Heterocyclic PAD4 inhibitors

Abstract

The present disclosure relates generally to compounds of formula I that are PAD4 inhibitors, methods of preparing these compounds, pharmaceutical compositions comprising these compounds, and the use of these compounds in the treatment of diseases or disorders associated with PAD4 enzyme activity. (I).

Description

Cross-references to related applications

[0001] This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 514,934, filed July 21, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure generally relates to substituted heterocyclic compounds, methods for preparing 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. By referencing the sequence list and incorporating

[0003] This application contains a sequence list submitted via EFS-WEB in .XML format and hereby incorporated in its entirety by reference. The XML copy created on June 19, 2023, is named 055920-606P01US_SeqList_ST26.xml and is 3 kilobytes in size. Background Technology

[0004] PAD4 (SEQ ID NO: 1) is a member of the peptidylarginine deiminase (PAD) enzyme family, which catalyzes the conversion of arginine to citrulline in peptide sequences. PAD4 is responsible for the deiminization or citrullination of a variety of proteins in vitro and in vivo, resulting in diverse functional responses in a variety of diseases (Jones JE et al., Curr. Opin. DrugDiscov. Devel., 12(5), (2009), 616-627). In addition to oncology indications, exemplary diseases or disorders include rheumatoid arthritis, neutrophil-related pathogenesis (e.g., vasculitis, systemic lupus erythematosus, ulcerative colitis). PAD4 inhibitors also have broad applicability as tools and therapeutics for human diseases and disorders through epigenetic mechanisms.

[0005] Inhibitors of PAD4 may be used to combat rheumatoid arthritis (RA), an autoimmune disease affecting approximately 1% of the population (Wegner N. et al., Immunol. Rev., 233(1), (2010), 34-54). RA is characterized by inflammation of the joints, leading to debilitating destruction of bone and cartilage. Although inconsistent, a weak genetic association between PAD4 polymorphism and susceptibility to RA has been proposed in numerous population studies (Kochi Y. et al., Ann. Rheum. Dis., 70, (2011), 512-515). PAD4 (along with its family member PAD2) has been detected in synovial tissue, where it is responsible for the deiminization of various joint proteins. It is speculated that in RA joints, this process leads to the disruption of tolerance to citrullinated substrates such as fibrinogen, vimentin, and collagen, and the initiation of immune responses to them. These anti-citrullinated protein antibodies (ACPA) contribute to the pathogenesis of the disease and can also be used as diagnostic tests for RA (e.g., commercially available CCP2 or cyclic citrullinated protein 2 tests). Additionally, enhanced citrullination can provide further direct contributions to the pathogenesis of the disease through its ability to directly affect several joint and inflammatory mediators (e.g., fibrinogen, antithrombin, and various chemokines). In a smaller subset of RA patients, anti-PAD4 antibodies can be measured and correlated with more aggressive forms of the disease.

[0006] PAD4 inhibitors can also be used to reduce pathological neutrophil activity in a variety of diseases. Studies have shown that the process of neutrophil extracellular trap (NET) formation (an innate defense mechanism through which neutrophils can fixate and kill pathogens) is associated with histone citrullination and is absent 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 damage and disease pathology. Such diseases include, but are not limited to, small vessel 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, asthma (Dworski R. et al., J. Allergy Clin. Immunol., 127(5), (2011), 1260-6), and deep vein thrombosis (Fuchs et al.). 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 that NETs may contribute to the pathology of diseases affecting the skin (e.g., 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)), therefore, PAD4 inhibitors may show benefits in addressing NET-related skin diseases when administered systemically or through the skin. PAD4 inhibitors may affect other functions within neutrophils and have broader applicability to neutrophilic diseases.

[0007] Studies have demonstrated the efficacy of PAD inhibitors (e.g., chloroamidine) in a variety of animal models of diseases, including collagen-induced arthritis (Willis VC et al., J. Immunol., 186(7), (2011), 4396-4404), sodium dextran sulfate (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). The DSS colitis report also demonstrated that chloroamidine induced apoptosis in inflammatory cells both in vitro and in vivo, suggesting that PAD4 inhibitors may be more universally effective in a wide range of inflammatory diseases.

[0008] PAD4 inhibitors have also been used to treat cancer (Slack JL et al., Cell.Mol.Life Sci., 68(4),(2011), 709-720). Overexpression of PAD4 has been demonstrated in many cancers (Chang X. et al., BMCCancer, 9,(2009), 40). The antiproliferative effect of PAD4 inhibitors has been demonstrated by observing that PAD4 citrullinates arginine residues in histones at the promoters of p53 target genes (such as p21) involved in cell cycle arrest and apoptosis induction (Li P. et al., Mol.Cell Biol., 28(15),(2008), 4745-4758).

[0009] The aforementioned role of PAD4 in deiminizing arginine residues in histones may indicate a role for PAD4 in the epigenetic regulation of gene expression. PAD4 is a major member of the PAD family observed to reside in the nucleus and cytoplasm. Early evidence suggesting that PAD4 can act as a histone demethyliminase and deiminase is inconsistent and unproven. However, it may indirectly reduce histone arginine methylation (and thus reduce epigenetic regulation associated with this marker) by depleting available arginine residues through conversion to citrulline. PAD4 inhibitors can be used as epigenetic tools or therapeutics to influence the expression of different target genes in other disease settings. Through such a mechanism, PAD4 inhibitors can also effectively control citrullination levels in stem cells and thus therapeutically influence the pluripotency and differentiation potential of diverse stem cells, including but not limited to embryonic stem cells, neural stem cells, hematopoietic stem cells, and cancer stem cells. Therefore, the need to identify and develop PAD4 inhibitors for the treatment of PAD4-mediated diseases or disorders remains unmet. Summary of the Invention

[0010] This disclosure relates to compounds of formula I: I And its pharmaceutically acceptable salts, isomers, enantiomers, or tautomers, in X1 and X2 are each independently CR8 or N; Y is selected from -(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-; R1 is independently -CH(NHR7)-(C1-C3 alkyl) or a 4- to 8-membered heterocyclic group containing at least one heteroatom selected from N, O, or S, wherein the alkyl or heterocyclic group is optionally surrounded by one or more R 11 replace; R2 is independently H or C1-C4 alkyl; R3 is independently H, halogen, or C1-C4 alkyl; R4 is independently hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; R5 and R6 are independently selected from H, halogens, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, heteroaryl, and aryl; wherein the heteroaryl or aryl is optionally substituted with one or more halogens or C1-C6 alkoxy groups, or R5 and R6, together with the atoms in between, form C3-C6 cycloalkyl groups or 4- to 8-membered heterocyclic groups, or R5, R6, and R9, together with their intermediate and adjacent atoms, form a C3-C6 cycloalkyl, 4- to 8-membered heterocyclic, heteroaryl, or aryl group, wherein the cycloalkyl, heterocyclic, heteroaryl, or aryl group is optionally surrounded by one or more R... 12 replace; 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 carbocyclic group; Each R 10 It is independently H, halogen, or C1-C4 alkyl; Each R 11 Independently selected from H, halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups; Each R 12 Independently selected from H, halogens, -OH, -NH2, -CN, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl and C3-C4 cycloalkyl, 3 to 10 membered heterocyclic groups, heteroaryl groups and C6-C 10 Aryl; L represents 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.

[0011] In another aspect, this disclosure provides a pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof, and one or more pharmaceutically acceptable carriers, excipients, or mediators. In some aspects, the provided pharmaceutical compositions are suitable for oral, parenteral, mucosal, transdermal, or topical application.

