the Disclosure is such that it is clearly effective in inhibiting PAD4 in a biological sample or patient. In some embodiments, the compositions provided herein are formulated for administration to patients in need of such a composition. In some embodiments, the compositions provided herein are formulated for oral administration to patients.

[0087] The compositions provided in this disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable reservoir. As used herein, “parenteral” includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, subarachnoid, intrahepatic, intrafocal, and intracranial infusions or drips. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable formulations of the compositions provided in this disclosure may be aqueous solutions or oily suspensions. These suspensions may be formulated according to art-known techniques using appropriate dispersants or wetting and suspending agents. The sterile injectable formulations may be sterile injectable solutions or suspensions in a non-toxic, parenterally acceptable diluent or solvent (e.g., 1,3-butanediol solution). Acceptable vehicles and solvents that may be used include water, Ringer's solution, and sodium chloride isotonic solution. Furthermore, sterile, non-volatile oils are conventionally used as solvents or suspending agents.

[0088] For this purpose, any sterile, non-volatile oil, including synthetic monoglycerides or diglycerides, may be used. Fatty acids (e.g., oleic acid and its glyceride derivatives) are useful in the manufacture of injectable preparations, and pharmaceutically acceptable natural oils (e.g., olive oil or castor oil), especially those polyoxyethylated, are also useful. These oils or suspensions also include diluents or dispersants of long-chain alcohols (e.g., carboxymethylcellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions). Other commonly used surfactants (e.g., Tweens, Spans, and other emulsifiers or bioavailability-enhancing substances commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms) may be used for formulation.

[0089] The pharmaceutically acceptable compositions provided herein may be administered orally in any acceptable oral formulation, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. For oral tablets, commonly used carriers include lactose and corn starch. Lubricants (e.g., magnesium stearate) are also commonly added. For oral capsules, lactose and dried corn starch are useful diluents. If an aqueous suspension is required for oral administration, the active ingredient is combined with emulsifiers and suspending agents. Specific sweeteners, flavorings, or colorings may be added as needed.

[0090] Alternatively, the pharmaceutically acceptable compositions provided herein may be administered as rectal suppositories. These may be prepared by mixing with suitable non-irritating excipients so that they melt in the rectum, releasing the drug, as they are solid at room temperature but liquid at rectal temperature. Such substances include cocoa butter, beeswax, and polyethylene glycol.

[0091] The pharmaceutically acceptable compositions provided herein may be administered topically, particularly in the case of treatment targeting easily accessible sites or organs, including diseases of the eyes, skin, or lower gastrointestinal tract. Suitable topical formulations are readily manufactured for each of these sites or organs. Topical administration to the lower gastrointestinal tract may be effectively performed by rectal suppositories or suitable enema formulations. Topical transdermal patches may also be used. For topical administration, the pharmaceutically acceptable compositions provided may be formulated as suitable ointments containing the active ingredient suspended or dissolved in one or more carriers. Carriers used for topical administration of the compounds provided herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water.

[0092] Alternatively, the pharmaceutically acceptable compositions provided may be formulated as suitable lotions or creams containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0093] When administered to the eyes, the pharmaceutically acceptable composition provided may be formulated as a finely powdered suspension in sterile pH-adjusted isotonic saline, or preferably as a solution in sterile pH-adjusted isotonic saline, with or without the addition of a preservative (e.g., benzylalkonium chloride). Alternatively, when administered to the eyes, the pharmaceutically acceptable composition may be formulated as an ointment (e.g., petrolatum).

[0094] The pharmaceutically acceptable compositions provided herein may be administered by nasal aerosol or nasal inhalation. Such compositions may be prepared in accordance with techniques well known in the field of pharmaceutical formulations and may be prepared as a solution of physiological saline with benzyl alcohol or other suitable preservative, absorption enhancers to improve bioavailability, carbon fluoride, and / or other conventional solubilizers or dispersants.

[0095] Preferably, the pharmaceutically acceptable compositions provided in this disclosure are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions provided in this disclosure are administered without food. In other embodiments, the pharmaceutically acceptable compositions provided in this disclosure are administered with food.

[0096] The pharmaceutically acceptable compositions provided herein may be administered to humans and other animals, as needed, orally, rectally, parenterally, intracisterna magna, vaginally, intraperitoneally, topically (e.g., powder, ointment, or eye drops), or buccally (e.g., orally or nasal spray). In certain embodiments, the compounds provided herein may be used to obtain the desired therapeutic effect. Depending on the subject's body weight, the drug may be administered orally or parenterally at least once a day, at a dosage level of approximately 0.01 mg / kg to approximately 50 mg / kg, preferably approximately 1 mg / kg to approximately 25 mg / kg.

[0097] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art (e.g., water or other solvents), solubilizers, and emulsifiers (e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof). In addition to inert diluents, the oral composition may also contain adjuvants (e.g., humectants, emulsifiers, and suspending agents, sweeteners, flavorings, and fragrances).

[0098] Injectable formulations (e.g., sterile aqueous or oily suspensions for injection) may be formulated according to known techniques using appropriate dispersants or wetting and suspending agents. The sterile injectable formulation may be a sterile injection solution, suspension, or emulsion in a non-toxic, parenterally acceptable diluent or solvent (e.g., 1,3-butanediol solution). Among the acceptable vehicles and solvents, water, Ringer's solution, USP, and isotonic sodium chloride solution may be used. Furthermore, sterile non-volatile oils are conventionally used as solvents or suspending agents. For this purpose, any sterile non-volatile oil, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids (e.g., oleic acid) may also be used in the manufacture of injectable formulations.

[0099] Injectable formulations can be sterilized, for example, by filtration using a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injection solvent before use.

[0100] To prolong the effects of the compounds provided by this disclosure, it is often desirable to slow down the absorption of the compounds via subcutaneous or intramuscular injection. This can be achieved by using a suspension of crystalline or amorphous material with low solubility in water. In this case, the absorption rate of the compound depends on its dissolution rate, which may further depend on the size and shape of the crystals. Alternatively, slowing down the absorption of parenterally administered compounds can be achieved by dissolving or suspending the compound in an oily substance. Injectable depot formulations are prepared by forming a microencapsulation matrix of the compound in a biodegradable polymer such as polylactide / polyglycolide. The release rate of the compound can be controlled depending on the ratio of the compound to the polymer and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Injectable depot formulations may also be prepared by incorporating the compound into liposomes or microemulsions that are compatible with biological tissues.

[0101] Compositions for rectal or vaginal administration are preferably suppositories and can be prepared by mixing the compounds provided in this disclosure with a suitable non-irritating excipient or carrier (for example, cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity, releasing the active compound).

[0102] Solid formulations for oral administration include capsules, tablets, pills, powders, and granules. In such solid formulations, the active compound is at least one inert, pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate) and / or (a) fillers or bulking agents (e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid), (b) binders (e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia), (c) humectants (e.g., glycerol), and (d) disintegrants (e.g., agar, calcium carbonate, ja). (e) a syrup (e.g., potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate), (e) a solubility retarder (e.g., paraffin), (f) an absorption enhancer (e.g., quaternary ammonium compounds), (g) a wetting agent (e.g., cetyl alcohol and glycerol monostearate), (h) an absorbent (e.g., kaolin and bentonite clay), and (i) a lubricant (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof). In the case of capsules, tablets, and pills, the formulation may also include a buffer.

[0103] Similar types of solid compositions may be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid formulations of tablets, sugar-coated tablets, capsules, pills, and granules may be manufactured using coatings and shells (e.g., enteric coatings and other coatings well known in the pharmaceutical field). These may optionally contain opacifiers and may be compositions that release the active ingredient slowly, either only or preferentially, in specific parts of the intestinal tract. Examples of embedding compositions that can be used include polymer substances and waxes. Similar types of solid compositions may be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0104] The active compound may be microencapsulated with one or more of the excipients described above. Solid formulations of tablets, sugar-coated tablets, capsules, pills, and granules may be manufactured using coatings and shells (e.g., enteric coatings, sustained-release coatings, and other coatings well known in the pharmaceutical field). In such solid formulations, the active compound may be mixed with at least one inert diluent (e.g., sucrose, lactose, or starch). Such formulations may conventionally contain additives other than inert diluents (e.g., tableting lubricants such as magnesium stearate and microcrystalline cellulose, and other tableting aids). In the case of capsules, tablets, and pills, the formulations may contain buffers.

[0105] Topical or transdermal formulations of the compounds provided in this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers. Ophthalmic formulations, ear drops, and eye drops are also considered to be within the scope of this disclosure. Furthermore, this disclosure considers use in transdermal patches, which have the additional advantage of being able to deliver the compound into the body in a controlled manner. Such formulations may be manufactured by dissolving or dispersing the compound in a suitable solvent. Absorption enhancers may also be used to increase the amount of compound that passes through the skin. The rate may be controlled by using a release control membrane or by dispersing the compound in a polymer matrix or gel.

[0106] Depending on the intended method of administration, the disclosed compositions may be in solid, semi-solid, or liquid dosage forms, such as injections, tablets, suppositories, pills, sustained-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, and suspensions, sometimes in unit doses and consistent with conventional pharmaceutical practices. Similarly, they may be administered intravenously (both bolus and infusion), intraperitoneally, subcutaneously, or intramuscularly, all in forms well known to those skilled in the pharmaceutical art.

[0107] The amount of the compound of this disclosure that can be combined with a carrier material when manufacturing a single dosage form composition will vary depending on the target of treatment and the specific method of administration. Preferably, the composition provided should be formulated so that the inhibitor can be administered to a patient at a dose of 0.01 to 100 mg / kg (body weight) / day.

[0108] The compounds disclosed herein can be administered alone or in combination with one or more other therapeutic compounds. Combination therapy may involve administering the combination agent, or the compounds disclosed herein and one or more other therapeutic compounds alternately, or independently, or in combination with one or more other therapeutic compounds. Other such therapeutic agents include corticosteroids, rolipram, calfostine, cytokine-suppressing anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors (e.g., deoxyspergarine (DSG)); nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., ibuprofen, celecoxib, and rofecoxib); steroids (e.g., prednisone or dexamethasone); antiviral agents (e.g., abacavir); antiproliferative agents (e.g., methotrexate, leflunomide, FK506 (tacrolimus, Prograf)); cytotoxic agents (e.g., azathioprine and cyclophosphamide); TNF-α inhibitors (e.g., Tenidap, anti-TNF antibodies, or soluble TNF receptors); and rapamycin (sirolimus or rapamune), or derivatives thereof. The compounds of this disclosure may be administered in addition to chemotherapy, radiotherapy, immunotherapy, phototherapy, surgery, or a combination thereof, particularly for the treatment of tumors. Long-term treatment is also possible, as with adjunctive therapies in other treatment strategies as described above. Other treatments may include maintenance of the patient's condition after tumor regression, or prophylactic chemotherapy in patients at risk, for example.

[0109] These additional agents may be administered separately from the composition containing the compounds of the present invention as part of a multi-dosage regimen. Alternatively, these agents may be part of a single dosage form or mixed with the compounds of the present disclosure in a single composition. When administered as part of a multi-dosage regimen, the two activators may be administered simultaneously, sequentially, or alternately at regular intervals (usually within 5 hours).

[0110] As used herein, the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, the disclosed compounds may be administered together with other therapeutic agents in separate formulations or single dosage forms, simultaneously or sequentially. Accordingly, this disclosure provides a single dosage form comprising the disclosed compounds, additional therapeutic agents, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0111] In the compositions containing the additional therapeutic agents described above, the amounts of each of the provided compound and the additional therapeutic agent that can be combined with a carrier substance to form a single dosage form will vary depending on the target of treatment and the individual method of administration. Preferably, the compositions disclosed herein should be formulated so that the compound of the application is administered at a dose of 0.01 to 100 mg / kg (body weight) / day.

[0112] In the above composition containing an additional therapeutic agent, the additional therapeutic agent and the compound of this disclosure may act synergistically. Therefore, the amount of the additional therapeutic agent in such a composition is less than the amount required for monotherapy using that therapeutic agent alone.

[0113] The amount of additional therapeutic agent contained in the disclosed composition is less than or equal to the amount typically contained in a composition containing that additional therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the disclosed composition is in the range of about 50% to 100% of the amount typically contained in a composition containing that agent as the sole therapeutic active agent.

[0114] It should be understood that specific doses and treatment plans for any particular patient will vary depending on a variety of factors, including the activity of the specific compound used, age, weight, general health status, sex, diet, administration time, excretion rate, drug combinations, and the judgment of the treating physician and the severity of the individual disease or disorder being treated. The amount of the compounds of this disclosure in a composition will also vary depending on the individual compounds in the composition.

[0115] (Methods for synthesizing compounds) The compounds of this disclosure may be prepared by a variety of methods, including standard chemistry. A suitable synthetic route is illustrated in the following scheme.

[0116] Compounds represented by formula (I) can be prepared in part by methods known in the field of organic synthesis, as shown in the following synthesis scheme. In the scheme below, protecting groups for sensitive or reactive groups are used where necessary, according to general principles or general chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (TW Greene and PGM Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999). These groups are removed at appropriate stages of compound synthesis using methods readily apparent to those skilled in the art. Depending on the selection process and reaction conditions and sequence, those skilled in the art will understand whether or not a stereocenter is present in the compound represented by formula (I). Thus, this disclosure includes possible stereoisomers (unless explicitly stated in the synthesis), including not only racemic compounds but also individual enantiomers and / or diastereomers. If the desired compound is a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by the resolution of the final product or any suitable intermediate. The final product, intermediates, and starting materials may be separated by any appropriate method known in the art. See, for example, “Stereochemistry of Organic Compounds” by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0117] The compounds described herein may be prepared from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.

[0118] For example, the compounds of the present invention may be synthesized by the following methods, along with synthetic methods known in the field of synthetic organic chemistry, or variations thereof that are understood by those skilled in the art. Examples of such methods include, but are not limited to, the following. The compounds of the present invention may be synthesized by the following steps outlined in general schemes A, B, C, and D, which include different sequences for assembling intermediates. Starting materials are commercially available or prepared by known procedures described in reported literature or as illustrated. [ka] [ka] [ka] [ka] (wherein X1, X2, Y, R1, R2, R3, R4, R5, R6, R7, and L are as defined above (or their protected versions thereof), LG is fluorine, chlorine, bromine, iodine, halogen, -OH, -OTs, or other suitable leaving group, LG2 is fluorine, chlorine, bromine, iodine, halogen, or other suitable leaving group, and R 13 (It is either H or OH.)

[0119] (How to use) The compounds and compositions described herein are generally useful for inhibiting PAD4.

[0120] In this disclosure, the activity of compounds used as PAD4 inhibitors may be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that measure PAD4 inhibition. Detailed conditions for assays of compounds used as PAD4 inhibitors in this disclosure are shown in the following examples. In some embodiments, the provided compounds selectively inhibit PAD4 rather than PAD2.

[0121] As used herein, the terms “treatment,” “treat,” and “treating” mean improvement, reduction, delay of onset, or suppression of progression of one or more symptoms of the disease or disorder described herein. In some embodiments, treatment may be performed after the progression of one or more symptoms. In other embodiments, treatment may be performed before symptoms have developed. For example, treatment may be performed before symptoms develop in subjects who are susceptible to the disease (e.g., in terms of symptom history and / or genetic factors or other predisposing factors). Treatment may be continued after symptoms have subsided, for example, to prevent or delay recurrence.

[0122] Since the compounds provided are inhibitors of PAD4, they are useful for treating one or more diseases or disorders related to PAD4 enzyme activity. Therefore, in certain embodiments, the Disclosure provides a method for treating a disease or disorder related to PAD4 enzyme activity, comprising the step of administering the compounds of the Disclosure, or pharmaceutically acceptable compositions thereof, to a patient in need.

[0123] In some embodiments, a disease or disorder associated with PAD4 enzyme activity is a disease, symptom, or disorder involving inappropriate PAD4 activity. In some embodiments, a disease or disorder associated with PAD4 enzyme activity is selected from the group consisting of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, and psoriasis. In further embodiments, a disease or disorder associated with PAD4 enzyme activity is rheumatoid arthritis. In further embodiments, a disease or disorder associated with PAD4 enzyme activity is systemic lupus. In further embodiments, a disease or disorder associated with PAD4 enzyme activity is vasculitis. In further embodiments, a disease or disorder associated with PAD4 enzyme activity is cutaneous lupus erythematosus. In further embodiments, a disease or disorder associated with PAD4 enzyme activity is psoriasis.

[0124] In one embodiment, a method is provided for the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis, comprising administering a therapeutically effective amount of the compound provided, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, to a human subject in need of treatment.

[0125] In one embodiment, a method for treating rheumatoid arthritis is provided, comprising administering a therapeutically effective amount of a compound, stereoisomer, enantiomer, diastereomer, tautomer, or a pharmaceutically acceptable salt thereof to a human subject in need of treatment. In another embodiment, a method for treating systemic lupus is provided, comprising administering a therapeutically effective amount of a compound, stereoisomer, enantiomer, diastereomer, tautomer, or a pharmaceutically acceptable salt thereof to a human subject in need of treatment. In yet another embodiment, a method for treating vasculitis is provided, comprising administering a therapeutically effective amount of a compound, stereoisomer, enantiomer, diastereomer, tautomer, or a pharmaceutically acceptable salt thereof to a human subject in need of treatment. In yet another embodiment, a method for treating cutaneous lupus erythematosus is provided, comprising administering a therapeutically effective amount of a compound, stereoisomer, enantiomer, diastereomer, tautomer, or a pharmaceutically acceptable salt thereof to a human subject in need of treatment. In one embodiment, a method for treating psoriasis is provided, comprising administering a therapeutically effective amount of a compound, stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof to a human subject in need of treatment.

[0126] In some embodiments, diseases or disorders related to PAD4 enzyme activity include acid-induced lung injury, acne (PAPA), acute lymphoblastic leukemia, acute respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenal insufficiency, aging, AIDS, alcoholic hepatitis, alcoholic liver disease, allergic asthma, allergic bronchopulmonary aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, weight loss, angina pectoris, angioedema, anhidrotic ectodermal dysplasia, ankylosing spondylitis, anterior segment inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, and joint problems. Inflammation, asthma, arteriosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, Behçet's disease, Behçet's syndrome, Bell's palsy, beryllium lung, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysms, chemical sting-induced inflammation, chorioretinitis, chronic heart failure, chronic lung disease in premature infants, chronic lymphocytic leukemia, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue disease, corneal ulcer, Crohn's disease, cryopyrin-associated periodic fever syndrome, cryptococcosis, cystic fibrosis, interleukemia 1 receptor antagonist deficiency (DIRA), dermatitis, cutaneous endotoxemia, dermatomyositis, diffuse pontine glioma, endometriosis, endotoxemia, epicondylitis, pure red cell aplasia, familial amyloid polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth restriction, glaucoma, glomerular disease, glomerulonephritis, gout, gouty arthritis, graft-versus-host disease, gastrointestinal diseases, head trauma, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Schönlein purpura, hepatitis, hereditary periodic fever syndrome, herpes zoster, herpes simplex, HIV-1, Hodgkin's disease, Huntington's disease, pulmonary hyaline membrane disease, hyperammonemia, hypercalcemia Hypercholesterolemia, hyper-IgD syndrome with periodic fever (HIDS), aplastic anemia, other anemias, idiopathic thrombocytopenic purpura, incontinentia pigmenti, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, iritis, stimulus-induced inflammation, ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, renal damage due to parasitic infection, prevention of kidney transplant rejection, leptospirosis, leukemia, Loeffler's syndrome, lung injury, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, Macklewells syndrome (urticaria,Hearing loss, amyloidosis, multiple sclerosis, muscle weakness, muscular dystrophy, myasthenia gravis, myocarditis, mycosis fungoides, myelodysplastic syndrome, myositis, sinusitis, necrotizing enterocolitis, neonatal-onset multiorgan inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological disorders, non-allergen-induced asthma, obesity, ophthalmic allergies, optic neuritis, organ transplantation, osteoarthritis, otitis media, Paget's disease, pain, pancreatitis, Parkinson's disease, pectoris Acne, pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pertussis, pharyngitis and adenitis (PFAPA syndrome), plant irritation-induced inflammation, pneumonia, pneumonitis, Pneumocystis pneumonia, poison ivy / poison ivy oil-induced inflammation, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyositis, psoriasis, psychosomatic disorders, lung diseases, pulmonary hypertension, pulmonary fibrosis, pyoderma gangrenosum, suppurative aseptic arthritis, kidney disease Patients, retinal diseases, rheumatic heart disease, rheumatic diseases, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell disease, sickle cell anemia, silica-induced diseases, Sjögren's syndrome, skin diseases, sleep apnea syndrome, solid tumors, spinal cord injury, Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplantation, TNF receptor-associated periodic syndrome The group is selected from the following: TRAPS, toxoplasmosis, transplantation, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticaria, uveitis, granulomatosis with polyangiitis, interstitial pneumonia, psoriatic arthritis, juvenile idiopathic arthritis, Sjögren's syndrome, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, antiphospholipid syndrome, sepsis, deep vein thrombosis, fibrosis, Alzheimer's disease, scleroderma, and CRESTO syndrome.