[0012] On the other hand, this disclosure provides a method for treating a disease or disorder associated with PAD4 enzyme activity, the method comprising administering to a subject requiring such treatment a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt, isomer, enantiomer or tautomer thereof.

[0013] On the other hand, this disclosure provides a method for treating diseases or disorders related to PAD4 enzyme activity, the method comprising administering to a subject requiring such treatment a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof. Such disorders or conditions particularly include rheumatoid arthritis, vasculitis, systemic lupus erythematosus, and ulcerative colitis.

[0014] Another aspect of this disclosure relates to a method for treating or preventing the condition disclosed herein in a subject in need. The method involves administering to a patient in need an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0015] Another aspect of this disclosure relates to compounds of formula (I) and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, said compounds and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof for use in the manufacture of medicaments for the treatment or prevention of the conditions disclosed herein.

[0016] Another aspect of this disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof in the treatment of the conditions disclosed herein.

[0017] In some respects, this disclosure provides intermediates as described herein, which are suitable for use in methods for preparing compounds as described herein (e.g., intermediates selected from the intermediates described in Examples 1-44).

[0018] In some respects, this disclosure provides a method for preparing the compounds of this disclosure.

[0019] In some respects, this disclosure provides a method for preparing a compound, the method comprising one or more steps described herein. Detailed Implementation

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In this specification, the singular form includes the plural unless the context clearly requires otherwise. Although similar or equivalent methods and materials to those described and materials herein may be used in the practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference. References cited herein are not recognized as prior art to the claimed disclosure. In case of conflict, this specification, including the definitions, shall prevail. Furthermore, materials, methods, and examples are illustrative only and are not intended to be restrictive. In case of conflict between the chemical structures and names of compounds disclosed herein, the chemical structure shall prevail. definition

[0021] The compounds disclosed herein include those generally described above, and are further described by the classes, subclasses and species disclosed herein. Unless otherwise indicated, the following definitions shall apply as used herein. For the purposes of this disclosure, chemical elements are identified according to the periodic table, CAS version, Handbook of Chemistry and Physics, 75th edition. Furthermore, 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 edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by way of incorporation.

[0022] As used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocyclic," "carbocyclic," "aliphatic," or "cycloalkyl") that is fully saturated or contains one or more unsaturated units but is not aromatic, having a single attachment point to the remainder of the molecule. Unless otherwise stated, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 4 aliphatic carbon atoms. In still other embodiments, the aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet another embodiment, the aliphatic group contains 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, etc.

[0023] In some embodiments, a "carbocyclic" (or "alicyclic" or "cycloalkyl") refers to a C3-C8 hydrocarbon, which may be monocyclic or polycyclic, fully saturated, or containing one or more unsaturated units but not aromatic, and has a single attachment point to the rest of the molecule. The rings of polycyclic carbocyclic compounds may be fused, bridged, and / or connected to one or two aromatic cycloalkyl or heterocyclic rings via one or more spirocyclic linkages. Typical non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, etc.

[0024] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any basic nitrogen or quaternized form of substituted nitrogen in a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolealkyl), or NR). + (e.g., in N-substituted pyrroleyl groups). In some embodiments, the oxidized forms of sulfur include S=O and S(=O)2.

[0025] As used in this article, the term "unsaturated" means that a portion has one or more unsaturated units.

[0026] The term "halogen" refers to F, Cl, Br, or I.

[0027] The term "aryl," as used alone or as part of a larger portion of "aralkyl," "arylalkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aromatic ring." In certain embodiments of this disclosure, "aryl" refers to an aromatic ring system, and exemplary groups include phenyl, biphenyl, naphthyl, anthracene, etc., which may carry one or more substituents. As used herein, the scope of the term "aryl" also includes groups in which an aromatic ring is fused with one or more non-aromatic rings, such as indanyl, phthalimide, naphthalimide, phenanthridine, or tetrahydronaphthyl, etc.

[0028] The terms “heteroaryl” and “heteroaryl-”, such as “heteroarylalkyl” or “heteroarylalkoxy”, used alone or as part of a larger part, refer to a group that has 5 to 10 ring atoms (preferably 5, 6, or 9 ring atoms); has 6, 10, or 14 π electrons shared in the cyclic array; and has one to five heteroatoms in addition to a carbon atom. 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. Exemplary heteroaryl groups include thienyl, furanyl, pyrroleyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indoleazinyl, purine, naphridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroary-" also include groups in which the heteroaryl ring is fused with one or more aryl, alicyclic, or heterocyclic rings, wherein a radical or attachment point is located on the heteroaryl ring. Exemplary groups include indolyl, isoindolyl, benzothiopheneyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, terpineyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, carbazoleyl, acridineyl, phenazinyl, phenothiazinyl, phenotoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl," or "heteroaryl family," any of which include optionally substituted rings. The term "heteroaryl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are optionally substituted independently.

[0029] As used herein, the terms “heterocycle,” “heterocyclic group,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic portion that is saturated or partially unsaturated and has one or more (preferably one to four) heteroatoms as defined above in addition to a carbon atom. When referring to the ring atom of the heterocycle, the term “nitrogen” includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen can be N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolealkyl), or... + NR (as in N-substituted pyrroleyl groups).

[0030] Heterocycles can attach to their side groups at any heteroatom or carbon atom to produce stable structures, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include tetrahydrofuranyl, tetrahydrothiophenylpyrrolyl, piperidinyl, pyrrololinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazine, dioxalyl, dioxopentyl, diazaphenyl, oxazphenyl, thioazphenyl, morpholinyl, and quininecycloyl. The terms “heterocycle,” “heterocyclic group,” “heterocyclic ring,” “heterocyclic moiety,” and “heterocyclic radical” are used interchangeably herein and also include groups in which the heterocyclic ring is fused with one or more aryl, heteroaryl, or alicyclic rings, such as indololinyl, 3H-indolyl, cromoglycanyl, phenanthridineyl, or tetrahydroquinolinyl, wherein the radical or attachment point is on the heterocyclic ring. Heterocyclic groups can be monocyclic or bicyclic. The term "heterocyclic alkyl" refers to an alkyl group substituted with a heterocyclic group, wherein the alkyl and heterocyclic groups are independently optional substituted.

[0031] As used herein, the term "partially unsaturated" refers to a ring moiety containing at least one double or triple bond. The term "partially unsaturated" is intended to cover rings having multiple unsaturated sites, but is not intended to include aryl or heteroaryl moiety as defined herein.

[0032] As described herein, compounds of this disclosure may contain an "optionally substituted" portion. Generally, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogens in the specified portion are replaced by suitable substituents. "Substituted" applies to one or more hydrogens explicitly or implicitly present in the structure (e.g., It means at least ;and It means at least , , or Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substituted position of the group, and the substituents may be the same or different at each position when more than one position in any given structure may be substituted by more than one substituent selected from a particular group. The combinations of substituents contemplated in this disclosure preferably result in those that lead to the formation of stable or chemically viable compounds. As used herein, the term "stable" means a compound that remains substantially unchanged when subjected to conditions that allow it to be produced, detected, and, in some embodiments, recovered, purified, and used for one or more purposes disclosed herein.

[0033] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group is independently a halogen; -(CH2) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R o -O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0- 4SR°;-(CH2) 0-4 Ph, which can be replaced by R°; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be substituted by R°; -CH=CHPh, which can be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 -Pyridyl group, which can be substituted by R°; -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 (linear or branched alkylene)ON(R°)2; or -(C 1-4 (straight-chain or branched alkylene)C(O)ON(R°)2, wherein each R° can be substituted as defined below and is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (5-6 membered heteroaryl ring) or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the foregoing definition, two independently occurring R° together with one or more atoms between them to form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, said ring may be substituted as defined below.

[0034] Suitable monovalent substituents on R° (or a ring formed by two independently occurring R° and the atom in between) are independently halogens, -(CH2). 0-2 R • -(halogenated R) • -(CH2) 0-2 OH, -(CH2) 0-2 OR • -(CH2) 0-2 CH(OR • )2;-O(halogenated R • -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 alkylene)C(O)OR • or -SSR • , where each R • It is either unsubstituted or, when preceded by a "halogenated group," substituted by only one or more halogens, and independently selected from C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated, or aryl ring with 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atom of R° include =O and =S.

[0035] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =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-, where each independently occurring R * Selected from hydrogen, C 1-6 Aliphatic (which may be substituted as defined below), or an unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to the adjacent substituted carbon of the "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independently occurring R * Selected from hydrogen, C 1-6Aliphatic (which may be substituted as defined below), or an unsubstituted 5-6 member saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0036] R * Suitable substituents on aliphatic groups include halogens, -R • -(halogenated R) • -OH, -OR • -O (halogenated R) • -CN, -C(O)OH, -C(O)OR • -NH2, -NHR • -NR • 2. or -NO2, where each R • It is either unsubstituted or, when preceded by a "halogenated group," substituted by only one or more halogens, and is independently C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include -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 † ; where each R † Independently, it is hydrogen, C 1-6 Aliphatic (which may be substituted as defined below), unsubstituted -OPh, or unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, despite the above definition, two independently occurring R... † Together with one or more atoms in between, they form unsubstituted 3-12 saturated, partially unsaturated, or aryl monocyclic or bicyclic rings with 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] R † Suitable substituents on the aliphatic group are independently halogens, -R• -(halogenated R) • -OH, -OR • -O (halogenated R) • -CN, -C(O)OH, -C(O)OR • -NH2, -NHR • -NR • 2 or -NO2, where each R • It is either unsubstituted or, when preceded by a "halogenated group," substituted by only one or more halogens, and is independently C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0039] As used herein, the term "subject" means and includes any human or non-human object that may potentially benefit from treatment with a PAD4 inhibitor. Exemplary subjects include humans and animals.

[0040] As used herein, the term “treating” means and includes treating a disease state in a subject (e.g., a human or animal), and includes: (a) suppressing the disease state (i.e., preventing its development); (b) alleviating the disease state (i.e. causing the remission of the disease state); and / or (c) preventing the occurrence of the disease state in the subject.

[0041] As used herein, the term "preventing" refers to and includes preventive treatment (i.e., prevention and / or risk reduction) of a subject's (e.g., human or animal) subclinical disease state, aimed at reducing the probability of the occurrence of a clinical disease state. Subjects are selected for preventive therapy based on factors known to increase the risk of developing a clinical disease state compared to the general population. "Preventive" therapy can be categorized into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment in subjects who have not yet presented with a clinical disease state, while secondary prevention is defined as prevention of a second occurrence of the same or similar clinical disease state.

[0042] As used herein, "therapeutic effective amount" means the amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response. In some embodiments, a therapeutically effective amount 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 dosing regimen to a subject who has or is susceptible to the disease, disorder, and / or condition. As will be understood by those skilled in the art, the effective amount of a substance can vary depending on factors such as the desired biological endpoint, the substance to be delivered, the target cells, or tissues. For example, an effective amount of a compound provided in a formulation for treating a disease, disorder, and / or condition is an amount that reduces, improves, alleviates, inhibits, prevents, delays the onset of one or more symptoms or features of the disease, disorder, and / or condition, reduces the severity of one or more symptoms or features, and / or reduces the incidence of one or more symptoms or features. In some embodiments, a "therapeutic effective amount" is at least the minimum amount of the provided compound or a composition containing the provided compound that is sufficient to treat one or more symptoms of an MK2-mediated disease or disorder. The term "therapeutic effective amount" refers to and includes the amount of a compound or composition according to this disclosure that, when applied alone or in combination, is effective in preventing or treating diseases or disorders related to PAD4 enzyme activity. When applied in combination, the term refers to the combined amount of active ingredients that produce a preventive or therapeutic effect, whether applied in combination, continuously, or simultaneously.

[0043] "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering a bioactive pharmaceutical agent to humans and / or animals. A pharmaceutically acceptable carrier is formulated based on a variety of factors known to those skilled in the art. These factors include, but are not limited to, the type and nature of the active pharmaceutical agent being formulated; the subject to be administered the composition containing the pharmaceutical agent; the intended route of administration of the compound or composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media. In addition to the active pharmaceutical agent, such carriers may contain a variety of different ingredients and additives, which are included in the formulation for a variety of reasons well known to those skilled in the art (e.g., stabilizing active pharmaceutical agents, binders, etc.). Typical non-limiting examples of such carriers include diluents, preservatives, fillers, flow conditioners, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antimicrobial agents, antifungal agents, lubricants, dispersants, coating agents, etc. Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in a variety of readily available sources, such as Allen, LV, Jr. et al., Remington: The Science and Practice of Pharmacy (Vol. 2), 22nd edition, Pharmaceutical Press (2012).

[0044] This disclosure is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include atoms that have the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium (symbol D or π). 2 H) and tritium (symbol T or H) 3 H). For example, a methyl group can be represented by CH3 or CD3. Carbon isotopes include... 13 C and 14 C. The isotopically labeled compounds of this disclosure can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using an appropriate isotopically labeled reagent instead of the originally employed unlabeled reagent.

[0045] Compounds of Formula I form salts, which are also within the scope of this disclosure. Unless otherwise indicated, references to compounds of Formula I described herein should be understood to include references to their salts. As used herein, the term "one or more salts" refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. Additionally, when compounds of Formula I contain both a basic and an acidic moiety, zwitterions ("internal salts") may be formed and included within the term "one or more salts" as used herein. Pharmaceutically acceptable salts include salts generally acceptable in the field of pharmaceutical science for administration to subjects, including humans and animals. Generally, pharmaceutically acceptable salts are non-toxic and physiologically acceptable salts. Salts of compounds according to this disclosure may be formed, for example, by reacting the compound with an amount (e.g., an equivalent amount) of an acid or base in a medium (e.g., a medium in which the salt precipitates) or in an aqueous medium, followed by lyophilization.

[0046] Compounds of formula I containing a basic moiety can form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as salts formed with acetic acid or trihaloacetic acid (e.g., trifluoroacetic acid)), adipates, alginates, ascorbic acid salts, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, diglucuronates, dodecyl sulfates, ethanesulfonates, fumarates, glucohepanoates, glycerophosphates, hemisulfates, heptarates, hexanoates, hydrochlorides (forming with hydrochloric acid), hydrobromide (forming with hydrogen bromide), hydroiodates, and 2-hydroxyl groups. Ethyl sulfonate, lactate, maleate (forms with maleic acid), methanesulfonate (forms with methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, salicylate, succinate, sulfate (such as salts formed with sulfuric acid), sulfonate (such as salts mentioned in this article), tartrate, thiocyanate, toluenesulfonate (such as tosylate), undecanoate, etc.