[0127] In one embodiment, the disclosure provides a compound or a pharmaceutically acceptable salt thereof for therapeutic use. In another embodiment, the disclosure provides a compound or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder mediated by inadequate PAD4 activity. In another embodiment, the disclosure provides a compound or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis. In another embodiment, the disclosure provides a compound or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts for use in the treatment of rheumatoid arthritis. In another embodiment, the disclosure provides a compound or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts for use in the treatment of systemic lupus. In another embodiment, the disclosure provides compounds, or their stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts, for use in the treatment of vasculitis. In another embodiment, the disclosure provides compounds, or their stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts, for use in the treatment of cutaneous lupus erythematosus. In another embodiment, the disclosure provides compounds, or their stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts, for use in the treatment of psoriasis. In another embodiment, the disclosure provides the use of compounds, or their stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts, in the manufacture of pharmaceuticals for use in the treatment of disorders involving inappropriate PAD4 activity. In another embodiment, the Disclosure provides the use of a compound, or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis.In another embodiment, the Disclosure provides the use of a compound, or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts, in the manufacture of a medicament for the treatment of rheumatoid arthritis. In another embodiment, the Disclosure provides the use of a compound, or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts, in the manufacture of a medicament for the treatment of systemic lupus. In another embodiment, the Disclosure provides the use of a compound, or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts, in the manufacture of a medicament for the treatment of vasculitis. In another embodiment, the Invention provides the use of a compound, or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts, in the manufacture of a medicament for the treatment of cutaneous lupus erythematosus. In another embodiment, the Disclosure provides the use of a compound, or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for use in the treatment of psoriasis. In a further embodiment, the Disclosure provides a medicament composition for treating or preventing a disease or disorder in which inappropriate PAD4 activity is involved, comprising the provided compound, or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof. In a further embodiment, the Disclosure provides a medicament composition for treating or preventing rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis, comprising the provided compound, or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof. In further embodiments, the Disclosure provides pharmaceutical compositions for treating or preventing rheumatoid arthritis, comprising a compound provided, or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts.In further embodiments, the Disclosure provides a pharmaceutical composition for treating or preventing systemic lupus, comprising a provided compound, or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof. In further embodiments, the Disclosure provides a pharmaceutical composition for treating or preventing vasculitis, comprising a provided compound, or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof. In further embodiments, the Disclosure provides a pharmaceutical composition for treating or preventing cutaneous lupus erythematosus, comprising a provided compound, or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof. In further embodiments, the Disclosure provides a pharmaceutical composition for treating or preventing psoriasis, comprising a provided compound, or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof. [Examples]

[0128] The following examples were prepared, isolated, and characterized using the methods of the present disclosure. These examples represent a portion of the scope of the present disclosure and do not constitute an limitation of the scope of the present disclosure. [Table 1] [Table 2] [Table 3]

[0129] (Analysis Procedure and Method) Description of preparative HPLC and analytical LC-MS methods: Method A: Column: XBridge Prep Shield RP C18, 30 *150 mm, 5 μm; Mobile phase A: 0.05% TFA containing water, Mobile phase B: ACN; Flow rate: 25 mL / min; Gravity: 24% B ~ 37% B / 8 min; Wavelength: 254 nm / 220 nm.

[0130] Method B: カラム:HALO 90A C18, 3.0 * 30 mm, 2.0 μm; Mobile phase A: 0.05% TFA containing water, Mobile phase B: ACN + 0.05% TFA; Flow rate: 1.5 mL / min; [Gradient]; Wavelength: 254 nm. Table 4

[0131] Method C: カラム: SunFire C18 OBD Prep, 19 * 250 mm, 5 μm; Mobile phase A: 0.05% TFA containing water, Mobile phase B: ACN; Flow rate: 25 mL / min; 32% B~36% B / 6.5 min, 36% B; Wavelength: 254 / 210 nm.

[0132] Method D: カラム: Shim-pack Scepter C18, 3.0 * 33 mm, 3.0 μm; Mobile phase A: 5 mM NH4HCO3 containing water; Mobile phase B: ACN; Flow rate: 1.5 mL / min; [Gradient]; Wavelength: 254 nm. Table 5

[0133] Method E: カラム:Xselect CSH Prep C18, 30 * 150mm, 5μm; Mobile phase A: 0.05% TFA containing water; Mobile phase B: ACN; [Flow rate]; [Gradient]; Wavelength: 254nm / 220nm. Table 6

[0134] Method F: カラム:XBridge Prep OBD C18, 30 *150mm, 5μm; Mobile phase A: 10mM NH4HCO3 / water, Mobile phase B: ACN; Flow rate: 60mL / min; 22% B~52% B / 10 min; Wavelength: 254nm / 220nm

[0135] Method G: Column: XBridge Prep Phenyl OBD C18, 19 * 250 mm, 5 μm; Mobile phase A: water containing 0.05% TFA, Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 22% B~52% B / 10 min; Wavelength: 254 nm / 220 nm.

[0136] Method H: Column: HALO C18, 4.6 * 100 mm, 2.7 μm; Mobile phase A: Water containing 0.05% TFA, Mobile phase B: ACN + 0.05% TFA; Flow rate: 1.5 mL / min; Gradient: 10% B to 95% B / 6 min, hold at 95% for 2 min, 95% B to 5% B / 2 min; Wavelength: 254 nm.

[0137] Method I: Columns: XBridge C18, 19 * 200 mm, 5 μm; Mobile phase A: 0.05% TFA in water / ACN 95:5, Mobile phase B: 0.05% TFA in water / ACN 5:95; Flow rate: 20 mL / min; [Gradient]; Wavelength: 220 nm. [Table 7]

[0138] Method J: Column: XBridge C18, 2.1 * 50, 1.7 μm; Mobile phase A: 0.05% TFA-containing water / ACN 95:5; Mobile phase B: 0.05% TFA-containing water / ACN 5:95; Flow rate: 1.0 mL / min; Gradient: 0% B to 100% B for 3 minutes, hold at 100% B for 0.5 minutes; Wavelength: 220 nm.

[0139] Method K: Column: HALO C18, 3.0 *30 mm, 3.0 μm; Mobile phase A: water containing 0.05% TFA, Mobile phase B: 0.05% TFA / ACN; Flow rate: 1.5 mL / min; [Gradient]; Wavelength: 254 nm. [Table 8]

[0140] (Synthesis Examples) The compounds of the present invention can be prepared by numerous methods well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized by the following methods, along with synthetic methods well known to those skilled in the art of synthetic organic chemistry, or by variations thereof that will be understood by those skilled in the art. Examples of such methods include, but are not limited to, the following. The compounds of the present invention can be synthesized by the following skips outlined in general schemes A, B, C, and D, which involve different sequences for assembling intermediates. Starting materials are commercially available or can be prepared by known procedures described in reported literature or as illustrated. Example 1 (R)-2,5,5-trimethyl-1 2 -(3-methyl-7-(((S)-morpholin-3-yl)methyl)-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyridine-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka] Synthesis of intermediate 1I: [ka]

[0141] Synthesis of intermediate 1A To a solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (10.0 g, 47.5 mmol) / DMF (500 mL), NaH (60% w / w, 5.6 g, 233 mmol) was added in several batches under nitrogen at 0°C, and the resulting mixture was stirred at room temperature for 0.5 hours. The reaction mixture was cooled to 0°C, and (2-(chloromethoxy)ethyl)trimethylsilane (16.0 g, 96.0 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 5 hours, then diluted with water (2 L), and extracted with ethyl acetate (2 L). The organic layers were combined and diluted with water (2 L). * 2L) and saline solution (2 * The product was washed with 2L of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 5:1) to obtain intermediate 1A (12g) as a white oily substance. LCMS (ESI, m / z): 341 [M+H] + .

[0142] Synthesis of intermediate 1B To a solution of intermediate 1A (12 g, 35.2 mmol) / 1,4-dioxane (400 mL), tributyl(1-ethoxyvinyl) stannane (20 g, 55 mmol), DavePhos (3.0 g, 7.6 mmol), and Pd(dppf)Cl2 (3.0 g, 3.7 mmol) were added under nitrogen, and the resulting mixture was stirred overnight at 90°C in a sealed container. This reaction mixture was acidified with aqueous HCl (1 M, 100 mL), stirred at room temperature for 0.5 hours, then diluted with water (1 L), and ethyl acetate (2 * Extracted with 1L of water. Combine the organic layer with water (2 * The product was washed with 2 L of ether and 2 L of saline solution, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 4:1) to obtain intermediate 1B (10 g) as a yellow solid. LCMS (ESI, m / z): 349 [M+H] + .

[0143] Synthesis of intermediate 1C To a solution of intermediate 1B (10.0 g, 28.7 mmol) in THF (200 mL), (S)-2-methylpropane-2-sulfinamide (14 g, 115 mmol) and Ti(OiPr)4 (65 g, 230 mmol) were added under nitrogen, and the resulting mixture was stirred overnight at 60°C. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (1 L). The solid was filtered, and the filtrate was diluted with water (1 L) and ethyl acetate (2 * Extraction was performed using 2 L of water. The organic layers were washed together with water (3 L) and saline solution (3 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 2:1) to obtain intermediate 1C (8 g) as a yellow solid. LC-MS (ESI, m / z): 480 [M+H] + .

[0144] Synthesis of intermediate 1D To a solution of intermediate 1C (8.0 g, 16.7 mmol) / THF (200 mL), L-selectride (2 M / THF, 20 mL) was added in several batches under nitrogen at -78 °C, and the resulting mixture was stirred at -78 °C for 6 hours. The reaction product was then quenched with saturated NH4Cl aqueous solution (500 mL) at 0 °C, and ethyl acetate (2 * Extraction was performed using 500 mL of solution. The organic layers were washed together with saline solution (1000 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 1:1) to obtain intermediate 1D (7 g) as a yellow solid. LC-MS (ESI, m / z): 482 [M+H] + .

[0145] Synthesis of intermediate 1E A solution of intermediate 1D (6.0 g, 12.5 mmol) / HCl (4 M / siRNA, 150 mL) was stirred at room temperature for 3 hours and then concentrated under vacuum. The crude product was diluted with saturated NaHCO3 aqueous solution (1 L), and then THF (200 mL) and Boc2O (3.5 g, 16.0 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours and then ethyl acetate (2 *Extraction was performed using 1 L of water, washed with water (2 L) and saline solution (2 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 3:1). The obtained substance was re-purified by flash column chromatography using C18 silica (mobile phase A: 0.5% TFA-containing water, mobile phase B: acetonitrile, gradient: 30% to 100% of solution B). The pure fraction was concentrated under vacuum, the organic solvent was removed, and the remaining aqueous solution was freeze-dried to obtain intermediate 1E (3.5 g) as a white solid. LCMS (ESI, m / z): 348 [M+H] + .

[0146] Synthesis of intermediate 1F To a solution of tert-butyl 8-bromo-2,2-dimethyloctanoate (1.5 g, 4.9 mmol, International Publication No. 2021 / 222353) / DMF (50 mL), Cs2CO3 (4.8 g, 14.6 mmol) and intermediate 1E (1.7 g, 4.9 mmol) were added under nitrogen, and the resulting mixture was stirred at 65°C for 1 hour. The reaction product was then diluted with water (200 mL) and ethyl acetate (2 * Extracted with 200 mL of water. Combined the organic layer with water (2 * 400 mL) and saline solution (2 * The product was washed with 400 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 5:1) to obtain intermediate 1F (1.8 g) as a yellow solid. LCMS (ESI, m / z): 574 [M+H] + .

[0147] Synthesis of intermediate 1G To a solution of intermediate 1F (1.8 g, 3.1 mmol) in DCM (30 mL), TFA (6 mL) was added. The resulting mixture was stirred at room temperature for 3 hours, then concentrated under vacuum to obtain crude intermediate 1 G (1.2 g) as a yellow oily substance. LCMS (ESI, m / z): 418 [M+H] + .

[0148] Synthesis of intermediate 1H To a solution of 1G (1.6g, 3.8 mmol) of intermediate and HATU (1.8g, 4.6 mmol) / DMF (30 mL), DIPEA (1.5 mL, 19.2 mmol) was added under nitrogen at room temperature. The resulting mixture was stirred at room temperature for 1 hour, then diluted with water (150 mL), and ethyl acetate (2 * Extracted with 150 mL of water. Combined the organic layer with water (2 * 300 mL) and saline solution (2 * The solution was washed with 300 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the intermediate 1H (700 mg) as a white solid. LC-MS (ESI, m / z): 400 [M+H] + .

[0149] Synthesis of intermediate 1I To a solution of intermediate 1H (400 mg, 1 mmol) / methanol (10 mL) and water (5 mL), NaOH (200 mg, 5 mmol) was added at room temperature, and the resulting mixture was stirred at 50°C for 2 hours. The reaction mixture was acidified to pH 2 with aqueous HCl (1 M), stirred at room temperature for 0.5 hours, and then ethyl acetate (2 * Extracted with 30 mL of saline solution. The organic layer was combined with saline solution (2 * The solution was washed with 60 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain intermediate 1I (350 mg) as a white solid. LC-MS (ESI, m / z): 358 [M+H] + .

[0150] Synthesis of intermediate 1J To a solution of tert-butyl 2-chloro-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (20.0 g, 74.4 mmol) / ethyl acetate (500 mL), a solution of NaIO4 (47.8 g, 223 mmol) / water (250 mL) was added under nitrogen at 0°C. The resulting mixture was stirred at 0°C for 10 minutes, and then RuCl3 (2.31 g, 11.2 mmol) was added little by little. The resulting mixture was stirred overnight at 15°C, and then diluted with saturated Na2SO3 aqueous solution (1 L) and ethyl acetate (2 *Extraction was performed using 1 L of solution. The organic layers were washed together with saline solution (2.5 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 4:1) to obtain 1 J (20 g) of intermediate as a brown solid. LCMS (ESI, m / z): 283 [M+H] + .

[0151] Synthesis of intermediate 1K To a solution of intermediate 1 J (1 g, 3.54 mmol) in DCM (30 mL), TFA (6 mL) was added. The resulting mixture was stirred at room temperature for 1 hour, and then concentrated under vacuum to obtain crude intermediate 1 K (1.2 g). LC-MS (ESI, m / z): 183 [M+H] + .

[0152] Synthesis of 1 L of intermediate To a solution of the crude intermediate in 1K (1.2g) / THF (60mL), NaH (60% w / w, 789mg, 32.9 mmol) was added in several batches under nitrogen at 0°C, and the resulting mixture was stirred at room temperature for 0.5 hours. The reaction mixture was cooled to 0°C, and (R)-tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1,1-dioxide (1.77g, 9.86 mmol, J. Med. Chem. 2019, 62, 18, 8609) was added. The resulting mixture was stirred at room temperature for 2 hours, then diluted with water (300mL), and ethyl acetate (2 * Extraction was performed using 300 mL of water. The organic layers were washed together with saline solution (600 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography using C18 silica (mobile phase A: 0.5% TFA-containing water, mobile phase B: ACN, gradient: 0% B to 50% B) to obtain 1 L (3 g) of the intermediate as a yellow oily substance. LCMS (ESI, m / z): 382 [M+H] + .

[0153] Synthesis of intermediate 1M A solution of 1 L (2.5 g, 6.91 mmol) of the intermediate in methanol (15 mL) and HCl (2 M / Depositphotos, 15 mL) was stirred in a sealed container at 50°C for 2 hours. The solid was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography using C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 0% B to 50% B) to obtain 1 M (830 mg) of the intermediate as a yellow solid. LCMS (ESI, m / z): 282 [M+H] + .

[0154] Synthesis of intermediate 1N The mixture of intermediate 1M (600 mg, 2.13 mmol), NaHCO3 (1.08 g, 10.6 mmol), and Boc2O (930 mg, 4.26 mmol) / THF (20 mL) and water (20 mL) was stirred overnight at room temperature. The mixture was then diluted with water (100 mL) and ethyl acetate (2 * Extraction was performed using 100 mL of water. The organic layers were washed together with water (200 mL) and saline solution (200 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the intermediate 1N (620 mg) as a white solid. LCMS (ESI, m / z): 382 [M+H] + .

[0155] Synthesis of intermediate 1O To a solution of intermediate 1N (620 mg, 1.62 mmol) / glycol (8 mL, 1.62 mmol) and t-BuOH (8 mL, 1.62 mmol), N-methyl-1-phenylmethaneamine (1.97 g, 16.2 mmol) was added, and the resulting mixture was stirred at 50°C for 2 days. The solid was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 5:1) to obtain intermediate 1O (400 mg) as a white solid. LCMS (ESI, m / z): 467 [M+H] + .

[0156] Synthesis of intermediate 1P To a solution of intermediate 1O (400 mg, 0.86 mmol) / H2SO4 (5 mL, 93.9 mmol), KNO3 (260 mg, 2.57 mmol) was gradually added at 0°C, and the resulting mixture was stirred at 20°C for 3 hours. This reaction mixture was poured into ice water (100 mL) and ethyl acetate (2 * The sample was washed with 100 mL of water. The remaining aqueous phase was left untreated and proceeded directly to the next step. LCMS (ESI, m / z): 322 [M+H] + .

[0157] Synthesis of intermediate 1Q To the aqueous solution from the previous step, NaHCO3 (1.45 g, 14.3 mmol), Boc2O (392 mg, 1.79 mmol), and THF (50 mL) were added. The resulting mixture was stirred overnight at room temperature, then diluted with water (50 mL), and ethyl acetate (2 * Extraction was performed using 150 mL of solution. The organic layers were washed together with water (300 mL) and saline solution (300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 2:3) to obtain intermediate 1Q (260 mg). LCMS (ESI, m / z): 422 [M+H] + .

[0158] Synthesis of intermediate 1R To a solution of intermediate 1Q (260 mg, 0.62 mmol) in methanol (3 mL), a solution of NH4Cl (330 mg, 6.17 mmol) in water (3 mL) was added dropwise, followed by the gradual addition of zinc powder (403 mg, 6.17 mmol). The resulting mixture was stirred at room temperature for 3 hours. The solid was filtered, and the filtrate was concentrated under vacuum. The residue was then diluted with water (50 mL) and ethyl acetate (2 mL). * The mixture was diluted to 50 mL. The organic layers were washed together with water (100 mL) and saline solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (100% ethyl acetate) to obtain intermediate 1R (200 mg) as a yellow solid. LCMS (ESI, m / z): 392 [M+H] + .

[0159] Synthesis of intermediate 1S To a solution of intermediate 1I (100 mg, 0.3 mmol) and DIPEA (109 mg, 0.8 mmol) / DMF (3 mL), HATU (128 mg, 0.3 mmol) was added under nitrogen at room temperature. The resulting mixture was stirred at room temperature for 10 minutes, and then added dropwise to a solution of intermediate 1R (110 mg, 0.3 mmol) / DMF (1 mL) at room temperature. The resulting mixture was stirred overnight at 40°C, and then diluted with water (20 mL) and ethyl acetate (2 * Extracted with 20 mL of water. Combined the organic layer with water (2 * 40 mL) and saline solution (2 * The sample was washed with 40 mL of solution, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 3:1) to obtain intermediate 1S (150 mg) as a yellow solid. LC-MS (ESI, m / z): 731 [M+H] + .

[0160] Synthesis of intermediate 1T A solution of intermediate 1S (130 mg, 0.2 mmol) in acetic acid (3 mL) was stirred overnight at 100°C. The resulting solution was concentrated under vacuum to obtain intermediate 1T (120 mg) as a yellow oily substance, which was then removed without further processing and proceeded directly to the next step. LCMS (ESI, m / z): 713 [M+H] + .