[0047] Compounds of Formula I containing an acidic moiety can form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts (such as sodium, lithium, and potassium salts), alkaline earth metal salts (such as calcium and magnesium salts), salts formed with organic bases (e.g., organic amines) (such as benzoxan, dicyclohexylamine, hebamin (formed with N,N-bis(dehydroabisulfonyl)-ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butylamine), and salts formed with amino acids (such as arginine, lysine), etc. Basic nitrogen-containing groups can be quaternized with reagents such as lower alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl), dialkyl sulfates (e.g., sulfates of dimethyl, diethyl, dibutyl, and dipentyl), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, lauryl, myristyl, and stearoyl), and aralkyl halides (e.g., bromides of benzyl and phenethyl).

[0048] This disclosure covers compounds of formula I or pharmaceutically acceptable salts thereof, methods for preparing such compounds, pharmaceutical compositions comprising such compounds, and the use of such compounds in the treatment of diseases or disorders related to PAD4 enzyme activity.

[0049] In some embodiments, this disclosure provides compounds of formula I: I, Or its pharmaceutically acceptable salt. Each of L, X1, X2, Y, R1, R2, R3, R4, R5, R6, and R7 is as defined and described herein.

[0050] In some embodiments, this disclosure provides compounds selected from any one of formulas Ia, Ia-1, Ia-2, Ia-3, Ia-4, and Ia-5: Or its pharmaceutically acceptable salt, isomer, enantiomer or tautomer; Where A is a C3-C8 cycloalkyl, a 3- to 8-membered heterocyclic group, an aryl or a heteroaryl group; X3 is CH2, NH, O, or S; and r is an integer from 1 to 3.

[0051] In some embodiments, this disclosure provides compounds selected from any one of formulas Ib, Ib-1, Ib-2, Ib-3, Ib-4, and Ib-5: Or its pharmaceutically acceptable salt, isomer, enantiomer or tautomer; Where A is a C3-C8 cycloalkyl, a 3- to 8-membered heterocyclic group, an aryl or a heteroaryl group.

[0052] In some embodiments, this disclosure provides compounds selected from any one of formulas Ic, Ic-1, Ic-2, Ic-3, Ic-4, and Ic-5: Or its pharmaceutically acceptable salt, isomer, enantiomer or tautomer; Where A is a C3-C8 cycloalkyl, a 3- to 8-membered heterocyclic group, an aryl or a heteroaryl group.

[0053] In some embodiments, this disclosure provides compounds selected from any one of formulas Id, Ie, and If: Or its pharmaceutically acceptable salt, isomer, enantiomer or tautomer; Where A is a C3-C8 cycloalkyl, a 3- to 8-membered heterocyclic group, an aryl or a heteroaryl group; X3 is CH2, NH, O, or S; and r is an integer from 1 to 3.

[0054] In some embodiments, X1 is selected from CR8 or N. In some embodiments of any of the forms described herein, X1 is CR8. In some embodiments of any of the forms described herein, X1 is N.

[0055] In some embodiments, X2 is selected from CR8 or N. In some embodiments of any of the forms described herein, X2 is CR8. In some embodiments of any of the forms described herein, X2 is N.

[0056] In some implementations, Y is selected from -(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-. In some embodiments of any of the forms described herein, Y is -(CR9R 10 )p -. In some embodiments of any of the forms described herein, Y is -O-(CR9R 10 ) p -. In some embodiments of any of the forms described herein, Y is -(CR9R 10 ) p -O-(CH2) m -. In some embodiments of any of the forms described herein, Y is -(CR9R 10 ) p -O-(CH2) m -O-CH2-. In some embodiments of any of the forms described herein, Y is -(CR9R 10 ) p -O-(CH2) m -O-.

[0057] In some embodiments, R1 is -CH(NHR7)-(C1-C3 alkyl) or a 4- to 8-membered heterocycle containing at least one heteroatom selected from N, O, or S, wherein the alkyl or heterocycle is optionally surrounded by one or more R... 11 Substitution. In some embodiments of any of the formulas described herein, R1 is -CH(NHR7)-(C1-C3 alkyl). In some embodiments of any of the formulas described herein, wherein R1 is -CH(NHR7)-(C1-C3 alkyl), the C1-C3 alkyl is replaced by one or more R 11 Replacement. In some embodiments of any of the formulas described herein, R1 is a 4- to 8-membered heterocycle containing at least one heteroatom. In some embodiments of any of the formulas described herein, the heteroatom is selected from N, O, or S. In some embodiments of any of the formulas described herein, the heteroatom is N. In some embodiments of any of the formulas described herein, the heteroatom is O. In some embodiments of any of the formulas described herein, the heteroatom is S. In some embodiments of any of the formulas described herein, the 4- to 8-membered heterocycle containing at least one heteroatom is replaced by one or more R... 11 replace.

[0058] In some embodiments, R2 is selected from H and C1-C4 alkyl. In some embodiments of any formula described herein, R2 is H. In some embodiments of any formula described herein, R2 is C1-C4 alkyl. In some embodiments of any formula described herein, R2 is C1-C3 alkyl. In some embodiments of any formula described herein, R2 is C1-C2 alkyl. In some embodiments of any formula described herein, R2 is C1 alkyl.

[0059] As generally defined above, R3 is selected from H, halogens, and C1-C4 alkyl groups. In some embodiments of any of the formulas described herein, R3 is H. In some embodiments of any of the formulas described herein, R3 is a halogen. In some embodiments of any of the formulas described herein, R3 is a C1-C4 alkyl group. In some embodiments of any of the formulas described herein, R3 is a C1-C3 alkyl group. In some embodiments of any of the formulas described herein, R3 is a C1-C2 alkyl group. In some embodiments of any of the formulas described herein, R3 is a C1 alkyl group.

[0060] In some embodiments, R4 is selected from hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl. In some embodiments of any of the formulas described herein, R4 is hydrogen. In some embodiments of any of the formulas described herein, R4 is C1-C4 alkyl. In some embodiments of any of the formulas described herein, R4 is C1-C3 alkyl. In some embodiments of any of the formulas described herein, R4 is C1-C2 alkyl. In some embodiments of any of the formulas described herein, R4 is C1 alkyl. In some embodiments of any of the formulas described herein, R4 is C2 alkyl. In some embodiments of any of the formulas described herein, R4 is C3 alkyl. In some embodiments of any of the formulas described herein, R4 is C4 alkyl. In some embodiments of any of the formulas described herein, R4 is C1-C4 haloalkyl. In some embodiments of any of the formulas described herein, R4 is C1-C3 haloalkyl. In some embodiments of any of the formulas described herein, R4 is C1-C2 haloalkyl. In some embodiments of any of the formulas described herein, R4 is C1 haloalkyl. In some embodiments of any of the formulas described herein, R4 is C2 haloalkyl. In some embodiments of any of the formulas described herein, R4 is a C3 haloalkyl. In some embodiments of any of the formulas described herein, R4 is a C4 haloalkyl.

[0061] In some embodiments, R5 is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, heteroaryl, or aryl; wherein the heteroaryl or aryl is optionally substituted with one or more halogens or C1-C6 alkoxy groups. In some embodiments of any formula described herein, R5 is H. In some embodiments of any formula described herein, R5 is a halogen. In some embodiments of any formula described herein, R5 is a C1-C4 alkyl. In some embodiments of any formula described herein, R5 is a C1-C3 alkyl. In some embodiments of any formula described herein, R5 is a C1-C2 alkyl. In some embodiments of any formula described herein, R5 is a C1 alkyl. In some embodiments of any formula described herein, R5 is a C2 alkyl. In some embodiments of any formula described herein, R5 is a C3 alkyl. In some embodiments of any formula described herein, R5 is a C4 alkyl. In some embodiments of any formula described herein, R5 is a C1-C4 alkoxy. In some embodiments of any formula described herein, R5 is a C1-C3 alkoxy. In some embodiments of any of the formulas described herein, R5 is a C1-C2 alkoxy. In some embodiments of any of the formulas described herein, R5 is a C1 alkoxy. In some embodiments of any of the formulas described herein, R5 is a C1-C4 haloalkyl. In some embodiments of any of the formulas described herein, R5 is a C1-C3 haloalkyl. In some embodiments of any of the formulas described herein, R5 is a C1-C2 haloalkyl. In some embodiments of any of the formulas described herein, R5 is a C1 haloalkyl. In some embodiments of any of the formulas described herein, R5 is a C2 haloalkyl. In some embodiments of any of the formulas described herein, R5 is a C3 haloalkyl. In some embodiments of any of the formulas described herein, R5 is a C4 haloalkyl. In some embodiments of any of the formulas described herein, R5 is a heteroaryl. In some embodiments of any of the formulas described herein, R5 is an aryl. In some embodiments of any of the formulas described herein, R5 is a heteroaryl or aryl, wherein the heteroaryl or aryl is substituted with one or more halogens. In some embodiments of any of the formulas described herein, R5 is a heteroaryl or aryl group, wherein the heteroaryl or aryl group is substituted with one or more C1-C6 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more halogens. In some embodiments of any of the formulas described herein, R5 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C1-C6 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C1-C5 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C1-C4 alkoxy groups.In some embodiments of any of the formulas described herein, R5 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C1-C3 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C1-C2 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C1 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C2 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C3 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C4 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C5 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C6 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is an aryl group, wherein the aryl group is substituted with one or more halogens. In some embodiments of any of the formulas described herein, R5 is an aryl group, wherein the aryl group is substituted with one or more C1-C6 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is an aryl group, wherein the aryl group is substituted with one or more C1-C5 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is an aryl group, wherein the aryl group is substituted with one or more C1-C4 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is an aryl group, wherein the aryl group is substituted with one or more C1-C3 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is an aryl group, wherein the aryl group is substituted with one or more C1-C2 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is an aryl group, wherein the aryl group is substituted with one or more C1 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is an aryl group, wherein the aryl group is substituted with one or more C2 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is an aryl group, wherein the aryl group is substituted with one or more C3 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is an aryl group, wherein the aryl group is substituted with one or more C4 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is an aryl group, wherein the aryl group is substituted with one or more C5 alkoxy groups. In some embodiments of any of the formulas described herein, R5 is an aryl group, wherein the aryl group is substituted with one or more C6 alkoxy groups.

[0062] In some embodiments, R6 is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, heteroaryl, or aryl; wherein the heteroaryl or aryl is optionally substituted with one or more halogens or C1-C6 alkoxy groups. In some embodiments of any formula described herein, R6 is H. In some embodiments of any formula described herein, R6 is a halogen. In some embodiments of any formula described herein, R6 is a C1-C4 alkyl. In some embodiments of any formula described herein, R6 is a C1-C3 alkyl. In some embodiments of any formula described herein, R6 is a C1-C2 alkyl. In some embodiments of any formula described herein, R6 is a C1 alkyl. In some embodiments of any formula described herein, R6 is a C2 alkyl. In some embodiments of any formula described herein, R6 is a C3 alkyl. In some embodiments of any formula described herein, R6 is a C4 alkyl. In some embodiments of any formula described herein, R6 is a C1-C4 alkoxy. In some embodiments of any formula described herein, R6 is a C1-C3 alkoxy. In some embodiments of any of the formulas described herein, R6 is a C1-C2 alkoxy. In some embodiments of any of the formulas described herein, R6 is a C1 alkoxy. In some embodiments of any of the formulas described herein, R6 is a C1-C4 haloalkyl. In some embodiments of any of the formulas described herein, R6 is a C1-C3 haloalkyl. In some embodiments of any of the formulas described herein, R6 is a C1-C2 haloalkyl. In some embodiments of any of the formulas described herein, R6 is a C1 haloalkyl. In some embodiments of any of the formulas described herein, R6 is a C2 haloalkyl. In some embodiments of any of the formulas described herein, R6 is a C3 haloalkyl. In some embodiments of any of the formulas described herein, R6 is a C4 haloalkyl. In some embodiments of any of the formulas described herein, R6 is a heteroaryl. In some embodiments of any of the formulas described herein, R6 is an aryl. In some embodiments of any of the formulas described herein, R6 is a heteroaryl or aryl, wherein the heteroaryl or aryl is substituted with one or more halogens. In some embodiments of any of the formulas described herein, R6 is a heteroaryl or aryl group, wherein the heteroaryl or aryl group is substituted with one or more C1-C6 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more halogens. In some embodiments of any of the formulas described herein, R6 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C1-C6 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C1-C5 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C1-C4 alkoxy groups.In some embodiments of any of the formulas described herein, R6 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C1-C3 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C1-C2 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C1 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C2 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C3 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C4 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C5 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is a heteroaryl group, wherein the heteroaryl group is substituted with one or more C6 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is an aryl group, wherein the aryl group is substituted with one or more halogens. In some embodiments of any of the formulas described herein, R6 is an aryl group, wherein the aryl group is substituted with one or more C1-C6 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is an aryl group, wherein the aryl group is substituted with one or more C1-C5 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is an aryl group, wherein the aryl group is substituted with one or more C1-C4 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is an aryl group, wherein the aryl group is substituted with one or more C1-C3 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is an aryl group, wherein the aryl group is substituted with one or more C1-C2 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is an aryl group, wherein the aryl group is substituted with one or more C1 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is an aryl group, wherein the aryl group is substituted with one or more C2 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is an aryl group, wherein the aryl group is substituted with one or more C3 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is an aryl group, wherein the aryl group is substituted with one or more C4 alkoxy groups. In some embodiments of any of the formulas described herein, R6 is an aryl group, wherein the aryl group is substituted with one or more C5 alkoxy groups.

[0063] In some embodiments of any of the formulas described herein, R5 and R6, together with their intermediate atoms, form a C3-C6 cycloalkyl or a 4- to 8-membered heterocyclic group. In some embodiments of any of the formulas described herein, R5 and R6, together with their intermediate atoms, form a C3-C6 cycloalkyl. In some embodiments of any of the formulas described herein, R5 and R6, together with their intermediate atoms, form a C3-C4 cycloalkyl. In some embodiments of any of the formulas described herein, R5 and R6, together with their intermediate atoms, form a C3 cycloalkyl. In some embodiments of any of the formulas described herein, R5 and R6, together with their intermediate atoms, form a 4- to 8-membered heterocyclic group. In some embodiments of any of the formulas described herein, R5 and R6, together with their intermediate atoms, form a 4- to 7-membered heterocyclic group. In some embodiments of any of the formulas described herein, R5 and R6, together with their intermediate atoms, form a 4- to 6-membered heterocyclic group. In some embodiments of any of the formulas described herein, R5 and R6 together with the atoms between them form a 4- or 5-membered heterocyclic group. In some embodiments of any of the formulas described herein, R5 and R6 together with the atoms between them form a 4-membered heterocyclic group.