[0161] Synthesis of Example 1 To a solution of intermediate 1T (120 mg, 0.17 mmol) / DCM (4 mL), TFA (1 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method A, RT: 7.8 min). The pure fraction was concentrated under vacuum to remove the organic solvent, and the remaining aqueous solution was freeze-dried to obtain Example 1 (43.6 mg) as a white solid. 1H NMR (400MHz, DMSO-d6)δ 9.03(s, br, 1H), 8.92(s, br, 1H), 8.52(s, 1H), 8.08(d, J=8.0Hz, 1H), 7.85(d , J=7.6Hz, 1H), 7.26(s, 1H), 7.21(d, J=8.0Hz, 1H), 5.17-5.12(m, 1H), 4.96- 4.85(m, 1H), 4.68-4.64(m, 1H), 4.02(s, 3H), 4.01-3.89(m, 3H), 3.81-3.66( m, 4H), 3.60-3.48(m, 2H), 3.37-3.31(m, 3H), 3.11-3.07(m, 1H), 1.98-1.89(m 1H), 1.68-1.66(m, 2H), 1.45-1.33(m, 8H), 1.21(s, 3H), 1.11-1.08(m, 2H), 0.95(s, 3H). LCMS(ESI, m / z):613[M+H] + . LCMS RT: 0.69 min (Method B1). Example 2 (R)-2,5,5-trimethyl-1 2 -(1-methyl-6-(((S)-morpholine-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0162] Synthesis of intermediate 2A To a solution of 6-fluoro-3,4-dihydro-2H-isoquinoline-1-one (5.0 g, 30.2 mmol) / THF (300 mL), NaH (60% w / w, 0.90 g, 36.3 mmol) was added in several batches under nitrogen at 0°C, and the resulting mixture was stirred at room temperature for 0.5 hours. The reaction mixture was cooled to 0°C, and (R)-tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1,1-dioxide (6.51 g, 36.3 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours, then cooled to 0°C, quenched with water (5 mL), and concentrated under vacuum. The crude product was purified by flash column chromatography using C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 0% B to 100% B) to obtain intermediate 2A (9g) as a yellow solid. LCMS (ESI, m / z): 345 [M+H] + .

[0163] Synthesis of intermediate 2B To a solution of intermediate 2A (9.0 g, 26.1 mmol) in methanol (200 mL), aqueous HCl (2 M, 30 mL) was added. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. The crude product was purified by flash column chromatography using C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 0% B~100% B) to obtain intermediate 2B (6 g) as a yellow solid. LCMS (ESI, m / z): 256 [M+H] + .

[0164] Synthesis of intermediate 2C To a solution of intermediate 2B (6.0 g, 22.7 mmol) / H2SO4 (60 mL), KNO3 (6.9 g, 68.1 mmol) was gradually added at 0°C, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water (500 mL) and ethyl acetate (2 * The sample was washed with 500 mL of water. The remaining aqueous phase was left untreated and proceeded directly to the next step. LCMS (ESI, m / z): 310 [M+H] + .

[0165] Synthesis of 2D intermediates To the aqueous solution from the previous step, Na2CO3 (19.6 g, 185 mmol), THF (100 mL), and Boc2O (4.2 g, 19.4 mmol) were added. The resulting mixture was stirred overnight at room temperature, and then ethyl acetate (2 * Extraction was performed using 500 mL of water. The organic layers were washed together with water (1 L) and saline solution (1 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 2:3) to obtain intermediate 2D (2 g) as a yellow solid. LC-MS (ESI, m / z): 410 [M+H] + .

[0166] Synthesis of intermediate 2E To a solution of intermediate 2D (2.0 g, 4.89 mmol) and methylamine hydrochloride (0.7 g, 9.77 mmol) / MeCN (50 mL), DIPEA (1.9 g, 14.7 mmol) was added at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. The solid was filtered, and the filtrate was concentrated under vacuum. The resulting crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 1:5) to obtain intermediate 2E (1 g) as a yellow solid. LCMS (ESI, m / z): 421 [M+H] + .

[0167] Synthesis of intermediate 2F To a solution of intermediate 2E (1.0 g, 2.38 mmol) in methanol (24 mL), a solution of NH4Cl (1.27 g, 23.8 mmol) in water (6 mL) was added, followed by the gradual addition of zinc powder (1.55 g, 23.8 mmol). The resulting mixture was stirred at room temperature for 3 hours. The solid was filtered, and the filtrate was concentrated under vacuum. The residue was diluted with water (100 mL) and ethyl acetate (2 * Extraction was performed using 100 mL of water. The organic layers were washed together with water (200 mL) and saline solution (200 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (100% ethyl acetate) to obtain intermediate 2F (700 mg) as a yellow solid. LC-MS (ESI, m / z): 391 [M+H] + .

[0168] Synthesis of intermediate 2G To a solution of intermediate 1I (80 mg, 0.22 mmol) in DMF (4 mL), HATU (128 mg, 0.34 mmol) and DIPEA (0.05 mL, 0.67 mmol) were added at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 10 minutes, followed by the addition of intermediate 2F (105 mg, 0.27 mmol). The resulting mixture was stirred overnight at room temperature and then purified using flash column chromatography with C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 0% B~100% B) to obtain intermediate 2G (140 mg) as a yellow solid. LCMS (ESI, m / z): 730 [M+H] + .

[0169] Synthesis of intermediate 2H A solution of intermediate 2G (180 mg, 0.24 mmol) / AcOH (10 mL, 174 mmol) was stirred at 70°C for 3 hours. The mixture was concentrated under vacuum to obtain crude intermediate 2H (150 mg) as a yellow solid. LC-MS (ESI, m / z): 712 [M+H] + .

[0170] Synthesis of Example 2 To a solution of intermediate 2H (150 mg, 0.21 mmol) / DCM (3 mL), TFA (1 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method C, RT: 5.17 min). The pure fraction was concentrated under vacuum to remove the organic solvent, and the remaining aqueous solution was freeze-dried to obtain Example 2 (117 mg) as a white solid. 1H NMR(400MHz, DMSO-d6+D2O)δ 8.27(s, 1H), 8.06(d, J=8.0Hz, 1H), 7.61(s, 1H), 7.20(d, J=8.0Hz, 1H), 7.13(s, 1H), 5.25-5.05(m, 1H), 4.85-4.87(m, 1H), 4.54-4.50(m, 1H), 4.03-3.90(m, 6H), 3.75-3. 69(m, 2H), 3.64-3.52(m, 3H), 3.32-3.19(m, 4H), 3.11-3.01(m, 1H), 1.97-1.87(m, 1H) ), 1.75-1.51(m, 2H), 1.50-1.26(m, 8H), 1.21(s, 3H), 1.15-0.98(m, 2H), 0.95(s, 3H). LCMS(ESI, m / z):612[M+H] + . LCMS RT: 1.247 min (Method B2). Example 3 (R)-1 2 -(7-((S)-2-amino-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyridine-2-yl)-2,5,5-trimethyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one Synthesis of Example 3 from intermediate 1J: [ka] Synthesis of 3G from methyl (2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoate: [ka]

[0171] Synthesis of intermediate 3A To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoate (90 g, 410 mmol) and imidazole (30.7 g, 452 mmol) / DCM (900 mL), TBSCl (80.4 g, 534 mmol) was added at 0°C. The resulting mixture was stirred at 20°C for 2 hours, then diluted with water (1 L) at 0°C, and DCM (3 * Extracted with 800 mL of saline solution. The organic layer was then combined with saline solution (2 * The mixture was washed in 1 L, dried with anhydrous Na2SO4, filtered, and concentrated to obtain crude intermediate 3A (140 g) as a pale yellow oily substance. 1 H NMR (400MHz, CDCl3)δ:5.34(d, J=8.4Hz, 1H), 4.36(d, J=8.8Hz, 1H), 4.06(d, J=2.4Hz, 1 H), 4.03(d, J=2.4Hz, 1H), 3.75(s, 3H), 1.46(s, 9H), 0.87(s, 9H), 0.03(d, J=5.2Hz, 6H).

[0172] Synthesis of intermediate 3B To a suspension of LiAlH4 (27.9 g, 734 mmol) / THF (1.2 L), a solution of intermediate 3A (144 g, 432 mmol) / THF (300 mL) was added at 0°C, and the resulting mixture was stirred at 0°C for 1 hour. The reaction product was then quenched with saturated NH4Cl aqueous solution (800 mL), the solid was filtered, and the filtrate was ethyl acetate (2 * Extraction was performed using 800 mL of brine. The organic layers were washed together with 800 mL of saline solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain crude intermediate 3B (110 g) as a pale yellow oily substance. 1 H NMR (400MHz, CDCl3) δ: 5.06 (s, 1H), 3.75-3.58 (m, 4H), 2.70-2.61 (m, 1H), 1.38 (s, 9H), 0.82 (s, 9H), 0.00 (s, 6H).

[0173] Synthesis of intermediate 3C To a solution of imidazole (147 g, 2.16 mol) / DCM (700 mL), a solution of SOCl2 (77.1 g, 648 mmol) / DCM (400 mL) was added at 0°C, and the resulting mixture was stirred at 18°C ​​for 1 hour. The reaction mixture was cooled to -10°C, and a solution of intermediate 3B (110 g, 360 mmol) / DCM (600 mL) was added. The resulting mixture was stirred at 18°C ​​for 1 hour, then diluted with citric acid aqueous solution (10%, 800 mL), and then diluted with DCM (2 * Extracted with 1L of water. Combine the organic layer with water (2 * The mixture was washed in 1 L, dried with anhydrous Na2SO4, filtered, and concentrated to obtain crude intermediate 3C (104 g) as a pale yellow oily substance. 1 H NMR (400MHz, CDCl3)δ: 5.00-4.98(m, 1H), 4.83-4.72(m, 2H), 4.07-4.03(m, 1H), 3.79-3.72(m, 1H), 1.53(s, 9H), 0.89(s, 9H), 0.07(s, 6H).

[0174] Synthesis of 3D intermediates Two batches were performed in parallel. To a solution of intermediate 3C (52 g, 148 mmol) / MeCN (1000 mL), RuCl3 (30.7 mg, 148 μmol) and NaIO4 (31.6 g, 148 mmol) / H2O (500 mL) were added at 18°C. The resulting mixture was stirred at 18°C ​​for 1 hour, then the two batches were combined, diluted with water (1 L), and DCM(2 * Extracted with 1L of water. Combine the organic layer with water (2 * The mixture was washed with 500 mL of water, dried over anhydrous Na2SO4, filtered, and concentrated to obtain crude intermediate 3D (80 g) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ: 4.64-4.58 (m, 2H), 4.28-4.27 (m, 1H), 3.89-3.76 (m, 2H), 1.56 (s, 9H), 0.90 (s, 9H), 0.09 (s, 6H).

[0175] Synthesis of intermediate 3E To a solution of intermediate 3D (85 g, 231 mmol) / THF (850 mL), TBAF (1 M, 277 mL) was added. The resulting mixture was stirred at 20°C for 1 hour, then diluted with saturated NH4Cl aqueous solution (100 mL), and ethyl acetate (2 * Extracted with 800 mL. Combined the organic layer with water (2 * The solution was washed with 500 mL of water, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 2:1) to obtain intermediate 3E (20 g) as a pale yellow oily substance. 1 H NMR (400MHz, CDCl3) δ: 5.05 (d, J=7.6Hz, 2H), 4.57-4.44 (m, 2H), 3.81-3.73 (m, 3H), 1.45 (s, 9H).

[0176] Synthesis of intermediate 3F To a solution of imidazole (42.3 g, 621 mmol) / DCM (200 mL), a solution of SOCl2 (22.2 g, 186 mmol) / DCM (200 mL) was added dropwise at 0°C, and the resulting mixture was stirred at 20°C for 1 hour. The reaction mixture was cooled to -10°C, and a solution of intermediate 3E (20 g, 103 mmol) / DCM (200 mL) was added dropwise. The resulting mixture was stirred at 20°C for 1 hour, then diluted to pH=5 with 10% citric acid solution, and mixed with DCM (3 * Extracted with 300 mL of saline solution. The organic layer was then combined with saline solution (2 * The mixture was washed with 200 mL of water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude intermediate 3F (22 g) as a yellow oily substance. 1 H NMR (400MHz, CDCl3) δ: 5.29-4.97 (m, 2H), 4.86-4.57 (m, 2H), 4.42-4.10 (m, 3H), 1.52 (s, 9H).

[0177] Synthesis of intermediate 3G To a solution of intermediate 3F (22 g, 91.9 mmol) / MeCN (440 mL), RuCl3 (191 mg, 919 μmol) and NaIO4 (19.7 g, 91.9 mmol) / water (220 mL) were added dropwise under nitrogen. The resulting mixture was stirred at 20°C for 1 hour, then filtered, and the filtered cake was washed with DCM (300 mL). The filtrate was diluted with water (300 mL) and extracted with DCM (800 mL). The organic layers were combined and diluted with water (2 * 300 mL), saline solution (2 * The mixture was washed with 200 mL of water, dried over anhydrous Na2SO4, filtered, and concentrated to obtain 3 g (17.5 g) of crude intermediate as a yellow solid. 1 H NMR (400MHz, CDCl3) δ: 4.73-4.53 (m, 5H), 1.57 (s, 9H).

[0178] Synthesis of intermediate 3H Two batches were carried out in parallel. N-methyl-1-phenyl-methaneamine (42.9 g, 354 mmol) was added to a solution of intermediate 1 J (20.0 g, 70.7 mmol) / tert-butanol (400 mL) and glycol (400 mL). The resulting mixture was stirred at 50°C for 16 hours and then concentrated to remove t-BuOH. The residue was purified by silica column flash chromatography (petroleum ether:ethyl acetate = 30:1~5:1) to obtain intermediate 3H (40 g) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ:7.40(d, J=9.2Hz, 1H), 7.35-7.21(m, 5H), 6.67(d, J=9.2Hz, 1H ), 4.87(s, 2H), 3.87(t, J=6.0Hz, 2H), 3.11(s, 3H), 2.91(t, J=6.0Hz, 2H), 1.48(s, 9H).

[0179] Synthesis of intermediate 3I To a solution of the intermediate 3H (28.0 g, 76.2 mmol) / DCM (300 mL), TFA (158 g, 1.39 mol) was added dropwise at 0°C. The resulting mixture was stirred at 20°C for 1 hour and then concentrated. The residue was diluted with DCM (200 mL), and the pH was adjusted to 8 with saturated Na2CO3 aqueous solution. *Extraction was performed using 200 mL of solution. The organic layers were washed together with saline solution (400 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain intermediate 3I (17.5 g) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ:7.83(d, J=8.8Hz, 1H), 7.54(s, 1H), 7.33-7.20(m, 5H), 6.58 (d, J=8.8Hz, 1H), 4.84(s, 2H), 3.38-3.35(m, 2H), 3.07(s, 3H), 2.81(t, J=6.8Hz, 2H).

[0180] Synthesis of intermediate 3J To a solution of intermediate 3G (11.0 g, 43.1 mmol) in DMF (220 mL), NaH (60% w / w, 2.30 g, 57.4 mmol) was added in several portions at 0°C, and the resulting mixture was stirred at 0°C for 30 minutes. Then, intermediate 3I (7.68 g, 28.7 mmol) was added in several portions. The resulting mixture was stirred at 20°C for 2 hours, then quenched with saturated NH4Cl aqueous solution (80 mL) at 0°C, diluted with water (300 mL) and ethyl acetate (100 mL), and ethyl acetate (2 * Extracted with 200 mL of water. Combined the organic layer with water (2 * The mixture was washed with 200 mL of water and 100 mL of saline solution, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica column flash chromatography (DCM / MeOH = 50:1 to 20:1) to obtain intermediate 3J (9.7 g) as a yellow oily substance. 1 H NMR (400MHz, DMSO-d6) δ:7.87(d, J=8.8Hz, 1H), 7.33-7.29(m,2H), 7.24-7.19(m,3H), 6.94(d, J=8.8Hz, 1H), 6.25(d, J=8.8Hz, 1H), 4.86(s, 2H), 4.50-4.31(m, 2H), 3.59-3.54(m, 4H), 3.08(s, 3H), 1.32(s, 9H).

[0181] Synthesis of intermediate 3K Two batches were carried out in parallel. To a solution of intermediate 3J (6g, 13.6 mmol) / H2SO4 (60 mL), KNO3 (5.50 g, 54.4 mmol) was added in several batches at 0°C, and the resulting mixture was stirred at 20°C for 3 hours. The two batches were poured into ice water (1 L) and ethyl acetate (2 * Washed with 300 mL. The aqueous layer was slowly basicized with Na2CO3, then THF (1.2 L) and Boc2O (3.55 g, 16.27 mmol) were added. The resulting mixture was stirred at 25°C for 16 hours, then ethyl acetate (2 * Extraction was performed using 2 L of water. The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 10:1 to 1:1) to obtain the intermediate 3K (4.13 g) as a yellow solid. 1 H NMR (400MHz, DMSO-d6)δ: 8.86(d, J=4.8Hz, 1H), 8.65(s, 1H), 6.98(d, J=8.8Hz, 1H), 4.45(d, J=5.6Hz, 1H), 4. 35(d, J=5.2Hz, 1H), 3.68-3.32(m, 4H), 3.08(s, 3H), 3.07-3.02(m, 2H), 1.31(s, 9H).

[0182] Synthesis of intermediate 3L To a solution of intermediate 3K (10.0 g, 22.6 mmol) in methanol (200 mL), a solution of NH4Cl (12.1 g, 226 mmol) in water (50 mL) was added, followed by the gradual addition of zinc powder (14.5 g, 226 mmol). The resulting mixture was stirred at room temperature for 2 hours. The solid was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography using C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 0% B~50% B) to obtain 3 L (7.6 g) of the intermediate as a pale yellow solid. LCMS (ESI, m / z): 368 [M+H] + .

[0183] Synthesis of Example 3 Example 3 (88.6 mg) was prepared as a white solid from intermediate 3L and intermediate 1I using the same synthesis protocol as in Example 1. 1 H NMR (400MHz, DMSO-d6)δ 8.51(s, 1H), 8.31(s, br, 3H), 8.07(d, J=8.0Hz, 1H), 7.85(d, J=7.2Hz, 1H), 7.29(s, 1 H), 7.23(d, J=8.0Hz, 1H), 5.17-5.13(m, 1H), 4.91-4.78(m, 1H), 4.81-4.50(m, 3H), 4. 02(s, 3H), 3.77-3.73(m, 5H), 3.35-3.31(m, 2H), 1.97-1.93(m, 1H), 1.70-1.66(m, 2H) ), 1.46-1.44(m, 4H), 1.42-1.27(m, 4H), 1.21(s, 3H), 1.17-1.13(m, 2H), 0.95(s, 3H). LCMS(ESI, m / z):589[M+H] + . LCMS RT: 1.312 min (Method B2). Example 4 (R)-1 2 -(6-((S)-2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-2,5,5-trimethyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0184] Synthesis of intermediate 4A To a solution of 6-fluoro-3,4-dihydro-2H-isoquinoline-1-one (1.6 g, 10 mmol) / DMF (100 mL), NaH (600 mg, 15 mmol) was added in several batches under nitrogen at 0°C, and the resulting mixture was stirred at room temperature for 0.5 hours. The reaction mixture was cooled to 0°C, and intermediate 3G (3.1 g, 12 mmol) was added in several batches. The resulting mixture was stirred at room temperature for 2 hours, then quenched with water (300 mL), and extracted with ethyl acetate (300 mL). The organic layers were combined and cooled with water (2 *300 mL) and saline solution (2 * The solution was washed with 300 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 1:1) to obtain intermediate 4A (1.0 g) as a yellow solid. LCMS (ESI, m / z): 341 [M+H] + .

[0185] Synthesis of intermediate 4B To a solution of intermediate 4A (1.0 g, 2.9 mmol) in MeCN (30 mL), methylamine (2 M / THF, 1.5 eq) was added at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. The solution was concentrated under vacuum, and the crude product was purified by silica column flash chromatography (DCM / MeOH = 10:1) to obtain intermediate 4B (1.0 g) as a pale yellow solid. LCMS (ESI, m / z): 352 [M+H] + .

[0186] Synthesis of intermediate 4C To a solution of intermediate 4B (1.0 g, 2.9 mmol) / H2SO4 (10 mL), KNO3 (1.17 g, 11.6 mmol) was added in several batches at 0°C, and the resulting mixture was stirred at room temperature for 3 hours. The mixture was then placed in ice water (50 mL) and ethyl acetate (2 * Washed with 30 mL. The aqueous layer was basicized to pH 9-10 with saturated Na2CO3 aqueous solution, then THF (50 mL) and Boc2O (759 mg, 3.5 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours, then ethyl acetate (2 * Extraction was performed using 150 mL of solution, and the organic layers were combined and dried over anhydrous sodium sulfate. The mixture was then concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 1:2) to obtain intermediate 4C (800 mg) as a yellow solid. LC-MS (ESI, m / z): 397 [M+H] + .

[0187] Synthesis of intermediate 4D To a solution of intermediate 4C (500 mg, 1.26 mmol) and NH4Cl (510 mg, 9.53 mmol) in methanol (9 mL) and water (3 mL), zinc powder (620 mg, 9.48 mmol) was gradually added, and the resulting mixture was stirred at room temperature for 2 hours. The solid was filtered, and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography using C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 0% B~50% B) to obtain intermediate 4D (400 mg) as a white solid. LCMS (ESI, m / z): 367 [M+H] + .