[0064] In some embodiments, each R7 is independently selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl. In some embodiments of any of the formulas described herein, at least one R7 is H. In some embodiments of any of the formulas described herein, at least one R7 is C1-C4 alkyl. In some embodiments of any of the formulas described herein, at least one R7 is C1-C3 alkyl. In some embodiments of any of the formulas described herein, at least one R7 is C1-C2 alkyl. In some embodiments of any of the formulas described herein, at least one R7 is C1 alkyl. In some embodiments of any of the formulas described herein, at least one R7 is C2 alkyl. In some embodiments of any of the formulas described herein, at least one R7 is C3 alkyl. In some embodiments of any of the formulas described herein, at least one R7 is C3-C4 cycloalkyl. In some embodiments of any of the formulas described herein, at least one R7 is C3 cycloalkyl. In some embodiments of any of the formulas described herein, at least one R7 is C4 cycloalkyl. In some embodiments of any of the formulas described herein, at least one R7 is cyclopropyl.

[0065] As generally defined above, each R8 is independently selected from H, halogen, -C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy. In some embodiments of any of the formulas described herein, at least one R8 is independently selected from halogen, alkoxy, and alkyl. In some embodiments of any of the formulas described herein, at least one R8 is H. In some embodiments of any of the formulas described herein, at least one R8 is a halogen. In some embodiments of any of the formulas described herein, at least one R8 is a C1-C4 alkyl. In some embodiments of any of the formulas described herein, at least one R8 is a C1-C3 alkyl. In some embodiments of any of the formulas described herein, at least one R8 is a C1-C2 alkyl. In some embodiments of any of the formulas described herein, at least one R8 is a C1 alkyl. In some embodiments of any of the formulas described herein, at least one R8 is a C2 alkyl. In some embodiments of any of the formulas described herein, at least one R8 is a C3 alkyl. In some embodiments of any of the formulas described herein, at least one R8 is a C4 alkyl. In some embodiments of any of the formulas described herein, at least one R8 is a C1-C4 haloalkyl. In some embodiments of any of the formulas described herein, at least one R8 is a C1-C3 haloalkyl. In some embodiments of any of the formulas described herein, at least one R8 is a C1-C2 haloalkyl. In some embodiments of any of the formulas described herein, at least one R8 is a C1 haloalkyl. In some embodiments of any of the formulas described herein, at least one R8 is a C2 haloalkyl. In some embodiments of any of the formulas described herein, at least one R8 is a C3 haloalkyl. In some embodiments of any of the formulas described herein, at least one R8 is a C4 haloalkyl. In some embodiments of any of the formulas described herein, at least one R8 is a C1-C4 alkoxy. In some embodiments of any of the formulas described herein, at least one R8 is a C1-C3 alkoxy. In some embodiments of any of the formulas described herein, at least one R8 is a C1-C2 alkoxy. In some embodiments of any of the formulas described herein, at least one R8 is a C1 alkoxy. In some embodiments of any of the formulas described herein, at least one R8 is a C2 alkoxy. In some embodiments of any of the formulas described herein, at least one R8 is a C3 alkoxy. In some embodiments of any of the formulas described herein, at least one R8 is a C4 alkoxy.

[0066] As generally defined above, each R9 is independently selected from H, halogen, C1-C4 alkyl, and C3-C4 carbocyclic groups. In some embodiments of any of the formulas described herein, R9 is H. In some embodiments of any of the formulas described herein, R9 is a halogen. In some embodiments of any of the formulas described herein, R9 is a C1-C4 alkyl. In some embodiments of any of the formulas described herein, R9 is a C1-C3 alkyl. In some embodiments of any of the formulas described herein, R9 is a C1-C2 alkyl. In some embodiments of any of the formulas described herein, R9 is a C1 alkyl.

[0067] In some embodiments of any of the formulas described herein, R9 is a C2 alkyl group. In some embodiments of any of the formulas described herein, R9 is a C3 alkyl group. In some embodiments of any of the formulas described herein, R9 is a C4 alkyl group. In some embodiments of any of the formulas described herein, R9 is a C3-C4 carbocyclic group. In some embodiments of any of the formulas described herein, R9 is a C3 carbocyclic group. In some embodiments of any of the formulas described herein, R9 is a C4 carbocyclic group.

[0068] As generally defined above, each R 10 Independently selected from H, halogens, and C1-C4 alkyl groups. In some embodiments of any of the formulas described herein, R 10 It is H. In some embodiments of any of the forms described herein, R 10 It is a halogen. In some embodiments of any of the forms described herein, R 10 It is a C1-C4 alkyl group. In some embodiments of any of the formulas described herein, R 10 It is a C1-C3 alkyl group. In some embodiments of any of the formulas described herein, R 10 It is a C1-C2 alkyl group. In some embodiments of any of the formulas described herein, R 10 It is a C1 alkyl group. In some embodiments of any of the formulas described herein, R 10 It is a C2 alkyl group. In some embodiments of any of the formulations described herein, R 10 It is a C3 alkyl group. In some embodiments of any of the formulations described herein, R 10 It is a C4 alkyl group.

[0069] In some embodiments of any of the formulas described herein, R5, R6, and R9, together with their intermediate and adjacent atoms, form a C3-C6 cycloalkyl, 4- to 8-membered heterocyclic, heteroaryl, or aryl group, wherein the cycloalkyl, heterocyclic, heteroaryl, or aryl group is optionally surrounded by one or more R... 12Substitution. In some embodiments of any of the formulas described herein, R5, R6, and R9, together with their intermediate and adjacent atoms, form a C3-C6 cycloalkyl group. In some embodiments of any of the formulas described herein, R5, R6, and R9, together with their intermediate and adjacent atoms, form a C3 cycloalkyl group. In some embodiments of any of the formulas described herein, R5, R6, and R9, together with their intermediate and adjacent atoms, form a C4 cycloalkyl group. In some embodiments of any of the formulas described herein, R5, R6, and R9, together with their intermediate and adjacent atoms, form a C5 cycloalkyl group. In some embodiments of any of the formulas described herein, R5, R6, and R9, together with their intermediate and adjacent atoms, form a C6 cycloalkyl group. In some embodiments of any of the formulas described herein, R5, R6, and R9, together with their intermediate and adjacent atoms, form a 4- to 8-membered heterocyclic group. In some embodiments of any of the formulas described herein, R5, R6, and R9, together with their intermediate and adjacent atoms, form a 4-membered heterocyclic group. In some embodiments of any of the formulas described herein, R5, R6, and R9, together with their intermediate and adjacent atoms, form a 5-membered heterocyclic group. In some embodiments of any of the formulas described herein, R5, R6, and R9, together with their intermediate and adjacent atoms, form a 6-membered heterocyclic group. In some embodiments of any of the formulas described herein, R5, R6, and R9, together with their intermediate and adjacent atoms, form a 7-membered heterocyclic group. In some embodiments of any of the formulas described herein, R5, R6, and R9, together with their intermediate and adjacent atoms, form an 8-membered heterocyclic group. In some embodiments of any of the formulas described herein, R5, R6, and R9, together with their intermediate and adjacent atoms, form a heteroaryl group. In some embodiments of any of the formulas described herein, R5, R6, and R9, together with their intermediate and adjacent atoms, form an aryl group. In some embodiments of any of the formulas described herein, R5, R6, and R9, together with their intermediate and adjacent atoms, form a C3-C6 cycloalkyl group, wherein the cycloalkyl group is influenced by one or more R... 12 Replacement. In some embodiments of any of the formulas described herein, R5, R6, and R9 together with their intermediate and adjacent atoms form a 4- to 8-membered heterocyclic group, wherein the heterocyclic group is replaced by one or more R... 12 Substitution. In some embodiments of any of the formulas described herein, R5, R6, and R9 together with their intermediate and adjacent atoms form a heteroaryl group, wherein the heteroaryl group is replaced by one or more R... 12 Substitution. In some embodiments of any of the formulas described herein, R5, R6, and R9 together with their intermediate and adjacent atoms form an aryl group, wherein the aryl group is replaced by one or more R... 12 replace.

[0070] As generally defined above, each R 11Independently selected from H, halogens, C1-C6 alkyl, and C1-C6 alkoxy groups. In some embodiments of any of the formulas described herein, R 11 It is H. In some embodiments of any of the forms described herein, R 11 It is a halogen. In some embodiments of any of the forms described herein, R 11 It is a C1-C6 alkyl group. In some embodiments of any of the formulas described herein, R 11 It is a C1-C5 alkyl group. In some embodiments of any of the formulas described herein, R 11 It is a C1-C4 alkyl group. In some embodiments of any of the formulas described herein, R 11 It is a C1-C3 alkyl group. In some embodiments of any of the formulas described herein, R 11 It is a C1-C2 alkyl group. In some embodiments of any of the formulas described herein, R 11 It is a C1 alkyl group. In some embodiments of any of the formulas described herein, R 11 It is a C2 alkyl group. In some embodiments of any of the formulations described herein, R 11 It is a C3 alkyl group. In some embodiments of any of the formulations described herein, R 11 It is a C4 alkyl group. In some embodiments of any of the formulations described herein, R 11 It is a C5 alkyl group. In some embodiments of any of the formulations described herein, R 11 It is a C6 alkyl group. In some embodiments of any of the formulations described herein, R 11 It is a C1-C6 alkoxy group. In some embodiments of any of the formulas described herein, R 11 It is a C1-C5 alkoxy group. In some embodiments of any of the formulas described herein, R 11 It is a C1-C4 alkoxy group. In some embodiments of any of the formulas described herein, R 11 It is a C1-C3 alkoxy group. In some embodiments of any of the formulas described herein, R 11 It is a C1-C2 alkoxy group. In some embodiments of any of the formulas described herein, R 11 It is a C1 alkoxy group. In some embodiments of any of the formulas described herein, R 11 It is a C2 alkoxy group. In some embodiments of any of the formulations described herein, R 11 It is a C3 alkoxy group. In some embodiments of any of the formulations described herein, R 11 It is a C4 alkoxy group. In some embodiments of any of the formulations described herein, R 11 It is a C5 alkoxy group. In some embodiments of any of the formulations described herein, R 11 It is a C6 alkoxy group.

[0071] In some implementations, each R 12 Independently selected from H, halogens, -OH, -NH2, -CN, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl and C3-C4 cycloalkyl, 3 to 10 membered heterocyclic groups, heteroaryl groups and C6-C 10 Aryl. In some embodiments of any of the forms described herein, at least one R 12 Selected from H, halogens, C1-C4 alkoxy groups, or C1-C6 alkyl groups. In some embodiments of any of the formulas described herein, R... 12 It is H. In some embodiments of any of the forms described herein, R 12 It is a halogen. In some embodiments of any of the forms described herein, R 12 It is -OH. In some embodiments of any of the formulas described herein, R 12 It is -NH2. In some embodiments of any of the forms described herein, R 12 It is -CN. In some implementations of any of the forms described herein, R 12 It is a C1-C6 alkyl group. In some embodiments of any of the formulas described herein, R 12 It is a C1-C5 alkyl group. In some embodiments of any of the formulas described herein, R 12 It is a C1-C4 alkyl group. In some embodiments of any of the formulas described herein, R 12 It is a C1-C3 alkyl group. In some embodiments of any of the formulas described herein, R 12 It is a C1-C2 alkyl group. In some embodiments of any of the formulas described herein, R 12 It is a C1 alkyl group. In some embodiments of any of the formulas described herein, R 12 It is a C2 alkyl group. In some embodiments of any of the formulations described herein, R 12 It is a C3 alkyl group. In some embodiments of any of the formulations described herein, R 12 It is a C4 alkyl group. In some embodiments of any of the formulations described herein, R 12 It is a C5 alkyl group. In some embodiments of any of the formulations described herein, R 12 It is a C6 alkyl group. In some embodiments of any of the formulations described herein, R 12 It is a C1-C4 alkoxy group. In some embodiments of any of the formulas described herein, R 12 It is a C1-C3 alkoxy group. In some embodiments of any of the formulas described herein, R 12 It is a C1-C2 alkoxy group. In some embodiments of any of the formulas described herein, R 12 It is a C1 alkoxy group. In some embodiments of any of the formulas described herein, R 12It is a C2 alkoxy group. In some embodiments of any of the formulations described herein, R 12 It is a C3 alkoxy group. In some embodiments of any of the formulations described herein, R 12 It is a C4 alkoxy group. In some embodiments of any of the formulations described herein, R 12 It is a C1-C4 haloalkoxy group. In some embodiments of any of the formulas described herein, R 12 It is a C1 haloalkoxy group. In some embodiments of any of the formulas described herein, R 12 It is a C2 haloalkoxy group. In some embodiments of any of the formulations described herein, R 12 It is a C3 haloalkoxy group. In some embodiments of any of the formulations described herein, R 12 It is a C4 haloalkoxy group. In some embodiments of any of the formulations described herein, R 12 It is a C1-C4 haloalkyl. In some embodiments of any of the formulas described herein, R 12 It is a C1 haloalkyl group. In some embodiments of any of the formulas described herein, R 12 It is a C2 haloalkyl group. In some embodiments of any of the formulas described herein, R 12 It is a C3 haloalkyl group. In some embodiments of any of the formulas described herein, R 12 It is a C4 haloalkyl group. In some embodiments of any of the formulas described herein, R 12 It is a C3-C4 cycloalkyl group. In some embodiments of any of the formulas described herein, R 12 It is a C3 cycloalkyl group. In some embodiments of any of the formulations described herein, R 12 It is a C4 cycloalkyl group. In some embodiments of any of the formulations described herein, R 12 It is a C5 cycloalkyl group. In some embodiments of any of the formulations described herein, R 12 It is a C6 cycloalkyl group. In some embodiments of any of the formulations described herein, R 12 It is a C7 cycloalkyl group. In some embodiments of any of the formulations described herein, R 12 It is a C8 cycloalkyl group. In some embodiments of any of the formulations described herein, R 12 It is a C9 cycloalkyl group. In some embodiments of any of the formulations described herein, R 12 It is C 10 Cycloalkyl. In some embodiments of any of the formulations described herein, R 12 It is a 3- to 10-membered heterocyclic group. In some embodiments of any of the forms described herein, R 12 It is a 3-membered heterocyclic group. In some embodiments of any of the forms described herein, R 12 It is a 4-membered heterocyclic group. In some embodiments of any of the forms described herein, R12 It is a 5-membered heterocyclic group. In some embodiments of any of the forms described herein, R 12 It is a 6-membered heterocyclic group. In some embodiments of any of the forms described herein, R 12 It is a 7-membered heterocyclic group. In some embodiments of any of the forms described herein, R 12 It is an 8-membered heterocyclic group. In some embodiments of any of the forms described herein, R 12 It is a 9-membered heterocyclic group. In some embodiments of any of the forms described herein, R 12 It is a 10-membered heterocyclic group. In some embodiments of any of the forms described herein, R 12 It is a heteroaryl group. In some embodiments of any of the forms described herein, R 12 It is C6-C 10 Aryl. In some embodiments of any of the forms described herein, R 12 It is C6 aryl. In some embodiments of any of the forms described herein, R 12 It is C8 aryl. In some embodiments of any of the forms described herein, R 12 It is C9 aryl. In some embodiments of any of the forms described herein, R 12 It is C 10 Aryl.