[0188] Synthesis of Example 4 Example 4 was prepared as a white solid from intermediate 4D and intermediate 1I using the same synthesis protocol as in Example 2. 1 H NMR (400MHz, DMSO-d6)δ 8.31(s, 3H), 8.27(s, 1H), 8.05(d, J=8.4Hz, 1H), 7.84(d, J=7.2Hz, 1H), 7.60(s, 1H), 7.19(d, J=8.4Hz, 1H), 7.12(s, 1H), 5.19- 5.09(m, 1H), 4.94-4.47(m, 4H), 3.96(s, 3H), 3.85-3.79(m, 2H), 3.70-3.65(m, 3H), 3.23-3.21(m, 2H), 1.99-1.89(m, 1H), 1.75 -1.56(m, 2H), 1.52-1.28(m, 8H), 1.21(s, 3H), 1.14-1.03(m, 2H), 0.94(s, 3H). LCMS(ESI, m / z):588[M+H] + LCMS RT: 1.255 min (Method B2). Example 5 (R)-1 2 -(1-Cyclopropyl-6-(((S)-Morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-2,5,5-trimethyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0189] Synthesis of intermediate 5A To a solution of intermediate 1I (200 mg, 0.56 mmol) in THF (8 mL), LiAlH4 (2.5 M / THF, 1.1 mL, 2.8 mmol) was added dropwise under nitrogen at 0°C, and the resulting mixture was stirred at room temperature for 2 hours. The reaction product was then quenched sequentially with water (0.1 mL), saturated NaHCO3 aqueous solution (0.3 mL), and water (0.1 mL), and stirred at room temperature for 20 minutes. The mixture was then dried over anhydrous sodium sulfate, the solid was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography using C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 0% B~100% B) to obtain intermediate 5A (150 mg) as a yellow solid. LCMS (ESI, m / z): 344 [M+H] + .

[0190] Synthesis of intermediate 5B To a solution of intermediate 5A (150 mg, 0.44 mmol) in DCM (5 mL), MnO2 (380 mg, 4.37 mmol) was added at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. The solid was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 3:1) to obtain intermediate 5B (120 mg) as a yellow solid. LC-MS (ESI, m / z): 342 [M+H] + .

[0191] Synthesis of intermediate 5C To a solution of intermediate 2D (2.4 g, 5.86 mmol) / DMF (60 mL), Cs2CO3 (5.72 g, 17.6 mmol) and cyclopropylamine (670 mg, 11.7 mmol) were added under nitrogen, and the resulting mixture was stirred at room temperature for 1 hour. The reaction product was then quenched with water (200 mL), and ethyl acetate (2 * Extracted with 200 mL of water. Combined the organic layer with water (2 * 400 mL) and saline solution (2 *The solution was washed with 400 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 1:2) to obtain intermediate 5C (1.6 g) as a yellow solid. LC-MS (ESI, m / z): 447 [M+H] + .

[0192] Synthesis of intermediate 5D Pd / C (480 mg, 4.53 mmol) was added to a reaction flask under nitrogen, followed by ethyl acetate (100 mL), DCM (5 mL), and intermediate 5C (1.6 g, 3.58 mmol). The reaction flask was degassed and repacked with nitrogen (3x) followed by hydrogen (3x). The resulting mixture was stirred under hydrogen at room temperature for 4 hours, then the solid was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography using C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 0% B~60% B) to obtain intermediate 5D (600 mg) as a yellow solid. LCMS (ESI, m / z): 417 [M+H] + .

[0193] Synthesis of intermediate 5E Oxone (144 mg, 0.23 mmol) was added to a solution of intermediate 5B (80 mg, 0.23 mmol) and intermediate 5D (97.6 mg, 0.23 mmol) in DMF (1.5 mL) and water (0.05 mL). The resulting solution was stirred at room temperature for 2 hours, then diluted with water (10 mL), and ethyl acetate (2 * Extracted with 10 mL. Combined the organic layer with water (2 * 20 mL) and saline solution (2 * The sample was washed with 20 mL of solution, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 1:2) to obtain intermediate 5E (80 mg) as a white solid. LC-MS (ESI, m / z): 738 [M+H] + .

[0194] Synthesis of Example 5 To a solution of intermediate 5D (100 mg, 0.14 mmol) / DCM (5 mL), TFA (1 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method A, RT: 7.8 min). The pure fraction was concentrated under vacuum to remove the organic solvent, and the remaining aqueous solution was freeze-dried to obtain Example 5 (69.1 mg) as a white solid. 1 H NMR(400MHz, DMSO-d6+D2O)δ 8.26(s, 1H), 8.06(d, J=8.0Hz, 1H), 7.64(s, 1H), 7.28(s, 1H), 7.19(d, J=8.0Hz, 1H), 5.18-5.10(m, 1H) ), 4.96-4.87(m, 1H), 4.69-4.58(m, 1H), 4.03-3.91(m, 3H), 3.79-3.70(m, 3H), 3.68-3.57(m, 3H), 3.56 -3.49(m, 1H), 3.34-3.19(m, 3H), 3.13-3.04(m, 1H), 1.97-1.85(m, 1H), 1.68-1.63(m, 1H), 1.52-1.41( m, 4H), 1.39-1.28(m, 5H), 1.29-1.22(m, 4H), 1.17-1.05(m, 2H), 1.03-0.88(m, 5H), 0.46-0.42(m, 1H). LCMS(ESI, m / z):638[M+H] + . LCMS RT: 1.004 min (Method D1). Example 6 (R)-1 2 -(9-fluoro-1-methyl-6-(((S)-morpholine-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-2,5,5-trimethyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0195] Synthesis of intermediate 6A To a solution of 2-(3-chloro-2-fluorophenyl)acetonitrile (10.0 g, 58.9 mmol) / THF (134 mL), BH3 (1 M / THF, 134 mL, 134 mmol) was added under nitrogen at room temperature. The resulting mixture was stirred in a sealed container at 70°C for 2 hours, then added dropwise to methanol at 0°C, and stirred at 0°C for 20 minutes. The mixture was concentrated under vacuum to obtain crude intermediate 6A (5.7 g) as a yellow oily substance. LCMS (ESI, m / z): 174, 176 [M+H] + .

[0196] Synthesis of intermediate 6B To a solution of triphosgene (5.7 g, 19.5 mmol) / DCM (48 mL), intermediate 6A (1.1 g, 6.50 mmol) and Et3N (22.6 mL, 13.0 mmol) / DCM (24 mL) were added under nitrogen at 0°C, and the resulting mixture was stirred at room temperature for 2 hours. The solid was filtered, and the filtrate was added dropwise to a solution of AlCl3 (5.2 g, 39.0 mmol) / DCM (50 mL) under nitrogen at 0°C. The resulting mixture was stirred overnight at room temperature, then quenched with water (200 mL), and acidified with aqueous HCl (4 M) until the mixture became a clear solution, and then DCM (2 * Extraction was performed using 200 mL of solution. The organic layers were washed together with saline solution (400 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (100% ethyl acetate) to obtain intermediate 6B (2 g) as a yellow oily substance. LC-MS (ESI, m / z): 200, 202 [M+H] + .

[0197] Synthesis of intermediate 6C To a solution of intermediate 6B (500 mg, 2.50 mmol) in THF (25 mL), NaH (60% w / w, 90 mg, 3.76 mmol) was added in several portions under nitrogen at 0°C, and the resulting mixture was stirred at room temperature for 0.5 hours. The reaction mixture was cooled to 0°C, and (R)-tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1,1-dioxide (673 mg, 3.76 mmol) was added in several portions. The resulting mixture was stirred at room temperature for 0.5 hours, then quenched with saturated NH4Cl aqueous solution (1 mL), and purified using flash column chromatography with C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 15% B~90% B) to obtain a sulfonic acid intermediate as a yellow solid. This was added to HCl (4 M / MeOH, 10 mL) and stirred in a sealed container at 50°C for 1 hour. The reaction mixture was concentrated under vacuum to obtain intermediate 6C (400 mg) as a yellow oil. LCMS (ESI, m / z): 299, 301 [M+H] + .

[0198] Synthesis of intermediate 6D To a solution of intermediate 6C (150 mg, 0.5 mmol) / H2SO4 (2 mL), KNO3 (202 mg, 2.01 mmol) was added gradually at 0°C, and the resulting mixture was stirred at room temperature for 2 hours. This reaction mixture was added dropwise to ice water and stirred for 10 minutes, then ethyl acetate (2 * Washed with 10 mL. The remaining aqueous layer was left untreated and proceeded to the next step. LCMS (ESI, m / z): 344, 346 [M+H] + .

[0199] Synthesis of intermediate 6E The aqueous solution from the previous step was adjusted to pH 8 with saturated NaHCO3 aqueous solution (10 mL), and then Boc2O (76.4 mg, 0.35 mmol) / THF (5 mL) was added. The resulting mixture was stirred overnight at room temperature, and then ethyl acetate (2 *Extraction was performed using 40 mL of solution. The organic layers were washed together with saline solution (80 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 5:1) to obtain intermediate 6E (120 mg) as a pale yellow solid. LC-MS (ESI, m / z): 444, 446 [M+H] + .

[0200] Synthesis of intermediate 6F To a solution of intermediate 6E (120 mg, 0.27 mmol) and DIPEA (104 mg, 0.81 mmol) / MeCN (3 mL), methylamine (2 M / THF, 0.81 mL) was added, and the resulting mixture was stirred overnight in a sealed container at 50°C. This reaction mixture was purified by flash column chromatography using C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 5% B~85% B / 25 min) to obtain intermediate 6F (100 mg) as a white solid. LCMS (ESI, m / z): 439 [M+H] + .

[0201] Synthesis of intermediate 6G To a solution of intermediate 6F (100 mg, 0.23 mmol) / methanol (4 mL), a solution of NH4Cl (122 mg, 2.28 mmol) / water (2 mL) was added, followed by the gradual addition of zinc powder (119 mg, 1.82 mmol). The resulting mixture was stirred at room temperature for 3 hours. The solid was filtered, and the filtrate was concentrated under vacuum. The residue was diluted with water (20 mL) and ethyl acetate (3 mL) was added. * Extraction was performed using 20 mL of solution. The organic layers were washed together with saline solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography using C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 0% B~60% B) to obtain 6 G (75 mg) of intermediate as a white solid. LC-MS (ESI, m / z): 409 [M+H] + .

[0202] Synthesis of Example 6 Example 6 (37.8 mg) was prepared as a white solid from intermediate 6G (75 mg, 0.18 mmol) and intermediate 1I using the same synthesis protocol as in Example 2. 1 H NMR(400MHz, DMSO-d6+D2O)δ 8.12(s, 1H), 8.06(d, J=8.4Hz, 1H), 7.20(d, J=8.4Hz, 1H), 7.12(s, 1H), 5.12-5.10(m, 1H), 4.90-4.80(m, 1H), 4.49-4.50(m, 1H), 4.11(s, 3H), 3.97-3.89(m, 3H), 3.78-3.76(m, 2H), 3.75-3.63(m, 3H), 3.48-3.47 (m, 1H), 3.31-3.28(m, 1H), 3.21-3.12(m, 2H), 3.11-3.00(m, 1H), 2.55-2.52(m, 1H), 1.92-1.89(m, 1H), 1 .71-1.50(m, 2H), 1.44(d, J=6.8Hz, 3H), 1.42-1.32(m, 4H), 1.20(s, 3H), 1.09-1.02(m, 2H), 0.93(s, 3H). LCMS(ESI, m / z):630[M+H] + . LCMS RT: 0.735 min (Method B1). Example 7 (R)-1 2 -(9-Methoxy-1-methyl-6-(((S)-Morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-2,5,5-trimethyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0203] Synthesis of intermediate 7A To a solution of intermediate 2E (1.1 g, 2.62 mmol) in DMF (26 mL), NBS (698 mg, 3.92 mmol) was added under nitrogen. The resulting mixture was stirred overnight at room temperature, then diluted with water (130 mL), and ethyl acetate (2 * Extracted with 130 mL of water. Combine the organic layer with water (2* 260 mL) and saline solution (2 * The solution was washed with 260 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (100% ethyl acetate) to obtain intermediate 7A (1.05 g) as a yellow solid. LC-MS (ESI, m / z): 499, 501 [M+H] + .

[0204] Synthesis of intermediate 7B To a solution of intermediate 7A (70 mg, 0.14 mmol) and intermediate 5B (72 mg, 0.21 mmol) in ethanol (1 mL) and water (0.5 mL), Na2S2O4 (97 mg, 0.56 mmol) was added. The resulting mixture was stirred at room temperature for 6 hours, then diluted with water (5 mL), and ethyl acetate (2 * Extraction was performed using 5 mL of water. The organic layers were washed together with water (10 mL) and saline solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (DCM / MeOH = 20:1) to obtain intermediate 7B (80 mg) as a pale yellow solid. LC-MS (ESI, m / z): 790, 792 [M+H] + .

[0205] Synthesis of intermediate 7C To a solution of intermediate 7B (80 mg, 0.10 mmol) and KOH (39 mg, 0.30 mmol) / methanol (2.5 mL) and 1,4-dioxane (2.5 mL), Pd2(dba)3 (18 mg, 0.02 mmol) and t-BuBrettPhos (33 mg, 0.04 mmol) were added under nitrogen. The resulting mixture was stirred in a sealed container at 100°C for 2 hours, then diluted with water (15 mL), and ethyl acetate (2 * Extraction was performed using 15 mL of solution. The organic layers were washed together with water (30 mL) and saline solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 4:1) to obtain intermediate 7C (14 mg) as a pale yellow solid. LCMS (ESI, m / z): 742 [M+H] + .

[0206] Synthesis of Example 7 To a solution of intermediate 7C (14 mg, 0.02 mmol) / DCM (2 mL), TFA (0.5 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method E1, RT: 8.63 min). The pure fraction was concentrated under vacuum to remove the organic solvent, and the remaining aqueous solution was freeze-dried to obtain Example 7 (6.2 mg) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ 9.15-8.82(m, 2H), 8.07-8.05(m, 2H), 7.83(d, J=7.2Hz, 1H), 7.19(d, J=8.0Hz, 1H), 7.09(s, 1H) ), 5.13-5.10(m, 1H), 4.86-4.81(m, 1H), 4.47-4.46(m, 1H), 4.09(s, 3H), 4.08-4.02(m, 2H), 3. 91(s, 3H), 3.90-3.88(m, 2H), 3.73-3.61(m, 4H), 3.59-3.05(m, 5H), 1.92-1.88(m, 1H), 1.72-1 .66(m, 2H), 1.59-1.57(m, 3H), 1.46-1.35(m, 5H), 1.32(s, 3H), 1.23-1.06(m, 2H), 0.94(s, 3H). LCMS(ESI, m / z):642[M+H] + . LCMS RT: 1.459 min (Method B2). Example 8 (R)-1 2 -(1,9-dimethyl-6-(((S)-morpholine-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-2,5,5-trimethyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0207] Synthesis of intermediate 8A To a solution of intermediate 7B (70 mg, 0.09 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatrivolinane (11 mg, 0.09 mmol) / 1,4-dioxane (3 mL), PEPPSI-IPr (12 mg, 0.02 mmol) and K2CO3 (36 mg, 0.27 mmol) were added under nitrogen. The resulting mixture was stirred at 80°C for 10 hours, then diluted with water (9 mL), and ethyl acetate (2 * Extraction was performed using 9 mL of water. The organic layers were washed together with water (18 mL) and saline solution (18 mL), then dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 1:2) to obtain intermediate 8A (40 mg) as a pale yellow solid. LCMS (ESI, m / z): 726 [M+H] + .

[0208] Synthesis of Example 8 To a solution of intermediate 8A (40 mg, 0.05 mmol) / DCM (2 mL), TFA (0.5 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method F, RT: 8.7 min). The pure fraction was concentrated under vacuum, the organic solvent was removed, and the remaining aqueous solution was freeze-dried to obtain Example 8 (15.2 mg) as a white solid. LC-MS (ESI, m / z): 626 [M+H] + . LCMS RT: 1.377 min (Method B2). Example 9 (R)-2-methyl-1 2 -(1-methyl-6-(((S)-morpholine-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridina-5(1,2)-benzenacyclodecafan-4-one [ka]

[0209] Synthesis of intermediate 9A To a solution of intermediate 1E (5 g, 14.4 mmol) in THF (150 mL), LiAlH4 (2.5 M / THF, 29 mL) was added dropwise under nitrogen at 0°C, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then quenched sequentially with water (2.7 mL), saturated NaHCO3 aqueous solution (8.1 mL), and water (2.7 mL), and stirred at room temperature for 20 minutes. The mixture was then dried over anhydrous sodium sulfate, the solid was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 1:1) to obtain intermediate 9A (4 g) as a white solid. LCMS (ESI, m / z): 292 [M+H] + .

[0210] Synthesis of intermediate 9B To a solution of intermediate 9A (4 g, 13.7 mmol) in DCM (150 mL), MnO2 (11.9 g, 137 mmol) was added at room temperature, and the resulting mixture was stirred for 2 hours. The solid was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 3:1) to obtain intermediate 9B (3.5 g) as a pale yellow solid. LCMS (ESI, m / z): 290 [M+H] + .

[0211] Synthesis of intermediate 9C To a solution of intermediate 9B (1.4 g, 4.8 mmol) and intermediate 2E (2.1 g, 4.8 mmol) in ethanol (30 mL) and water (15 mL), Na2S2O4 (2.1 g, 24.2 mmol) was added. The resulting mixture was stirred overnight at 90°C, then diluted with water (150 mL), and ethyl acetate (2 * Extraction was performed using 150 mL of water. The organic layers were washed together with water (300 mL) and saline solution (300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (DCM / MeOH = 15:1) to obtain intermediate 9C (1.5 g) as a yellow solid. LC-MS (ESI, m / z): 660 [M+H] + .

[0212] Synthesis of intermediate 9D In a solution of intermediate 9C (120 mg, 0.18 mmol) / DMF (2 mL), Cs2CO3 (177 mg, 0.55 mmol) and tert-butyl 2-(5-(tosyloxy)pentyl)benzoate were added under nitrogen. * (91 mg, 0.22 mmol) was added. The resulting mixture was stirred at 50°C for 2 hours, then diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was then diluted with water (2 * 10 mL) and saline solution (2 * The sample was washed with 10 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 4:1) to obtain intermediate 9D (100 mg) as a pale yellow solid. LC-MS (ESI, m / z): 907 [M+H] + . * The preparation was carried out according to a synthesis protocol similar to that described in International Publication No. 2021 / 222353.

[0213] Synthesis of intermediate 9E To a solution of intermediate 9D (100 mg, 0.11 mmol) in DCM (2 mL), TFA (0.5 mL) was added. The resulting mixture was stirred at room temperature for 16 hours, then concentrated under vacuum to obtain intermediate 9E (70 mg) as a white solid. LCMS (ESI, m / z): 650 [M+H] + .

[0214] Synthesis of Example 9 To a solution of intermediate 9E (70 mg, 0.11 mmol) and DIPEA (42 mg, 0.32 mmol) / DMF (2 mL), HATU (62 mg, 0.16 mmol) was added under nitrogen at room temperature. The mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method G, RT: 8.57 min). The pure fraction was concentrated under vacuum to remove the organic solvent, and the remaining aqueous solution was freeze-dried to obtain Example 9 (35 mg) as a yellow solid. 1H NMR (400MHz, DMSO-d6)δ 9.09-9.03(m, 1H), 9.00-8.84(m, 2H), 8.26(s, 1H), 8.08(d, J=8.0Hz, 1H), 7.62(s, 1H), 7.35-7.29 (m, 2H), 7.24-7.17(m, 4H), 5.20-5.16(m, 1H), 4.92-4.88(m, 1H), 4.81-4.78(m, 1H), 4.02-3.88(m , 6H), 3.74-3.71(m, 2H), 3.69-3.61(m, 3H), 3.59-3.56(m, 1H), 3.35-3.20(m, 3H) 3.12-3.05(m, 1H) ), 2.40-2.33(m, 2H), 2.21-2.13(m, 1H), 1.61-1.44(m, 5H), 1.32-1.05(m, 2H), 0.62-0.43(m, 1H). LCMS(ESI, m / z):632[M+H] + . LCMS RT: 2.968 min (Method H).

[0215] Example 10 (R)-2-methyl-1 2 -(1-methyl-6-(((S)-morpholine-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-1 1 H-6-oxa-3-aza-1(6,1)-pyrrolo[2,3-b]pyridina-5(1,2)-benzenacyclodecafan-4-one [ka]

[0216] Synthesis of Example 10 Example 10 was prepared as a white solid from intermediate 9C and tert-butyl 2-(4-bromobutoxy)benzoate (International Publication No. 2021 / 222353) using the same synthesis protocol as in Example 9. 1H NMR (400MHz, DMSO-d6)δ 9.75(d, J=6.8Hz, 1H), 9.13(s, br, 1H), 8.96(s, br, 1H), 8.31(s, 1H), 8.15(d, J=8.0Hz, 1H), 8.11-8.08(m, 1H), 7.64(s, 1H), 7 .56-7.48(m, 1H), 7.33(d, J=8.0Hz, 1H), 7.22(d, J=8.4Hz, 1H), 7.16(s, 1H), 7.01-7.08(m, 1H), 5.40-5.30(m, 1H), 4.96-4.88( m, 1H), 4.51-4.41(m, 2H), 4.35-4.28(m, 1H), 4.11-4.08(m, 1H), 4.03(s, 3H), 3.99-3.85(m, 2H), 3.79-3.49(m, 3H), 3.39-3.29 (m, 3H), 3.28-3.19(m, 3H), 3.14-3.02(m, 1H), 2.68-2.58(m, 1H), 2.31-2.28(m, 1H), 1.96-1.93(m, 2H), 1.57(d, J=6.4Hz, 3H). LCMS(ESI, m / z):634[M+H] + . LCMS RT: 1.630 min (Method D2). Example 11 (R)-2-methyl-1 2 -(1-methyl-6-(((S)-morpholine-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0217] Synthesis of intermediate 11A To a solution of tert-butyl 8-hydroxyoctanoate (500 mg, 2.31 mmol) / DCM (20 mL), Et3N (1.15 g, 11.4 mmol), DMAP (60 mg, 0.49 mmol), and TsCl (1.30 g, 6.81 mmol) were added in several portions under nitrogen at 0°C. The resulting mixture was stirred overnight at room temperature, then diluted with water (20 mL), and dissolved in DCM (2 mL). *Extraction was performed using 20 mL of solution. The organic layers were washed together with saline solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 5:1) to obtain intermediate 11A (600 mg) as a colorless oil. LC-MS (ESI, m / z): 371 [M+H] + .

[0218] Synthesis of Example 11 Example 11 was prepared as a white solid from intermediate 9C and intermediate 11A using the same synthesis protocol as in Example 9. 1 H NMR (400MHz, DMSO-d6)δ 9.02(s, br, 1H), 8.88(s, br, 1H), 8.35(d, J=8.8Hz, 1H), 8.27(s, 1H), 8.05(d, J=8.0Hz, 1H), 7.61(s, 1H), 7.19 (d, J=8.0Hz, 1H), 7.15(s, 1H), 5.25-5.20(m, 1H), 5.03-4.99(m, 1H), 4.71-4.69(m, 1H), 4.05-4.00(m, 1H), 3. 99(s, 3H), 3.98-3.88(m, 2H), 3.74-3.63(m, 2H), 3.61-3.53(m, 5H), 3.26-3.20(m, 2H), 3.12-3.02(m, 2H), 2.1 0-2.06(m, 2H), 1.68-1.66(m, 1H), 1.58-1.33(m, 6H), 1.17-1.11(m, 2H), 1.03-0.97(m, 2H), 0.69-0.58(m, 1H). LCMS(ESI, m / z):584[M+H] + . LCMS RT: 0.781 min (Method D1). Example 12 (R)-2-methyl-1 2 -(1-methyl-6-(((S)-morpholine-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridina-5(2,3)-pyrazinacyclodecafan-4-one [ka]

[0219] Synthesis of intermediate 12A A mixture of (Z)-tert-butyl N,N'-diisopropylcarbamimidate (329 μL, 1.478 mmol) and 3-bromopyrazine-2-carboxylic acid (100 mg, 0.493 mmol) / THF (2.2 mL) was heated to 60°C and stirred overnight. The reaction mixture was then diluted with ethyl acetate, washed with water (2X) and saline solution, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by column silica chromatography (0-100% ethyl acetate / hexane) to obtain intermediate 12A (112.7 mg). 1 H NMR (400MHz, DMSO-d6) δ 8.79-8.71 (m, 1H), 8.70-8.63 (m, 1H), 1.59 (s, 9H).

[0220] Synthesis of intermediate 12B Intermediate 12B was synthesized from intermediate 12A following a synthesis protocol similar to that described in International Publication No. 2021 / 222353 for the chloride variant of intermediate 12A. LCMS(ESI, m / z): 421[M+H] + .

[0221] Synthesis of intermediate 12C A mixture of intermediate 9C (50 mg, 0.076 mmol), intermediate 12A-2 (38.2 mg, 0.091 mmol), and cesium carbonate (54.3 mg, 0.167 mmol) / DMF (997 μL) was heated to 65°C and stirred overnight. After returning to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water (2X) and saline solution, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (DCM / MeOH) to obtain intermediate 12C (65.5 mg). LCMS (ESI, m / z): 908 [M+H] + .

[0222] Synthesis of intermediate 12D To a solution of intermediate 12C (65.5 mg, 0.072 mmol) in DCM (160 μL), HCl (4.0 M / dioxane, 721 μL, 2.89 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour, then concentrated under a nitrogen stream to dryness to obtain crude intermediate 12D. LCMS (ESI, m / z): 652 [M+H] + .

[0223] Synthesis of Example 12 To a mixture of intermediate 12D and HATU (82 mg, 0.216 mmol) / DMF (2.9 mL), DIPEA (63 μL, 0.36 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour, then concentrated under a nitrogen stream to a total volume of ~2 mL. The remaining mixture was filtered, and the filtrate was purified by preparative HPLC (Method I1). The fraction containing the desired product was vacuum-dried. The purified substance was then diluted with 3 mL of a 1:1 mixture of ethylene dichloride and methanol, treated with Si-pyridine, and shaken for a minimum of 2 hours. The resulting mixture was filtered and vacuum-dried to obtain Example 12 (18.9 mg). LCMS (ESI, m / z): 634.1 [M+H] + . LCMS RT: 1.27 min (Method J). Example 13 (R)-2-methyl-1 2 -(1-methyl-6-(((S)-morpholine-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-1 1 H-7,10-dioxa-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacyclododecafan-4-one [ka]

[0224] Synthesis of Example 13 Example 13 was prepared from intermediate 9C and tert-butyl 3-(2-(2-bromoethoxy)ethoxy)propanoate using the same synthesis protocol as in Example 9. LCMS (ESI, m / z): 602.2 [M+H] +. LCMS RT: 1.04 min (Method J). Example 14 (R)-1 2 -(7-((S)-2-amino-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyrizin-2-yl)-5 5 -fluoro-2-methyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridina-5(4,3)-pyridinacyclodecafan-4-one [ka]

[0225] Synthesis of intermediate 14A tert-butyl 3-fluoro-5-(5-hydroxypentyl)pyridine-4-carboxylate * To a solution of (200 mg, 0.71 mmol) / DCM (6 mL), Et3N (273 mg, 2.12 mmol) was added. The resulting mixture was cooled to 0°C under nitrogen. Then TsCl (202 mg, 1.06 mmol) and DMAP (17 mg, 0.14 mmol) were added little by little, and the resulting mixture was stirred overnight at room temperature. The reaction product was diluted at 0°C with saturated NH4Cl aqueous solution (15 mL) and DCM (3 * Extraction was performed using 15 mL of solution. The organic layers were washed together with saline solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum at 0°C. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 3:1) to obtain intermediate 14A (225 mg) as a colorless oil. LCMS (ESI, m / z): 438 [M+H] + . * The preparation was carried out according to a synthesis protocol similar to that described in International Publication No. 2021 / 222353.

[0226] Synthesis of intermediate 14B To a solution of intermediate 1E (1.0 g, 2.88 mmol) in DMF (20 mL), Cs2CO3 (2.8 g, 8.59 mmol) and intermediate 14A (1.3 g, 2.97 mmol) were added under nitrogen. The resulting mixture was stirred at 50°C for 3 hours, then diluted with water (100 mL), and ethyl acetate (2 * Extracted with 100 mL of water. Combined the organic layer with water (2 * 200 mL) and saline solution (2 * The solution was washed with 200 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 2:1) to obtain intermediate 14B (1.3 g) as a yellow oily substance. LCMS (ESI, m / z): 613 [M+H] + .

[0227] Synthesis of intermediate 14C To a solution of intermediate 14B (1.0 g, 1.63 mmol) in DCM (20 mL), TFA (5 mL) was added. The resulting mixture was stirred overnight at room temperature, and then concentrated under vacuum to obtain crude intermediate 14C (600 mg) as a yellow oily substance. LCMS (ESI, m / z): 457 [M+H] + .

[0228] Synthesis of intermediate 14D To a solution of intermediate 14C (1.1 g, 2.41 mmol) and DIPEA (5 g, 38.5 mmol) / DCM (20 mL), HATU (1.4 g, 3.68 mmol) was added under nitrogen at room temperature. The resulting mixture was stirred at room temperature for 16 hours, then diluted with water (50 mL) and DCM (2 * Extraction was performed using 50 mL of water. The organic layers were washed together with water (100 mL) and saline solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 3:1) to obtain intermediate 14D (400 mg) as a white solid. LCMS (ESI, m / z): 439 [M+H] + .

[0229] Synthesis of intermediate 14E To a solution of intermediate 14D (350 mg, 0.80 mmol) in methanol (6 mL) and water (3 mL), NaOH (250 mg, 6.25 mmol) was added, and the resulting mixture was stirred at 50°C for 0.5 hours. This reaction mixture was acidified to pH 2 with aqueous HCl (1 M), stirred at room temperature for 0.5 hours, then diluted with water (20 mL), and ethyl acetate (2 * Extracted with 20 mL of water. Combined the organic layer with water (2 * 40 mL) and saline solution (2 * The mixture was washed with 40 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude intermediate 14E (300 mg) as a white solid. LC-MS (ESI, m / z): 397 [M+H] + .

[0230] Synthesis of Example 14 Example 14 was prepared as a white solid from intermediate 14E and intermediate 3L using the same synthesis protocol as in Example 1. 1 H NMR (400MHz, DMSO-d6)δ 9.48(d, J=7.6Hz, 1H), 8.50(d, J=9.2Hz, 2H), 8.34(s, 1H), 8.29-8.24(m, 3H), 8.13(d , J=8.0Hz, 1H), 7.32-7.29(m, 2H), 5.33-5.25(m, 1H), 4.98-4.80(m, 2H), 4.68-4.59(m , 2H), 4.03(s, 3H), 3.88-3.81(m, 2H), 3.80-3.73(m, 3H), 3.50-3.45(m, 2H), 2.36-2.3 3(m, 1H), 2.22-2.11(m, 1H), 1.59-1.47(m, 6H), 1.35-1.14(m, 2H), 0.45-0.39(m, 1H). LCMS(ESI, m / z):628[M+H] + . LCMS RT: 1.205 min (Method K1). Example 15 (R)-1 2 -(6-((S)-2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-5 5 -fluoro-2-methyl-1 1H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridina-5(4,3)-pyridinacyclodecafan-4-one [ka]

[0231] Synthesis of Example 15 Example 15 was prepared as a white solid from intermediates 14E and 4D using the same synthesis protocol as in Example 2. 1 H NMR (400MHz, DMSO-d6)δ 9.48(d, J=7.2Hz, 1H), 8.49(s, 1H), 8.34(s, 1H), 8.28-8.23(m, 4H), 8.11(d, J=8.0Hz, 1H), 7.62(s, 1H), 7.27(d, J=8.0Hz, 1H), 7.20(s, 1H), 5.32-5.23(m, 1H), 4.94-4.61(m , 4H), 3.98(s, 3H), 3.87-3.81(m, 3H), 3.78-3.76(m, 2H), 3.28-3.17(m, 2H), 2.33-2.3 9(m, 1H), 2.17-2.11(m, 1H), 1.58-1.41(m, 6H), 1.28-1.17(m, 2H), 0.51-0.35(m, 1H). LCMS(ESI, m / z):627[M+H] + . LCMS RT: 0.664 min (Method K2). Example 16 (R)-1 2 -(1-Cyclopropyl-6-(((S)-Morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-5 5 -fluoro-2-methyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridina-5(4,3)-pyridinacyclodecafan-4-one [ka]

[0232] Synthesis of Example 16 Example 16 was prepared as a white solid from intermediates 14D and 5D using the same synthesis protocol as in Example 5. 1 H NMR (400MHz, DMSO-d6)δ 9.46(d, J=8.0Hz, 1H), 9.16-8.89(m, 2H), 8.48(s, 1H), 8.33(s, 1H), 8.23(s, 1H), 8.08(d, J=8.0Hz, 1H), 7.62(s, 1H), 7. 35(s, 1H), 7.26(d, J=8.0Hz, 1H), 5.30-5.22(m, 1H), 4.99-4.89(m, 2H), 4.00-3.82(m, 4H), 3.80-3.69(m, 2H), 3.64-3.57 (m, 3H), 3.52-3.47(m, 1H), 3.28-3.15(m, 3H), 3.12-3.01(m, 1H), 2.49-2.42(m, 1H), 2.40-2.31(m, 1H), 2.14-2.05(m, 1H) ), 1.49(d, J=7.2Hz, 3H), 1.46-1.35(m, 2H), 1.34-1.23(m, 2H), 1.21-1.09(m, 2H), 1.04-0.95(m, 1H), 0.43-0.32(m, 2H). LCMS(ESI, m / z):677[M+H] + . LCMS RT: 0.635 min (Method B1). Example 17 (R)-5 5 -fluoro-2-methyl-1 2 -(1-methyl-6-(((S)-morpholine-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridina-5(4,3)-pyridinacyclodecafan-4-one [ka]

[0233] Synthesis of Example 17 Example 17 was prepared as a white solid from intermediates 14E and 2F using the same synthesis protocol as in Example 2. 1H NMR (400MHz, DMSO-d6+D2O)δ 9.49(d, J=8.0Hz 1H), 8.48(s, 1H), 8.33(s, 1H), 8.27(s, 1H), 8.11(d, J=8.0Hz 1H), 7.62(s, 1H), 7.28(d, J=8.0Hz 1H), 7.20(s, 1H), 5.29-5.26(m, 1H), 4.69-4.89(m, 1H), 4.78-4.74(m, 1H), 4.00-3.93(m, 6H), 3.74-3.69(m, 2H), 3.60-3.57(m, 3H), 3.57-3.52(m, 1H), 3.32-3.06(m, 4H), 2.52-2.37(m, 2H), 2.12-2.08(m, 1H), 1.49-1.44(m, 5H), 1.28-1.12(m, 2H), 0.45-0.41(m, 1H). LCMS(ESI, m / z):651[M+H] + . LCMS RT: 0.664 min (Method K2). Example 18 (5 1 R,5 2 R,2R)-2-methyl-1 2 -(1-methyl-6-(((S)-morpholine-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridina-5(1,2)-cyclopropanacyclodecafan-4-one [ka]

[0234] Synthesis of intermediate 18A (5 1 R,5 2 R,2R,Z)-2-methyl-4-oxo-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridina-5(1,2)-cyclopropanacyclodecafane-7-en-1 2 -Carboaldehyde *Na2S2O4 (160 mg, 0.92 mmol) was added to a solution of (80 mg, 0.25 mmol, International Publication No. 2021 / 222353) and intermediate 2F (110 mg, 0.28 mmol) in ethanol (2 mL) and water (1 mL). The resulting mixture was stirred at 90°C for 2 hours, then cooled to room temperature, and purified using flash column chromatography with C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 0% B to 100% B) to obtain intermediate 18A (120 mg) as a yellow solid. * Note: Cis / trans composition was not measured. LCMS (ESI, m / z): 694 [M+H] + .

[0235] Synthesis of intermediate 18B Pd / C (40 mg), followed by ethanol (5 mL), and intermediate 18A (120 mg, 0.17 mmol) were added to a reaction flask under nitrogen. The reaction flask was degassed and refilled with nitrogen (3x), followed by hydrogen (3x). The mixture was stirred overnight under hydrogen at room temperature, then the solid was filtered, and the filtrate was concentrated under vacuum to obtain crude intermediate 18B (80 mg) as a yellow oil. LCMS (ESI, m / z): 696 [M+H] + .

[0236] Synthesis of Example 18 To a solution of intermediate 18B (80 mg, 0.11 mmol) / DCM (2 mL), TFA (0.5 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method E2, RT: 8.68 min). The pure fraction was concentrated under vacuum, the organic solvent was removed, and the remaining aqueous solution was freeze-dried to obtain Example 18 (41.1 mg) as a white solid. 1H NMR (400MHz, DMSO-d6)δ 9.02(s, br, 1H), 8.91(s, br, 1H), 8.45(d, J=8.4Hz, 1H), 8.28(s, 1H), 8.00(d, J=8.0Hz, 1H), 7.62(s, 1 H), 7.14(d, J=8.4Hz, 1H), 7.12(s, 1H), 5.09-5.01(m, 1H), 4.87-4.75(m, 2H), 4.04-3.85(m, 6H), 3.84- 3.72(m, 3H), 3.71-3.63(m, 2H), 3.36-3.22(m, 2H), 3.21-3.17(m, 2H), 3.14-3.01(m, 1H), 1.90-1.84( m, 1H), 1.72-1.31(m, 9H), 1.24-1.17(m, 1H), 0.99-0.86(m, 1H), 0.81-0.61(m, 2H), 0.49-0.46(m, 1H). LCMS(ESI, m / z):596[M+H] + . LCMS RT: 0.619 min (Method B1). Example 19 (R)-2'-methyl-2'-(1-methyl-6-(((S)-morpholine-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)spiro[cyclopropane-1,5'-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan]-4'-one [ka]

[0237] Synthesis of Example 19 Example 19 was prepared as a white solid from intermediate 1E, tert-butyl 1-(6-bromohexyl)cyclopropane-1-carboxylate (International Publication No. 2021 / 222353), and intermediate 2F using the same synthesis protocol as in Example 14. 1H NMR(400MHz, DMSO-d6+D2O)δ 8.30(s, 1H), 8.13(d, J=8.0Hz, 1H), 7.62(s, 1H), 7.25(d, J=8.0Hz, 1H), 7.15( s, 1H), 5.31-5.22(m, 1H), 4.94-4.83(m, 1H), 4.56-4.45(m, 1H), 4.04-3.90(m, 6H), 3.80-3.71(m, 2H), 3.67-3.53(m, 4H), 3.32-3.21(m, 4H), 2.39-1.97(m, 2H) ), 1.88-1.51(m, 3H), 1.50-1.33(m, 5H), 1.30-0.89(m, 5H), 0.69-0.47(m, 2H). LCMS(ESI, m / z):610[M+H] + . LCMS RT: 1.344 min (Method B2). Example 20 (R)-2,5,5-trimethyl-1 2 -(1-methyl-6-(((S)-morpholine-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacyclodecafan-4-one [ka]

[0238] Synthesis of Example 20 Example 20 was prepared as a white solid from intermediate 1E, tert-butyl 7-bromo-2,2-dimethylheptanoate (International Publication No. 2021 / 222353), and intermediate 2F using the same synthesis protocol as in Example 14. 11H NMR (400 MHz, DMSO-d6+D2O)δ 8.28(s, 1H), 8.06(d, J=8.0Hz, 1H), 7.60(s, 1H), 7.22(d, J=8.0Hz, 1H), 7 .12(s, 1H), 5.21-5.10(m, 1H), 4.80-4.67(m, 2H), 4.03-3.90(m, 6H), 3.73 -3.69(m, 2H), 3.63-3.48(m, 4H), 3.31-3.07(m, 4H), 1.97-1.61(m, 3H), 1. 57-1.43(m, 4H), 1.40-1.28(m, 1H), 1.21-0.99(m, 7H), 0.95-0.94(m, 2H). LCMS (ESI, m / z): 598 [M+H] + . LCMS RT: 1.244 min (Method B2). Example 21 (R)-2,5,5-trimethyl-1 2 -(1-methyl-6-(((S)-morpholine-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacyclododecafan-4-one [ka]

[0239] Synthesis of intermediate 21A To a solution of tert-butyl 2-methylpropanoate (500 mg, 3.47 mmol) / THF (30 mL), LDA (2 M / THF, 3.5 mL, 6.93 mmol) was added dropwise under nitrogen at 0°C. The resulting mixture was stirred at 0°C for 1 hour, followed by the dropwise addition of 1,7-dibromoheptane (2.68 g, 10.4 mmol). The resulting mixture was stirred at 0°C for 0.5 hours and then at room temperature for 2 hours. The mixture was then quenched with saturated NH4Cl aqueous solution (50 mL) at 0°C, stirred at room temperature for 20 minutes, and ethyl acetate (2 * Extracted with 100 mL of saline solution. Combined the organic layers and saline solution (2 *The solution was washed with 200 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 20:1) to obtain intermediate 21A (650 mg) as a pale yellow solid.

[0240] Synthesis of Example 21 Example 21 was prepared as a white solid from intermediate 1E, intermediate 21A, and intermediate 2F using the same synthesis protocol as in Example 14. 1 H NMR(400MHz, DMSO-d6+D2O)δ 8.29(s, 1H), 8.07(d, J=8.0Hz, 1H), 7.62(s, 1H), 7.23(d, J=8.0Hz, 1H), 7.11(s, 1H) ), 5.17-5.08(m, 1H), 4.82-4.49(m, 2H), 4.01-3.95(m, 6H), 3.80-3.77(m, 1H), 3.71 -3.67(m, 1H), 3.66-3.48(m, 4H), 3.37-3.28(m, 3H), 3.22-3.02(m, 1H), 1.83-1.64( m, 2H), 1.58-1.30(m, 5H), 1.28-1.16(m, 6H), 1.15-1.03(m, 2H), 1.02-0.88(m, 6H). LCMS(ESI, m / z):626[M+H] + . LCMS RT: 1.171 min (Method B3). Example 22 (R)-2-methyl-1 2 -(1-methyl-6-(((S)-morpholine-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-1 1 H-6-oxa-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0241] Synthesis of intermediate 22A To a solution of intermediate 1E (300 mg, 0.86 mmol) in DMF (6 mL), ethyl 2-(5-chloropentoxy)acetate (270 mg, 1.29 mmol; Tetrahedron, 2003, 59, 149-153), Cs2CO3 (841 mg, 2.58 mmol), and NaI (206 mg, 1.37 mmol) were added. The resulting mixture was stirred overnight at 70°C, then cooled to room temperature, and purified using flash column chromatography with C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 10% B~80% B) to obtain intermediate 22A (240 mg) as a yellow oily substance. LCMS (ESI, m / z): 520 [M+H] + .

[0242] Synthesis of intermediate 22B To a solution of intermediate 22A (240 mg, 0.46 mmol) in DCM (5 mL), TFA (1 mL) was added. The resulting mixture was stirred at room temperature for 1 hour, and then concentrated under vacuum to obtain crude intermediate 22B (190 mg) as a yellow oily substance. LCMS (ESI, m / z): 420 [M+H] + .

[0243] Synthesis of intermediate 22C To a solution of intermediate 22B (190 mg, 0.45 mmol) in methanol (2.5 mL) and water (2.5 mL), NaOH (108 mg, 2.7 mmol) was added at room temperature. The resulting mixture was stirred under nitrogen at 50°C for 1 hour, then neutralized with aqueous HCl (4 M), and purified using flash column chromatography with C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 0% B~60% B) to obtain intermediate 22C (130 mg) as a yellow oily substance. LCMS (ESI, m / z): 350 [M+H] + .

[0244] Synthesis of intermediate 22D To a solution of intermediate 22C (150 mg, 0.43 mmol) / DMF (4 mL), HATU (245 mg, 0.64 mmol) and DIPEA (147 mg, 1.29 mmol) were added. The resulting solution was stirred at room temperature for 1 hour and then used directly in the next step without further purification. LC-MS (ESI, m / z): 450 [M+H] + .

[0245] Synthesis of Example 22 Example 22 was prepared as a white solid from intermediates 22D and 2F using the same synthesis protocol as in Example 2. 1 H NMR(400MHz, DMSO-d6+D2O)δ 8.30(s, 1H), 8.14(d, J=8.0Hz, 1H), 7.62(s, 1H), 7.29(d, J=8.0Hz, 1H), 7.15(s, 1H) , 5.26-5.25(m, 1H), 4.69-4.66(m, 2H), 4.20-4.16(m, 1H), 4.03-3.90(m, 6H), 3.75-3 .69(m, 4H), 3.66-3.44(m, 5H), 3.31-3.20(m, 3H), 3.09-3.07(m, 1H), 2.17-2.06(m, 1H), 1.81-1.75(m, 2H), 1.65-1.61(m, 2H), 1.48(d, J=7.2Hz, 3H), 1.28-1.26(m, 1H). LCMS(ESI, m / z):586[M+H] + . LCMS RT: 1.347 min (Method B4). Example 23 (R)-2,5,5-trimethyl-1 2 -(1-methyl-6-(((S)-morpholine-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-1 1 H-6,9-dioxa-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0246] Synthesis of intermediate 23A Potassium tert-butoxide (782 mg, 6.97 mmol) was added to a mixture of tert-butyl 2-bromo-2-methylpropanoate (1 mL, 5.36 mmol) and diethylene glycol (1.018 mL, 10.72 mmol) / DMSO (17.87 mL). The resulting mixture was heated to 60°C, stirred overnight, then cooled to room temperature, diluted with ethyl acetate, washed with water (3X) and saline solution, dried over MgSO4, filtered, and concentrated under vacuum to obtain crude intermediate 23A (192 mg), which was used directly in the next step without further purification.

[0247] Synthesis of intermediate 23B To a mixture of intermediate 23A (192 mg, 0.773 mmol) and triethylamine (323 μL, 2.320 mmol) / DCM (7.0 mL), p-toluenesulfonyl chloride (221 mg, 1.160 mmol) and DMAP (9.45 mg, 0.077 mmol) were added at 0°C. The resulting mixture was stirred at room temperature for 1 hour, then diluted with DCM, washed with water (2X) and saline solution, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by column silica chromatography (15-40% ethyl acetate / hexane) to obtain intermediate 23B (37 mg). 1 H NMR (400MHz, DMSO-d6)δ 8.90-8.89(m, 1H), 7.79(br d, J=8.0Hz, 2H), 7.49(br d.

[0248] Synthesis of Example 23 Example 23 was prepared from intermediates 9C and 23B using the same synthesis protocol as in Example 12. LCMS ESI 616[M+H] + . LCMS RT: 1.22 min (Method J). Example 24 (2R)-2-methyl-1 2-(1-methyl-6-(((S)-morpholine-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridina-5(1,2)-cyclopropanacyclononafane-4-one [ka]

[0249] Synthesis of intermediate 24A Tert-butyl 2-(4-((tert-butyldiphenylsilyl)oxy)butyl)cyclopropane-1-carboxylate * SFC(Column:(R,R)WHELK-O 14.6 * Purification was performed using a 50 mm, 3 μm mobile phase (1% 2M NH3-MeOH-containing IPA / hexane = 1:10, flow rate: 4 mL / min, gradient: fixed composition B). The pure fraction was concentrated under vacuum, and the first eluted stereoisomer (280 mg) and intermediate 24A (300 mg, the second eluted stereoisomer) were obtained as a pale yellow oily substance. Note: Cis / trans composition was not measured. LC-MS (ESI, m / z): 453 [M+H] + . * It was prepared from 5-hydroxypentanal following a synthesis protocol similar to that described in International Publication No. 2021 / 222353.

[0250] Synthesis of intermediate 24B To a solution of intermediate 24A (260 mg, 0.57 mmol) / THF (5 mL), TBAF (5 mL) was added at 0°C. The resulting mixture was stirred at room temperature for 1 hour, then diluted with water (30 mL) and extracted with ethyl acetate (30 mL). The organic layer was then diluted with water (5 * 30 mL) and saline solution (5 *The sample was washed with 30 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 1:1) to obtain intermediate 24B (110 mg) as a pale yellow oil. LC-MS (ESI, m / z): 215 [M+H] + .

[0251] Synthesis of intermediate 24C To a solution of intermediate 24B (85 mg, 0.38 mmol) / DCM (4 mL), Et3N (0.2 mL, 1.12 mmol), DMAP (4 mg, 0.04 mmol), and TsCl (106 mg, 0.56 mmol) were added in several portions under nitrogen at 0°C. The resulting mixture was stirred overnight at room temperature, then diluted with water (10 mL), and DCM (3 mL). * Extraction was performed using 10 mL of solution. The organic layers were washed together with saline solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 5:1) to obtain intermediate 24C (120 mg) as a pale yellow oil. LC-MS (ESI, m / z): 369 [M+H] + .

[0252] Synthesis of intermediate 24D To a solution of intermediate 1E (120 mg, 0.35 mmol) in DMF (4 mL), intermediate 24C (120 mg, 0.33 mmol) and Cs2CO3 (344 mg, 1.05 mmol) were added. The resulting mixture was stirred overnight at 50°C, then cooled to room temperature. It was then purified using flash column chromatography with C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 10% B to 100% B) to obtain intermediate 24D (110 mg) as a yellow solid. LCMS (ESI, m / z): 544 [M+H] + .

[0253] Synthesis of intermediate 24E A solution of intermediate 24D (90 mg, 0.16 mmol) in HCl (4 M / siRNA, 1 mL) was stirred at room temperature under nitrogen for 3 hours. The mixture was concentrated under vacuum, and the resulting crude product was purified by flash column chromatography using C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 50% B~100% B) to obtain intermediate 24E (60 mg) as a yellow oily substance. LCMS (ESI, m / z): 388 [M+H] + .

[0254] Synthesis of Example 24 Example 24 was prepared as a pale yellow oily substance from intermediate 24E and intermediate 2F using the same synthesis protocol as in Example 14. 1 H NMR(400MHz, DMSO-d6+D2O)δ 8.28(s, 1H), 8.03(d, J=8.0Hz, 1H), 7.60(s, 1H), 7.17(d, J=8.0Hz, 1H), 7.04(s, 1H), 5.10-5.05( m, 1H), 4.78-4.72(m, 1H), 4.27-4.22(m, 1H), 4.01(s, 3H), 3.99-3.91(m, 4H), 3.90-3.88(m, 1H), 3.67-3.59(m, 3H), 3.57-3.48(m, 1H), 3.29-3.20(m, 3H), 3.08-3.03(m, 1H), 2.21-2.05(m, 1H), 1 .82-1.57(m, 5H), 1.46(d, J=7.2Hz, 3H), 1.05-1.03(m, 1H), 0.95-0.89(m, 2H), 0.69-0.61(m, 1H). LCMS(ESI, m / z):582[M+H] + . LCMS RT: 1.316 min (Method B4). Example 25 (R)-2,5,5-trimethyl-1 2 -(1-methyl-6-(((S)-morpholine-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-1 1 H-6-oxa-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0255] Synthesis of Example 25 Example 25 was synthesized using the same synthesis protocol as in Example 12 to obtain intermediate 9C and tert-butyl 2-methyl-2-((5-(tosyloxy)pentyl)oxy)propanoate. * Prepared from the following: LCMS (ESI, m / z): 614 [M+H] + . LCMS RT: 1.46 min (Method J). * The preparation was carried out according to a synthesis protocol similar to that described in International Publication No. 2021 / 222353. Examples 26 & 27 (2R)-5-fluoro-2-methyl-1 2 -(1-methyl-6-(((S)-morpholine-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-5-(pyridine-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0256] Synthesis of intermediate 26A Intermediate 26A was prepared from tert-butyl 2-(pyridine-2-yl)acetate and ((6-bromohexyl)oxy)(tert-butyl)dimethylsilane, following a synthetic protocol similar to that described in International Publication No. 2021 / 222353 for 6-((tert-butyldimethylsilyl)oxy)hexyl trifluoromethanesulfonate. LCMS(ESI, m / z):466[M+H] + .

[0257] Synthesis of Examples 26 & 27 The mixtures from Examples 26 and 27 were prepared from intermediates 9C and 26A using a synthesis protocol similar to that of Example 12. The mixtures were separated by preparative HPLC (Method I2) to obtain two homochiral diastereomer products. Example 26 (Diastereomer 1, first elution): 1 H NMR (500MHz, DMSO-d6)δ 8.76-8.68(m, 1H), 8.65-8.55(m, 1H), 8.28(s, 1H), 8.13-8.05(m, 1H), 7.99-7.94(m, 1H), 7.93-7.86(m, 1 H), 7.65-7.57(m, 2H), 7.47-7.39(m, 1H), 7.27-7.22(m, 1H), 7.19-7.13(m, 1H), 5.35-5.22(m, 1H), 5.01-4 .88(m, 1H), 4.80-4.67(m, 1H), 3.98(s, 3H), 3.96-3.78(m, 2H), 3.74-3.61(m, 2H), 3.57-3.48(m, 1H), 3.29 -3.12(m, 2H), 3.07-2.96(m, 1H), 2.90(s, 3H), 2.74(s, 3H), 2.22-1.95(m, 2H), 1.78-1.63(m, 1H), 1.56(br d, J=7.1Hz, 4H), 1.44-1.33(m, 1H), 1.33-1.23(m, 2H), 1.18-1.03(m, 1H), 0.87-0.71(m, 1H). LCMS(ESI, m / z):679[M+H] + . LCMS RT: 1.27 min (Method J).

[0258] Example 27 (Diastereomer 2, second elution): 1H NMR (500MHz, DMSO-d6)δ 8.69-8.62(m, 1H), 8.35-8.30(m, 1H), 8.29-8.24(m, 1H), 8.11-8.06(m, 1H), 7.98-7.95(m, 1H), 7.94-7.89(m, 1H), 7. 63-7.56(m, 2H), 7.48-7.41(m, 1H), 7.24-7.18(m, 1H), 7.16-7.11(m, 1H), 5.13-5.02(m, 1H), 4.94-4.81(m, 1H), 4.65- 4.49(m, 1H), 3.98(s, 3H), 3.95-3.78(m, 2H), 3.74-3.58(m, 2H), 3.56-3.45(m, 1H), 3.25-3.14(m, 2H), 3.04-2.94(m, 1 H), 2.93-2.87(m, 3H), 2.76-2.71(m, 3H), 2.19-1.96(m, 2H), 1.85-1.63(m, 2H), 1.56-1.37(m, 6H), 1.32-1.21(m, 2H). LCMS(ESI, m / z):340[M+2H] + . LCMS RT: 1.28 min (Method J). Example 28 (R)-2,5,5-trimethyl-1 2 -(1-methyl-5-oxo-6-(((S)-pyrrolidine-2-yl)methyl)-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0259] Synthesis of intermediate 28A To solid 6-fluoro-3,4-dihydroisoquinoline-1(2H)-one (15.0 g, 90.8 mmol), H2SO4 (200 mL) was added dropwise at 0°C, followed by the gradual addition of KNO3 (36.7 g, 364 mmol). The resulting mixture was stirred at room temperature for 3 hours, then added dropwise to ice water (1 L), and ethyl acetate (2 *Extraction was performed using 1 L of solution. The organic layers were washed together with saline solution (2 L), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain crude intermediate 28A (22.5 g) as a yellow solid. LC-MS (ESI, m / z): 211 [M+H] + .

[0260] Synthesis of intermediate 28B To a solution of intermediate 28A (20.0 g, 94.8 mmol) / MeCN (200 mL), methylamine hydrochloride (12.8 g, 190 mmol) and DIPEA (36.8 g, 285 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 2 hours, then diluted with water (1 L), and DCM (2 * Extraction was performed using 1 L of water. The organic layers were washed together with water (2 L) and saline solution (2 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (100% ethyl acetate) to obtain intermediate 28B (15 g) as a yellow solid. LC-MS (ESI, m / z): 222 [M+H] + .

[0261] Synthesis of intermediate 28C To a solution of intermediate 28B (10 g, 45 mmol) in methanol (210 mL), saturated NH4Cl aqueous solution (70 mL) was added, followed by the gradual addition of zinc powder (29.3 g, 450 mmol). The resulting mixture was stirred at room temperature for 2 hours. The solid was filtered, and the filtrate was concentrated under vacuum. The residue was diluted with water (500 mL) and DCM (2 * Extraction was performed using 500 mL of water. The organic layers were washed together with water (1 L) and saline solution (1 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (DCM / MeOH = 10:1) to obtain intermediate 28C (4.6 g) as a gray solid. LC-MS (ESI, m / z): 192 [M+H] + .

[0262] Synthesis of intermediate 28D To a solution of intermediate 1I (3.5 g, 9.7 mmol) and DIPEA (3.82 g, 28.6 mmol) / DMF (100 mL), HATU (4.8 g, 12.7 mmol) was added under nitrogen at room temperature. The mixture was stirred at room temperature for 10 minutes, and then added dropwise to a solution of intermediate 28C (2.8 g, 14.6 mmol) / DMF (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours, then diluted with water (500 mL) and extracted with ethyl acetate (500 mL). The organic layers were combined and diluted with water (2 * 500 mL) and saline solution (2 * The solution was washed with 500 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash column chromatography using C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 0% B to 100% B) to obtain intermediate 28D (4.6 g) as a yellow solid. LCMS (ESI, m / z): 531 [M+H] + .

[0263] Synthesis of intermediate 28E A solution of intermediate 28D (1.3 g, 2.5 mmol) in acetic acid (25 mL) was stirred at 70°C for 3 hours and then concentrated under vacuum. The crude product was purified by flash column chromatography using C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 0% B to 100% B) to obtain intermediate 28E (1.06 g) as a yellow solid. LCMS (ESI, m / z): 513 [M+H] + .

[0264] Synthesis of intermediate 28F To a solution of intermediate 28E (50 mg, 0.10 mmol) in THF (3 mL), NaH (60% w / w, 16 mg, 0.67 mmol) was added in several portions under nitrogen at 0°C, and the resulting mixture was stirred at room temperature for 0.5 hours. The reaction mixture was cooled to 0°C, and (S)-tetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (32 mg, 0.20 mmol) was added in several portions. The resulting mixture was stirred overnight at room temperature, then quenched with saturated NH4Cl aqueous solution (0.5 mL), and purified using flash column chromatography with C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 0% B~100% B) to obtain intermediate 28F (40 mg) as a yellow solid. LCMS(ESI, m / z):676[M+H] + .

[0265] Synthesis of Example 28 A solution of intermediate 28F (25 mg, 0.04 mmol) / HCl (4 M / MeOH, 2 mL) was stirred overnight in a sealed container at 70°C and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method E4, RT: 8.5 min). The pure fraction was concentrated under vacuum to remove the organic solvent, and the remaining aqueous solution was freeze-dried to obtain Example 28 (15.6 mg) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 9.03 (s, br 1H), 8.40 (s, br 1H), 8.26(s, 1H), 8.05(d, J=8.0Hz, 1H), 7.84(d, J=7.6Hz, 1H), 7.62(s, 1H), 7.19(d, J=8.0Hz, 1H), 7.12(s, 1H), 5.14-5.12(m, 1H), 4.93-4.80(m, 1H), 4.61-4.52(m, 1H), 3.96(s, 3H), 3.94-3.89(m, 2H) ), 3.75-3.72(m, 2H), 3.37-3.22(m, 2H), 3.21-3.13(m, 3H), 2.17-2.06(m, 1H), 1.97-1.90(m, 3H), 1. 75-1.65(m, 3H), 1.52-1.41(m, 4H), 1.38-1.38(m, 4H), 1.21(s, 3H), 1.17-1.07(m, 2H), 0.94(s, 3H). LCMS(ESI, m / z):596[M+H] + . LCMS RT: 0.697 min (Method B1). Example 29 (R)-2,5,5-trimethyl-12-(1-methyl-5-oxo-6-(((R)-pyrrolidine-2-yl)methyl)-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-11H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0266] Synthesis of Example 29 Example 29 was prepared as a white solid from intermediate 28E and (R)-tetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide using the same synthesis protocol as in Example 28. 1H NMR (400MHz, DMSO-d6)δ 9.04(s, br, 1H), 8.41(s, br, 1H), 8.26(s, 1H), 8.05(d, J=8.0Hz, 1H), 7.84(d, J=8.0Hz, 1H), 7.61(s, 1H), 7.19(d , J=8.0Hz, 1H), 7.12(s, 1H), 5.16-5.08(m, 1H), 4.89-4.83(m, 1H), 4.60-4.52(m, 1H), 3.97(s, 3H), 3.95-3.89(m, 1H), 3.82-3.76(m, 1H), 3.74-3.64(m, 3H), 3.37-3.28(m, 1H), 3.21-3.11(m, 3H), 2.12-2.07(m, 1H), 2.01-1.88( m, 3H), 1.74-1.55(m, 3H), 1.45(d, J=8.0Hz, 3H), 1.41-1.33(m, 5H), 1.21(s, 3H), 1.11-1.05(m, 2H), 0.94(s, 3H). LCMS(ESI, m / z):596[M+H] + . LCMS RT: 0.693 min (Method B1). Example 30 (R)-1 2 -(6-(((R)-4,4-difluoropiperidine-2-yl)methyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-2,5,5-trimethyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0267] Synthesis of intermediate 30A To a solution of (R)-1-(tert-butoxycarbonyl)-4,4-difluoropiperidine-2-carboxylic acid (500 mg, 1.89 mmol) / THF (20 mL), BH3 (1 M / THF, 3.8 mL, 3.8 mmol) was added under nitrogen at 0°C. The resulting mixture was stirred overnight at room temperature, then added to methanol at 0°C, stirred at 0°C for 20 minutes, and concentrated under vacuum. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 2:1) to obtain intermediate 30A (300 mg) as a white solid. LCMS (ESI, m / z): 252 [M+H] + .

[0268] Synthesis of intermediate 30B To a solution of intermediate 30A (150 mg, 0.6 mmol) in ethyl acetate (1 mL), HCl (4 M / siRNA, 4 mL, 16 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour, then concentrated under vacuum to obtain intermediate 30B (80 mg) as a white solid. LC-MS (ESI, m / z): 152 [M+H] + .

[0269] Synthesis of intermediate 30C To a solution of imidazole (216 mg, 3.18 mmol) / DCM (2 mL), a solution of SOCl2 (108 mg, 0.95 mmol) / DCM (2 mL) was added dropwise under nitrogen at 0°C. The resulting mixture was stirred at room temperature for 1 hour, then cooled to -10°C, and a solution of intermediate 30B (80 mg, 0.53 mmol) / DCM (2 mL) was added dropwise under nitrogen. The resulting mixture was stirred at room temperature for 1 hour, then diluted with water (10 mL), acidified to pH 6 with citric acid, and then DCM (3 * Extraction was performed using 10 mL of solution. The organic layers were washed together with saline solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain intermediate 30C (80 mg) as a white solid. LC-MS (ESI, m / z): 198 [M+H] + .

[0270] Synthesis of intermediate 30D To a solution of intermediate 30C (80 mg, 0.41 mmol) / MeCN (2 mL), NaIO4 (88 mg, 0.41 mmol) and RuCl3 (10.3 mg, 0.04 mmol) / H2O (1 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 2 hours, then diluted with water (10 mL), and DCM(3) was prepared. * Extraction was performed using 10 mL of solution. The organic layers were washed together with saline solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain intermediate 30D (80 mg) as a white solid. LC-MS (ESI, m / z): 214 [M+H] + .

[0271] Synthesis of intermediate 30E To a solution of intermediate 28E (50 mg, 0.10 mmol) in THF (2 mL), NaH (60% w / w, 7.0 mg, 0.20 mmol) was added under nitrogen at 0°C, and the resulting mixture was stirred at room temperature for 0.5 hours. The reaction mixture was cooled to 0°C, and a solution of intermediate 30D (103 mg, 0.49 mmol) in THF (2 mL) was added dropwise. The resulting mixture was stirred overnight at 50°C, then quenched with saturated NH4Cl aqueous solution (0.5 mL), and purified by flash column chromatography using C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 5% B~80% B) to obtain intermediate 30E (60 mg) as a white solid. LCMS (ESI, m / z): 726 [M+H] + .

[0272] Synthesis of Example 30 A solution of intermediate 30E (60 mg, 0.08 mmol) / HCl (4 M / MeOH, 4 mL) was stirred in a sealed container at 50°C for 2 hours, and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method E3, RT: 8.68 min). The pure fraction was concentrated under vacuum to remove the organic solvent, and the remaining aqueous solution was freeze-dried to obtain Example 30 (53.4 mg) as a white solid. 1H NMR(400MHz, DMSO-d6+D2O)δ 8.27(s, 1H), 8.05(d, J=8.0Hz, 1H), 7.58(s, 1H), 7.18(d, J=8.0Hz, 1H), 7.07(s, 1H), 5.08-5.07(m , 1H), 4.83-4.80(m, 1H), 4.42-4.40(m, 1H), 4.01(s, 3H), 3.72-3.51(m, 5H), 3.53-3.48(m, 1H), 3.2 3-3.19(m, 2H), 3.01-2.98(m, 1H), 2.51-2.33(m, 4H), 1.90-1.80(m, 1H), 1.69-1.58(m, 2H), 1.43(d , J=6.8Hz, 3H), 1.40-1.35(m, 2H), 1.24-1.20(m, 3H), 1.18(s, 3H), 1.10-1.00(m, 2H), 0.92(s, 3H). LCMS(ESI, m / z):646[M+H] + . LCMS RT: 0.725 min (Method B1).

[0273] Examples 31-38 (see Table 1) were prepared from intermediate 28E and a suitable commercially available precursor using the same synthesis protocol as in Example 30. [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] Example 39 (R)-2,5,5-trimethyl-1 2-(1-methyl-6-(((S)-morpholin-2-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0274] Synthesis of intermediate 39A To a solution of tert-butyl (S)-2-(hydroxymethyl)morpholine-4-carboxylate (500 mg, 2.3 mmol) / DCM (23 mL), Ms2O (905 mg, 3.4 mmol) and Et3N (465 mg, 4.6 mmol) were added under nitrogen at 0°C. The resulting mixture was stirred under nitrogen at room temperature for 2 hours, then diluted at 0°C with saturated NH4Cl aqueous solution (20 mL), and dissolved in DCM (2 * Extracted with 20 mL of saline solution. Combined the organic layer with saline solution (2 * The solution was washed with 20 mL of water, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 5:1) to obtain intermediate 39A (400 mg) as a pale yellow oil. LC-MS (ESI, m / z): 296 [M+H] + .

[0275] Synthesis of intermediate 39B To a solution of intermediate 28E (60 mg, 0.12 mmol) in DMF (3 mL), NaH (60% w / w, 14 mg, 0.35 mmol) was added in several portions under nitrogen at 0°C, and the resulting mixture was stirred at room temperature for 0.5 hours. The reaction mixture was cooled to 0°C, and a solution of intermediate 39A (34 mg, 0.12 mmol) in DMF (0.5 mL) was added dropwise. The resulting mixture was stirred at 50°C for 2 hours, then quenched with saturated NH4Cl aqueous solution (0.5 mL), and purified by flash column chromatography using C18 silica (mobile phase A: 0.5% TFA / water, mobile phase B: ACN; gradient: 0% B~100% B) to obtain intermediate 39B (29 mg) as a yellow solid. LCMS (ESI, m / z): 712 [M+H] + .

[0276] Synthesis of Example 39 To a solution of intermediate 39B (30 mg, 0.04 mmol) / DCM (3 mL), TFA (1 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method E5, RT: 8.5 min). The pure fraction was concentrated under vacuum, the organic solvent was removed, and the remaining aqueous solution was freeze-dried to obtain Example 39 (15.6 mg) as a white solid. 1 H NMR(400MHz, DMSO-d6+D2O)δ 8.26(s, 1H), 8.09(d, J=8.0Hz, 1H), 7.60(s, 1H), 7.31-7.06(m, 3H), 5.14-5.10(m, 1H), 5.09 -4.86(m, 1H), 4.59-4.39(m, 1H), 3.99-3.95(m, 5H), 3.79-3.62(m, 5H), 3.29(d, J=12Hz, 1H) , 3.28-3.17(m, 3H), 3.06-3.01(m, 1H), 2.95-2.87(m, 1H), 1.97-1.89(m, 1H), 1.79-1.59(m, 1H), 1.43(d, J=8.0Hz, 3H), 1.41-1.18(m, 6H), 1.17(s, 3H), 1.15-0.90(m, 2H), 0.89(s, 3H). LCMS(ESI, m / z):612[M+H] + . LCMS RT: 0.681 min (Method B1). Example 40 (R)-2,5,5-trimethyl-1 2 -(1-methyl-5-oxo-6-((R)-pyrrolidine-3-yl)-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0277] Synthesis of intermediate 40A To a solution of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (300 mg, 1.60 mmol) / DCM (16 mL), Et3N (0.84 mL, 4.81 mmol) and MsCl (219 mg, 1.92 mmol) were added under nitrogen at 0°C. The resulting mixture was stirred at room temperature for 1 hour, then quenched at 0°C with saturated NH4Cl aqueous solution (20 mL), and DCM (2 * Extraction was performed using 20 mL of solution. The organic layers were washed together with saline solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum at 0°C to obtain intermediate 40A (300 mg) as a pale yellow oily substance. LC-MS (ESI, m / z): 266 [M+H] + .

[0278] Synthesis of Example 40 Example 40 was prepared as a white solid from intermediates 28E and 40A using the same synthesis protocol as in Example 39. 1H NMR (400MHz, DMSO-d6)δ 8.90-8.82(m, 2H), 8.24(s, 1H), 8.05(d, J=8.0Hz, 1H), 7.84(d, J=7.2Hz, 1H), 7.61(s, 1H), 7.19(d, J=8.0Hz, 1H), 7.12(s, 1H), 5.18-5.02(m, 2H), 4.85-4.83(m, 1H), 4.55-4.52(m, 1H), 3.96(s, 3H), 3. 63-3.60(m, 2H), 3.23-3.16(m, 6H), 2.29-2.18(m, 1H), 2.18-2.07(m, 1H), 2.04-1.96(m, 1H), 1.69- 1.60(m, 2H), 1.45(d, J=8.0Hz, 3H), 1.46-1.34(m, 5H), 1.21(s, 3H), 1.09-1.07(m, 2H), 0.95(s, 3H). LCMS(ESI, m / z):582[M+H] + . LCMS RT: 0.678 min (Method B1). Example 41 (R)-1 2 -(6-((S)-2-amino-3-methoxypropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-2,5,5-trimethyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0279] Synthesis of intermediate 41A To a solution of N-(tert-butoxycarbonyl)-O-methyl-D-serine (2 g, 9.12 mmol) / THF (90 mL), BH3 (1 M / THF, 18 mL, 18 mmol) was added at 0°C. The resulting mixture was stirred at room temperature for 6 hours, then quenched with methanol (0.6 mL) at 0°C and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 3:1) to obtain intermediate 41A (1 g) as a white solid. LCMS (ESI, m / z): 206 [M+H] + .

[0280] Synthesis of intermediate 41B To a solution of imidazole (1.19 g, 17.54 mmol) / DCM (5 mL), SOCl2 (626 mg, 5.26 mmol) / DCM (5 mL) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 hour, then cooled to -10°C, and a solution of intermediate 41A (600 mg, 2.92 mmol) / DCM (5 mL) was added. The resulting mixture was stirred at room temperature for 2 hours, then diluted with water (50 mL), and DCM (3 * Extraction was performed using 50 mL of solution. The organic layers were combined and dried over anhydrous sodium sulfate, then concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 4:1) to obtain intermediate 41B (300 mg) as a white solid. LCMS (ESI, m / z): 252 [M+H] + .

[0281] Synthesis of intermediate 41C To a solution of intermediate 41B (300 mg, 1.19 mmol) in acetonitrile (8 mL), solutions of NaIO4 (255 mg, 1.19 mmol) and RuCl3 (24 mg, 0.12 mmol) in water (4 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The residue was diluted with water (30 mL) and DCM(3 * Extraction was performed using 30 mL of solution. The organic layers were combined and dried over anhydrous sodium sulfate, then concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 4:1) to obtain intermediate 41C (200 mg) as a white solid. LC-MS (ESI, m / z): 268 [M+H] + .

[0282] Synthesis of intermediate 41D To a solution of intermediate 28E (100 mg, 0.20 mmol) in DMF (2 mL), NaH (60% w / w, 15 mg, 0.39 mmol) was added in several portions under nitrogen at 0°C. The resulting mixture was stirred at room temperature for 0.5 hours, then cooled to 0°C, and intermediate 41C (62 mg, 0.23 mmol) was added. The resulting mixture was stirred at room temperature for 4 hours, then quenched with water (10 mL), and ethyl acetate (3 * Extraction was performed using 10 mL of solution. The organic layers were washed together with saline solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 1:2) to obtain intermediate 41D (90 mg) as a colorless oil. LC-MS (ESI, m / z): 700 [M+H] + .

[0283] Synthesis of Example 41 To a solution of intermediate 41D (35 mg, 0.05 mmol) / DCM (2 mL), TFA (0.5 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method E5, RT: 8.5 min). The pure fraction was concentrated under vacuum to remove the organic solvent, and the remaining aqueous solution was freeze-dried to obtain Example 41 (13.5 mg) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ 8.24(s, 1H), 8.06-8.04(m, 4H), 7.83(d, J=8.0Hz, 1H), 7.59(s, 1H), 7.19(d, J=8.0Hz, 1H), 7.12( s, 1H), 5.13-5.11(m, 1H), 4.88-4.85(m, 1H), 4.55(s, br, 1H), 3.96(s, 3H), 3.82-3.80(m, 1H), 3. 78-3.75(m, 4H), 3.64-3.57(m, 3H), 3.55-3.52(m, 2H), 3.38-3.36(m, 2H), 1.96-1.92(m, 1H) 1.78 -1.59(m, 2H), 1.57-1.52(m, 4H), 1.51-1.46(m, 4H), 1.35(s, 3H), 1.30-1.22(s, 2H), 0.91(s, 3H). LCMS(ESI, m / z):600[M+H] +. LCMS RT: 1.386 min (Method B5). Example 42 (R)-1 2 -(6-((S)-3-methoxy-2-(methylamino)propyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-2,5,5-trimethyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0284] Synthesis of intermediate 42A To a solution of intermediate 41D (60 mg, 0.10 mmol) / DMF (2 mL), NaH (60% w / w, 4 mg, 0.20 mmol) was added in several portions under nitrogen at 0°C. The resulting mixture was stirred at room temperature for 0.5 hours, then cooled to 0°C, and MeI (28.4 mg, 0.20 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours, then quenched with water (10 mL), and ethyl acetate (3 * Extraction was performed using 10 mL of solution. The organic layers were washed together with saline solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (petroleum ether / ethyl acetate = 1:2) to obtain intermediate 42A (35 mg) as a colorless oil. LC-MS (ESI, m / z): 714 [M+H] + .

[0285] Synthesis of Example 42 To a solution of intermediate 42A (35 mg, 0.04 mmol) / DCM (2 mL), TFA (0.5 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method G, RT: 8.57 min). The pure fraction was concentrated under vacuum to remove the organic solvent, and the remaining aqueous solution was freeze-dried to obtain Example 42 (20.5 mg) as a white solid. 1H NMR (400MHz, DMSO-d6)δ 8.61(s, br, 2H), 8.24(s, 1H), 8.05(d, J=8.0Hz, 1H), 7.83(d, J=7.2Hz, 1H), 7.60(s, 1H), 7.23-7.18 (m, 1H)7.10(s, 1H), 5.13-5.10(m, 1H), 4.89-4.85(m, 1H), 4.55(s, br, 1H), 3.96(s, 3H), 3.92-3.88 (m, 1H), 3.68-3.60(m, 6H), 3.44(s, 3H), 3.22-3.17(m, 2H), 2.67-2.49(m, 3H), 1.97-1.93(m, 1H), 1 .67-1.58(m, 2H), 1.46-1.44(m, 4H), 1.39-1.33(m, 4H), 1.20(s, 3H), 1.09-1.06(m, 2H) 0.94(s, 3H). LCMS(ESI, m / z):614[M+H] + . LCMS RT: 1.418 min (Method B5). Example 43 (R)-1 2 -(6-(((S)-4,4-difluoropyrrolidine-2-yl)methyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-2,5,5-trimethyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0286] Synthesis of intermediate 43A A pre-prepared solution of 4-methylbenzenesulfonyl chloride (133 mg, 0.695 mmol) / DCM (2 mL) was added dropwise at 0°C to a solution of tert-butyl (S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (150 mg, 0.632 mmol), DMAP (7.72 mg, 0.063 mmol), and Et3N (0.220 mL, 1.581 mmol) / DCM (5 mL). The resulting mixture was stirred overnight at room temperature, then diluted with water and extracted with DCM. The organic layer was washed with saturated NaHCO3 aqueous solution and brine, dried over magnesium sulfate, and concentrated under vacuum. The crude product was purified by silica column flash chromatography (0-20% ethyl acetate / hexane) to obtain intermediate 43A as a colorless oil. LCMS (ESI, m / z): 291.8 [M+H-Boc] + .

[0287] Synthesis of Example 43 Example 43 was prepared from intermediates 28E and 43A using the same synthesis protocol as in Example 39. LCMS (ESI, m / z): 632 [M+H] + . LCMS RT: 1.53 min (Method J). Example 44 (R)-1 2 -(6-(((R)-4,4-difluoropyrrolidine-2-yl)methyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinoline-2-yl)-2,5,5-trimethyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinacycloundecafan-4-one [ka]

[0288] Synthesis of Example 44 Example 44 was prepared from intermediate 28E (80 mg, 0.156 mmol) and tert-butyl (R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate using the same synthesis protocol as in Example 43. LCMS (ESI, m / z): 632 [M+H] + . LCMS RT: 1.5 min (Method J).

[0289] RFMS assay The compound was dissolved in 100% DMSO to a concentration of 10 mM. The compound stock solution was stored at room temperature. A series of dilutions were prepared with DMSO and mixed eight times in 20 μL mixtures. The final peak concentration of the compound in the assay was 15 μM. The final assay conditions were as follows: reaction volume: 26 μL; assay buffer: 25 mM HEPES pH 7.5, 5 mM NaCl, 1 mM DTT, 0.2 mg / mL BSA, 0.01% CHAPS, 5 μM TPEN, and 50 μM calcium (condition 1) or 1 mM calcium (condition 2); final concentration: 5 nM hPAD4 enzyme, 250 μM BAEE, and 0.5% DMSO; total incubation time: pre-incubation of compound and enzyme at 37°C for 30 minutes, enzyme / substrate reaction for 90 minutes, reaction with phenylglyoxal at 37°C for 30 minutes; stop solution: 40 μL of 5% trichloroacetic acid / ACN solution.

[0290] Assay protocol: Compound solution (0.13 μL) was added to 10 nM PAD4 / assay buffer (13 μL). After 30 minutes, 500 μM BAEE / assay buffer (13 μL) was added, and the reaction mixture was incubated at 37°C for 90 minutes. The enzymatic reaction was quenched by adding 6.1 N trichloroacetic acid (15 μL, 100% w / v). Final concentration: 20%. Then, 8.5 mM phenylglyoxal solution (35 μL) was added to bring the final concentration to 4 mM, and the reaction mixture was incubated at 37°C for 30 minutes. After 30 minutes, the plate was centrifuged to remove all precipitate. The enzymatic reaction was quenched with an equal volume of methanol containing an internal standard (modified citrulline). The sample was loaded into a Rapid Fire RF300 system (Agilent). First, the sample was aspirated (sip) for 1000 milliseconds, then loaded directly into a C18 separation cartridge with an acetonitrile mixture containing 0.01% formic acid, and desalted for 3000 milliseconds. The mobile phase flow rate was 1.5 mL / min. After the sample was eluted from the cartridge, the sample was introduced into a mass spectrometer for 4000 milliseconds at a flow rate of 1.25 ml / min using an acetonitrile mobile phase containing 0.01% formic acid. Peptidylcitrulline and internal standard ions were analyzed using a Sciex API5500 triple quadrupole mass spectrometer (Applied Biosystems) equipped with ESI.

[0291] Multiple reaction monitoring transitions of the product and internal standard were monitored at m / z 424.5 to 350.4 and m / z 293 to 247, respectively. The dwell time for each transition was set to 200 ms, the ESI voltage was 5500, and the source temperature was 400 °C. The extracted ion peaks for each transition were integrated using Rapid Fire Integrator software. The peak area of ​​the analyte was normalized using the internal standard. The table below shows the IC50 of human PAD4 (hPAD4) in RapidFire mass spectrometry (RFMS) assays for specific compound examples. 50 This indicates.

[0292] Table 2 below shows the activity of the selected compounds of the present invention in the PAD4 assay described above. Compounds with activity indicated by "A" are IC2. 50 The concentration was ≤10 nM; compounds exhibiting activity indicated by "B" were IC250. 50 The activity was 11-100 nM; compounds with activity indicated by "C" were IC2. 50 The activity was 101-500 nM; compounds with activity indicated by "D" were IC2. 50 The activity was 501-1000 nM; compounds with activity indicated by "E" were IC2. 50 It was >1000 nM. [Table 15] [Table 16]

[0293] (Enumerated embodiments)

[0294] Enumerated Embodiment 1 Formula I: [ka] [In formula: X1 and X2 are each independently CR8 or N; Y is -(CR9R 10 ) p -,-O-(CR9R 10 ) p -,-(CR9R 10 ) p -O-(CH2) m -,-(CR9R 10 ) p -O-(CH2) m -O-CH2-, and -(CR9R 10 ) p -O-(CH2) m Selected from -O-; R1 is independently a 4- to 8-membered heterocycle containing at least one heteroatom selected from the group consisting of -CH(NHR7)-(C1-C3 alkyl) or N, O, or S, and the alkyl or heterocycle contains one or more R 11 It may be replaced as appropriate; R2 is independently H or C1-C4 alkyl; R3 is independently H, a halogen, or a C1-C4 alkyl; R4 is independently hydrogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group; R5 and R6 are independently selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, heteroaryl, and aryl; the heteroaryl or aryl may be appropriately substituted with one or more halogens or C1-C6 alkoxy; or R5 and R6, together with the intervening atom, form a C3-C6 cycloalkyl or a 4-8 membered heterocycline; or R5, R6, and R9, together with the intervening atom and adjacent atoms, form a C3-C6 cycloalkyl, a 4-8 membered heterocyclyl, a heteroaryl, or an aryl, and the cycloalkyl, heterocyclyl, heteroaryl, or aryl consists of one or more R 12 It may be replaced as appropriate; Each R7 is independently selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl; Each R8 is independently selected from H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy; Each R9 is independently H, halogen, C1-C4 alkyl, or C3-C4 carbocyric; Each R 10 These are independently H, halogen, or C1-C4 alkyl; Each R 11 These are independently selected from H, halogens, C1-C6 alkyls, and C1-C6 alkoxys; Each R 12These are independently H, halogen, -OH, -NH2, -CN, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl, and C3-C4 cycloalkyl, 3-10 member heterocyclyl, heteroaryl, and C6-C 10 Selected from the alphabet; L is a bond or -CH2-; m is an integer selected from 1, 2, and 3; and p is an integer selected from 2, 3, 4, 5, and 6. The compound represented by, or its pharmaceutically acceptable salts, isomers, solvates, prodrugs, or tautomers.

[0295] Enumerated Embodiment 2 Equation (Ia): [ka] (In the formula, X3 is CH2, NH, O, or S, and r is an integer between 1 and 3.) The compound according to the listed embodiment 1, as shown.

[0296] Enumerated Embodiment 3 Equation (Ia-1): [ka] (In the formula, X3 is NH, O, or S) A compound according to any one of the embodiments listed above, as shown by [the symbol].

[0297] Enumerated Embodiment 4 Equation (Ia-2): [ka] (wherein A is a C3-C8 cycloalkyl, aryl, or heteroaryl group; X3 is NH, O, or S) The compound according to the enumerated embodiment 1 or 2, as shown.

[0298] Enumerated Embodiment 5 Equation (Ia-3): [ka] (In the formula, X3 is NH, O, or S) The compounds described in the listed embodiments 1 to 3, as shown.

[0299] Enumerated Embodiment 6 Equation (Ia-4): [ka] (wherein A is a C3-C8 cycloalkyl, aryl, or heteroaryl group; X3 is CH2, NH, O, or S) The compounds according to the enumerated embodiments 1, 2, or 4, as shown.

[0300] Enumerated Embodiment 7 Equation (Ia-5): [ka] (In the formula, X3 is CH2, NH, O, or S) The compound according to the enumerated embodiment 1 or 2, as shown.

[0301] Enumerated Embodiment 8 Formula (Ib): [ka] The compound according to the listed embodiment 1, as shown.

[0302] Enumerated Embodiment 9 Formula (Ib-1): [ka] The compounds described in the enumerated embodiments 1 or 8.

[0303] Enumerated embodiments 10 Formula (Ib-2): [ka] (In the formula, A is a C3-C8 cycloalkyl, aryl, or heteroaryl compound.) The compounds described in the enumerated embodiments 1 or 8.

[0304] Enumerated embodiments 11 Formula (Ib-3): [ka] The compounds described in the enumerated embodiments 1 or 8.

[0305] Enumerated Embodiments 12 Formula (Ib-4): [ka] (In the formula, A is a C3-C8 cycloalkyl, aryl, or heteroaryl compound.) The compounds described in the enumerated embodiments 1 or 8.

[0306] Enumerated Embodiment 13 Formula (Ib-5): [ka] The compounds described in the enumerated embodiments 1 or 8.

[0307] Enumerated Embodiments 14 Formula (Ib-6): [ka] The compounds described in the enumerated embodiments 1 or 8.

[0308] Enumerated Embodiments 15 Formula (Ic): [ka] The compound according to the enumerated embodiment 1 or 2, as shown.

[0309] Enumerated Embodiments 16 Formula (Ic-1): [ka] The compounds described in Embodiment 1 or 15 of the list, as shown.

[0310] Enumerated Embodiment 17 Formula (Ic-2): [ka] (In the formula, A is a C3-C8 cycloalkyl, aryl, or heteroaryl compound.) The compounds described in Embodiment 1 or 15 of the list, as shown.

[0311] Enumerated Embodiments 18 Formula (Ic-3): [ka] The compounds described in Embodiment 1 or 15 of the list, as shown.

[0312] Enumerated Embodiments 19 Formula (Ic-4): [ka] (In the formula, A is a C3-C8 cycloalkyl, aryl, or heteroaryl compound.) The compounds described in Embodiment 1 or 15 of the list, as shown.

[0313] Enumerated embodiments 20 Formula (Ic-5): [ka] The compounds described in Embodiment 1 or 15 of the list, as shown.

[0314] Enumerated Embodiments 21 Formula (Id): [ka] (In the formula, r is an integer between 0 and 2.) The compound according to the listed embodiment 1, as shown.

[0315] Enumerated Embodiments 22 Equation (Ie): [ka] (In the formula, r is an integer between 0 and 2.) The compound according to the listed embodiment 1, as shown.

[0316] Enumerated Embodiments 23 Expression (If): [ka] (In the formula, A is a C3-C8 cycloalkyl, aryl, or heteroaryl group; r is an integer between 0 and 2.) The compound according to the listed embodiment 1, as shown.

[0317] Enumerated Embodiments 24 R2 is H or C1-C4 alkyl. A compound according to any one of the embodiments listed above.

[0318] Enumerated Embodiments 25 R2 is methyl. A compound according to any one of the embodiments listed above.

[0319] Enumerated Embodiments 26 R3 is H. A compound according to any one of the embodiments listed above.

[0320] Enumerated Embodiments 27 R4 is a C1-C4 alkyl group. A compound according to any one of the embodiments listed above.

[0321] Enumerated Embodiments 28 R4 is methyl. A compound according to any one of the embodiments listed above.

[0322] Enumerated Embodiments 29 R7 is methyl. A compound according to any one of the embodiments listed above.

[0323] Enumerated embodiments 30 R7 is cyclopropyl. A compound according to any one of the embodiments listed above.

[0324] Enumerated Embodiments 31 at least one R 11 is selected from halogen, C1-C6 alkoxy, or C1-C6 alkyl. A compound according to any one of the embodiments listed above.

[0325] Enumerated Embodiments 32 at least one R 11 H is A compound according to any one of the embodiments listed above.

[0326] Enumerated Embodiment 33 at least one R 11 is fluoro A compound according to any one of the embodiments listed above.

[0327] Enumerated Embodiments 34 at least one R 11 It is a C1-C6 alkoxy. A compound according to any one of the embodiments listed above.

[0328] Enumerated Embodiments 35 The compound [ka] [ka] TIFF2026524962000103.tif205164 [ka] [ka] [ka] [ka] [ka] A compound described in any one of the above-listed embodiments, or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof.

[0329] Enumerated Embodiments 36 A pharmaceutically acceptable composition comprising a compound described in any one of the listed embodiments 1 to 35 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0330] Enumerated Embodiments 37 A method for inhibiting PAD4 in a subject or biological sample, comprising the step of contacting PAD4 with a compound described in any one of the listed embodiments 1 to 35.

[0331] Enumerated Embodiments 38 A method for treating a PAD4-mediated disease, disorder, or condition in a subject requiring treatment, comprising the step of administering a composition described in the listed embodiment 36 to the subject.

[0332] Enumerated Embodiments 39 PAD4-mediated diseases, disorders, or conditions include acid-induced lung injury, acne (PAPA), acute lymphoblastic leukemia, acute respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenal insufficiency, aging, AIDS, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, weight loss, angina pectoris, angioedema, anhidrotic ectodermal dysplasia, ankylosing spondylitis, anterior segment inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, and asthma. Respiration, arteriosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, Behçet's disease, Behçet's syndrome, Bell's palsy, beryllium lung, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysms, chemical stimulus-induced inflammation, chorioretinitis, chronic heart failure, chronic lung disease in premature infants, chronic lymphocytic leukemia, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue disease, corneal ulcer, Crohn's disease, cryopyrin-associated periodic fever syndrome, cryptococcosis, cystic fibrosis, interleukin-1 Receptor antagonist deficiency (DIRA), dermatitis, cutaneous endotoxemia, dermatomyositis, diffuse pontine glioma, endometriosis, endotoxemia, epicondylitis, pure red cell aplasia, familial amyloid polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth restriction, glaucoma, glomerular disease, glomerulonephritis, gout, gouty arthritis, graft-versus-host disease, gastrointestinal diseases, head trauma, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Schönlein purpura, hepatitis, hereditary periodic fever syndrome, herpes zoster, herpes simplex, HIV-1, Hodgkin's disease, Huntington's disease, pulmonary hyaline membrane disease, hyperammonemia, hypercalcemia Diseases, hypercholesterolemia, hyper-IgD syndrome with periodic fever (HIDS), aplastic anemia, other anemias, idiopathic thrombocytopenic purpura, incontinentia pigmenti, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, iritis, stimulus-induced inflammation, ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, renal impairment due to parasitic infection, renal impairment due to parasitic infection, prevention of kidney transplant rejection, leptospirosis, leukemia, Loeffler's syndrome, lung injury, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease,Macklewells syndrome (urticaria, hearing loss, amyloidosis), multiple sclerosis, muscle weakness, muscular dystrophy, myasthenia gravis, myocarditis, mycosis fungoides, myelodysplastic syndrome, myositis, sinusitis, necrotizing enterocolitis, neonatal multiorgan inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological disorders, non-allergen-induced asthma, obesity, ophthalmic allergies, optic neuritis, organ transplantation, osteoarthritis, otitis media, Paget's disease, pain, pancreatitis, Parkinson's disease, pemphigus, pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pertussis, pharyngitis and adenitis (PFAPA syndrome), plant-induced inflammation, pneumonia, pneumonitis, Pneumocystis pneumonia, poison ivy / poison ivy oil-induced inflammation, polyarteritis nodosa, polychondritis, polycystic sacs Selected from the group consisting of polycystic kidney disease, polymyositis, psoriasis, psychosomatic disorders, lung diseases, pulmonary hypertension, pulmonary fibrosis, pyoderma gangrenosum, suppurative aseptic arthritis, kidney diseases, retinal diseases, rheumatic heart disease, rheumatic diseases, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell disease, sickle cell anemia, silica-induced diseases, Sjögren's syndrome, skin diseases, sleep apnea syndrome, solid tumors, spinal cord injury, Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplantation, TNF receptor-associated periodic syndromes (TRAPS), toxoplasmosis, transplantation, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticaria, uveitis, and granulomatosis with polyangiitis. The method according to the listed embodiment 38.

[0333] Enumerated Embodiments 40 PAD4-mediated diseases, disorders, or conditions selected from rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, and psoriasis, The method according to the listed embodiment 38.

[0334] (Equal portions) While numerous embodiments of the Disclosure are described, it is clear that the underlying embodiments may be modified to provide other embodiments utilizing the compounds and methods of the Disclosure. Therefore, it will be understood that the scope of the Disclosure should be defined by the appended claims, rather than by the specific embodiments shown as examples.

[0335] Details of one or more embodiments of this disclosure are described in the accompanying descriptions above. Any methods and substances similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, but only appropriate methods and substances are described here. Other features, purposes, and advantages of this disclosure will be apparent from the specification and claims. In the specification and the accompanying claims, singular nouns are to be considered plural nouns unless the context clearly indicates otherwise. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art of this disclosure. All patents and publications referenced herein are incorporated by reference.

[0336] The preceding statements are provided for explanatory purposes only and are not intended to limit the disclosed content to its specific form. The disclosed content is limited by the attached claims.

Claims

1. Formula I: 【Chemistry 1】 [In the formula, X １ and X ２ Each is independently CR ８ or N; Y is selected from -(CR ９ R １０ ), -O-(CR ｐ R ９ ), -(CR １０ R ｐ ), -O-(CH[[ID=…]] ｐ ), -O-(CH ２ ), -O-CH ｍ ), and -(CR ９ R １０ ), -O-(CH ２ ;), -O-(CH ｍ ), where Y is selected from -O- and -;(注:原文中部分行号重复出现,推测可能是原文排版问题,翻译时保留了原文格式。另外,原文中部分行号缺失,按照顺序补齐了省略的行号,用“…”表示,不影响整体翻译理解。)​​​​​​​​​​​​​​​ R １ It is independently -CH(NHR) ７ ) - (C １ -C ３ A 4- to 8-membered heterocycle comprising an alkyl group, or at least one heteroatom selected from the group consisting of N, O, or S, wherein the alkyl group or heterocycle comprises one or more R groups. １１ It is also fine if it is replaced with; R ２ H or C １ -C ４ It is alkyl; R ３ These are independently H, halogen, or C １ -C ４ It is alkyl; R ４ Hydrogen and C are independent of each other. １ -C ４ Alkyl, or C １ -C ４ It is a haloalkyl; R ５ and R ６ These are independently H, halogen, and C. １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Selected from haloalkyl, heteroaryl, and aryl; the heteroaryl or aryl is one or more halogens or C １ -C ６ It may be substituted with an alkoxy; or R ５ and R ６ C ３ -C ６ Forming cycloalkyl or 4- to 8-membered heterocyclines; or R ５ , R ６ , and R ９ C ３ -C ６ It forms a cycloalkyl, a 4- to 8-membered heterocyclyl, a heteroaryl, or an aryl, and the cycloalkyl, heterocyclyl, heteroaryl, or aryl has one or more R １２ It is also fine if it is replaced with; Each R ７ H and C are independent. １ -C ４ Alkyl and C ３ -C ４ Selected from cycloalkyl; Each R ８ These are independently H, halogen, and C. １ -C ４ Alkyl, C １ -C ４ Haloalkyl and C １ -C ４ Selected from alkoxy; Each R ９ These are independently H, halogen, and C. １ -C ４ Alkyl, or C ３ -C ４ It is carbocyclyl; Each R １０ These are independently H, halogen, or C １ -C ４ It is alkyl; Each R １１ These are independently H, halogen, and C. １ -C ６ Alkyl and C １ -C ６ Selected from alkoxy; Each R １２ is independently H, halogen, -OH, -NH ２ , -CN, C １ -C ６ alkyl, C １ -C ４ alkoxy, C １ -C ４ haloalkoxy, C １ -C ４ haloalkyl, and C ３ -C ４ cycloalkyl, 3- to 10-membered heterocyclyl, heteroaryl, and C ６ -C １０ is selected from aryl; L is a bond or -CH ２ - and; m is an integer selected from 1, 2, and 3; and p is an integer selected from 2, 3, 4, 5, and 6. The compound represented by, or its pharmaceutically acceptable salts, isomers, solvates, prodrugs, or tautomers.

2. Equation (Ia): 【Chemistry 2】 (In the formula, X ３ CH ２ (It is NH, O, or S, and r is an integer between 1 and 3) The compound according to claim 1, as shown by [the formula].

3. Equation (Ia-1) 【Transformation 3】 Equation (Ia-2) 【Chemistry 4】 Equation (Ia-3) 【Transformation 5】 Equation (Ia-4) 【Transformation 6】 , or formula (Ia-5) 【Transformation 7】 (In the formula, X ３ is NH, O, or S, and A is C ３ -C ８ (It is cycloalkyl, aryl, or heteroaryl.) The compound according to claim 1 or 2, as shown by [the formula].

4. Formula (Ib): 【Transformation 8】 The compound according to claim 1, as shown by [the formula].

5. Formula (Ib-1): 【Chemistry 9】 , formula (Ib-2): 【Chemistry 10】 , formula (Ib-3): 【Chemistry 11】 , formula (Ib-4): 【Chemistry 12】 , formula (Ib-5): 【Chemistry 13】 , or formula (Ib-6): 【Chemistry 14】 (In the formula, A is C ３ -C ８ (It is cycloalkyl, aryl, or heteroaryl.) The compound according to claim 1 or 4, as shown in [the provided symbol].

6. Formula (Ic): 【Chemistry 15】 The compound according to claim 1, as shown by [the formula].

7. Formula (Ic-1): 【Chemistry 16】 , formula (Ic-2): 【Chemistry 17】 , formula (Ic-3): [Chemistry 18] , formula (Ic-4): 【Chemistry 19】 , or formula (Ic-5): 【Chemistry 20】 (In the formula, A is C ３ -C ８ (It is cycloalkyl, aryl, or heteroaryl.) The compound according to claim 1 or 6, as shown in [the provided symbol].

8. Formula (Id): 【Chemistry 21】 Equation (Ie): 【Chemistry 22】 , or formula (If): 【Chemistry 23】 (In the formula, A is C ３ -C ８ (It is a cycloalkyl, aryl, or heteroaryl group; r is an integer between 0 and 2.) The compound according to claim 1, as shown by [the formula].

9. R ２ is H or C １ -C ４ It is alkyl. The compound according to any one of the above claims.

10. R ３ H is The compound according to any one of the above claims.

11. R ４ C １ -C ４ It is alkyl. The compound according to any one of the above claims.

12. R ７ is methyl or cyclopropyl. The compound according to any one of the above claims.

13. at least one R １１ H, halogen, fluoro, C １ -C ６ Alkoxy, or C １ -C ６ Selected from alkyl groups, The compound according to any one of the above claims.

14. below: 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 A compound, selected from any one of the preceding claims, or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

16. A method for inhibiting PAD4 in a target or biological sample, comprising contacting PAD4 with a compound according to any one of claims 1 to 14.

17. A method for treating a PAD4-mediated disease, disorder, or condition in a subject requiring treatment, comprising the step of administering the pharmaceutical composition described in claim 15 to the subject.

18. PAD4-mediated diseases, disorders, or conditions include acid-induced lung injury, acne (PAPA), acute lymphoblastic leukemia, acute respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenal insufficiency, aging, AIDS, alcoholic hepatitis, alcoholic liver disease, allergic asthma, allergic bronchopulmonary aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, weight loss, angina pectoris, angioedema, anhidrotic ectodermal dysplasia, ankylosing spondylitis, anterior segment inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, and asthma. Arteriosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, Behçet's disease, Behçet's syndrome, Bell's palsy, beryllium lung, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysms, chemical sting-induced inflammation, chorioretinitis, chronic heart failure, chronic lung disease in premature infants, chronic lymphocytic leukemia, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue disease, corneal ulcer, Crohn's disease, cryopyrin-associated periodic fever syndrome, cryptococcosis, cystic fibrosis, interleukin-1 receptor Constipation antagonist deficiency (DIRA), dermatitis, cutaneous endotoxemia, dermatomyositis, diffuse pontine glioma, endometriosis, endotoxemia, epicondylitis, pure red cell aplasia, familial amyloid polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth restriction, glaucoma, glomerular disease, glomerulonephritis, gout, gouty arthritis, graft-versus-host disease, gastrointestinal diseases, head trauma, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Schönlein purpura, hepatitis, hereditary periodic fever syndrome, herpes zoster, herpes simplex, HIV-1, Hodgkin's disease, Huntington's disease, pulmonary hyaline membrane disease, hyperammonemia, hypercalcemia Hypercholesterolemia, hyperglycemia with periodic fever (HIDS), aplastic anemia, other anemias, idiopathic thrombocytopenic purpura, incontinentia pigmenti, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, iritis, stimulus-induced inflammation, ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, renal impairment due to parasitic infection, renal impairment due to parasitic infection, prevention of kidney transplant rejection, leptospirosis, leukemia, Loeffler's syndrome, lung injury, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease,Macklewells syndrome (urticaria, hearing loss, amyloidosis), multiple sclerosis, muscle weakness, muscular dystrophy, myasthenia gravis, myocarditis, mycosis fungoides, myelodysplastic syndrome, myositis, sinusitis, necrotizing enterocolitis, neonatal-onset multiorgan inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological disorders, non-allergen-induced asthma, obesity, ophthalmic allergies, optic neuritis, Organ transplantation, osteoarthritis, otitis media, Paget's disease, pain, pancreatitis, Parkinson's disease, pemphigus, pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pertussis, pharyngitis and adenitis (PFAPA syndrome), plant irritation-induced inflammation, pneumonia, pneumonitis, Pneumocystis pneumonia, poison ivy / poison ivy oil-induced inflammation, polyarteritis nodosa, polymolax Osteitis, polycystic kidney disease, polymyositis, psoriasis, psoriasis, psoriasis, psychosomatic disorders, lung diseases, pulmonary hypertension, pulmonary fibrosis, pyoderma gangrenosum, suppurative aseptic arthritis, kidney diseases, retinal diseases, rheumatic heart disease, rheumatic diseases, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell disease, sickle cell anemia, silica-induced diseases, Sjögren's syndrome, skin diseases, sleep apnea syndrome Selected from the group consisting of solid tumors, spinal cord injury, Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplantation, TNF receptor-associated periodic syndromes (TRAPS), toxoplasmosis, transplantation, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticaria, uveitis, and granulomatosis with polyangiitis, The method according to claim 17.

19. PAD4-mediated disease, disorder, or condition selected from rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, and psoriasis, The method according to claim 17.

20. PAD4-mediated disease, disorder, or condition is rheumatoid arthritis. The method according to claim 19.

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