[0072] In some embodiments, L is selected from covalent bonds and -CH2-. In some embodiments of any of the formulas described herein, L is a covalent bond. In some embodiments of any of the formulas described herein, L is -CH2-.

[0073] In some embodiments, m is an integer selected from 1, 2, and 3. In some embodiments of any of the expressions described herein, m is 1. In some embodiments of any of the expressions described herein, m is 2. In some embodiments of any of the expressions described herein, m is 3.

[0074] In some embodiments, p is an integer selected from 2, 3, 4, 5, and 6. In some embodiments of any of the forms described herein, p is 2. In some embodiments of any of the forms described herein, p is 3. In some embodiments of any of the forms described herein, p is 4. In some embodiments of any of the forms described herein, p is 5. In some embodiments of any of the forms described herein, p is 6.

[0075] In some embodiments, X3 is selected from CH2, NH, O, and S. In some embodiments of any of the formulas described herein, X3 is CH2. In some embodiments of any of the formulas described herein, X3 is NH. In some embodiments of any of the formulas described herein, X3 is O. In some embodiments of any of the formulas described herein, X3 is S.

[0076] In some embodiments, A is selected from C3-C8 cycloalkyl, aryl, and heteroaryl. In some embodiments of any formula described herein, A is C3-C8 cycloalkyl. In some embodiments of any formula described herein, A is C3 cycloalkyl. In some embodiments of any formula described herein, A is C4 cycloalkyl. In some embodiments of any formula described herein, A is C5 cycloalkyl. In some embodiments of any formula described herein, A is C6 cycloalkyl. In some embodiments of any formula described herein, A is C7 cycloalkyl. In some embodiments of any formula described herein, A is C8 cycloalkyl. In some embodiments of any formula described herein, A is aryl. In some embodiments of any formula described herein, A is heteroaryl.

[0077] In some embodiments, r is an integer from 0 to 3. In some embodiments of any of the forms described herein, r is from 1 to 3. In some embodiments of any of the forms described herein, r is from 0 to 2. In some embodiments of any of the forms described herein, r is 0. In some embodiments of any of the forms described herein, r is 1. In some embodiments of any of the forms described herein, r is 2. In some embodiments of any of the forms described herein, r is 3.

[0078] In some embodiments, the compounds of formula I are selected from: Or its pharmaceutically acceptable salt.

[0079] It should be understood that all isomers are included in this disclosure, including mixtures thereof. If the compound contains a double bond, the substituents may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration. All tautomers are also intended to be included.

[0080] The compounds disclosed herein, as well as their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs, can exist in their tautomeric forms (e.g., as amides or imino ethers). All such tautomeric forms are considered herein as part of this disclosure.

[0081] The compounds disclosed herein may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of this disclosure, as well as mixtures thereof (including racemic mixtures), constitute a part of this disclosure. Furthermore, this disclosure includes all geometric and positional isomers. For example, if a compound of this disclosure incorporates a double bond or a fused ring, both the cis and trans forms, as well as mixtures thereof, are included within the scope of this disclosure. Each compound disclosed herein includes all enantiomers conforming to the general structure of the compound. Compounds may be in racemic or enantiomerically pure forms, or any other form for stereochemical purposes. Measurement results may reflect data collected in the racemic form, the enantiomerically pure form, or any other form for stereochemical purposes.

[0082] A mixture of diastereomers can be separated into their respective diastereomers based on their physicochemical differences using methods well known to those skilled in the art, such as, for example, chromatography and / or fractional crystallization. Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the respective diastereomers into their corresponding pure enantiomers. Furthermore, some compounds in this disclosure can be transisomers (e.g., substituted biaryl groups) and are considered part of this disclosure. Enantiomers can also be separated using a chiral HPLC column.

[0083] It is also possible that the compounds of this disclosure can exist in different tautomeric forms, and all such forms are included within the scope of this disclosure. Furthermore, for example, all keto-enol and imine-enamine forms of the compounds are included in this disclosure.

[0084] All stereoisomers of the compounds of this invention (e.g., geometric isomers, optical isomers, etc.) (including salts, solvates, esters, and prodrugs of the compounds, as well as salts, solvates, and esters of prodrugs), such as those due to the presence of asymmetric carbons on various substituents, including enantiomers (which may even be present in the absence of asymmetric carbons), rotational isomers, trans-blocking isomers, and diastereomeric isomers, are also included within the scope of this disclosure, as are positional isomers (e.g., 4-pyridyl and 3-pyridyl). (For example, if the compound of formula (I) contains a double bond or a fused ring, both cis and trans forms, as well as mixtures, are included within the scope of this disclosure. Furthermore, for example, all keto-enol and imine-enamine forms of the compounds are included in this disclosure.) A single stereoisomer of a compound of this disclosure may, for example, be substantially free of other isomers, or may be mixed, for example, as a racemic mixture or mixed with all other stereoisomers or selected other stereoisomers. The chiral center of this disclosure may have an S or R configuration as defined in IUPAC 1974 Recommendations. The use of the terms “salt,” “solvent,” “ester,” “prodrug,” etc., is intended to equally apply to salts, solvates, esters, and prodrugs of enantiomers, stereoisomers, rotational isomers, tautomers, positional isomers, racemates, or prodrugs of the compounds of this invention. Pharmaceutical Composition

[0085] In some embodiments, this disclosure provides a composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator. The amount of the compound in the composition of this disclosure is such that it effectively and measurably inhibits PAD4 in a biological sample or patient. In some embodiments, the amount of the compound in the composition of this disclosure is such that it effectively and measurably inhibits PAD4 in a biological sample or patient. In some embodiments, the composition provided herein is formulated for administration to a patient requiring such a composition. In some embodiments, the composition provided herein is formulated for oral administration to a patient.

[0086] The compositions provided in this disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted receptacle. As used herein, the term "parenterally" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions provided in this disclosure can be an aqueous or oil-based suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable formulation can also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable media and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixative oils are conventionally used as solvents or suspending media.

[0087] For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids (such as oleic acid and its glycerol derivatives) can be used to prepare injectables; these are pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially in their polyoxyethylated form. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

[0088] The pharmaceutically acceptable compositions provided in this disclosure can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are typically added as well. For oral administration in capsule form, available diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. Certain sweeteners, flavoring agents, or coloring agents may also be added if desired.

[0089] Alternatively, the pharmaceutically acceptable compositions provided in this disclosure can be administered in the form of suppositories for rectal use. They can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the agent. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0090] The pharmaceutically acceptable compositions provided in this disclosure can also be applied topically, particularly when the target of treatment includes areas or organs easily accessible through topical application, including diseases of the eyes, skin, or lower intestine. Suitable topical formulations can be readily prepared for each of these areas or organs. Topical applications for the lower intestine can function in rectal suppository formulations or suitable enema formulations. Topical transdermal patches can also be used. For topical applications, the provided pharmaceutically acceptable compositions can be formulated in suitable ointments containing active ingredients suspended or dissolved in one or more carriers. Carriers for the topical application of the compounds provided in this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water.

[0091] Alternatively, the provided pharmaceutically acceptable composition may be formulated in a suitable lotion or cream 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-octyldodecyl alcohol, benzyl alcohol, and water.

[0092] For ophthalmic applications, the provided pharmaceutically acceptable composition may be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline with or without a preservative (such as benzyl ammonium chloride). Alternatively, for ophthalmic applications, the pharmaceutically acceptable composition may be formulated in an ointment (such as petrolatum).

[0093] The pharmaceutically acceptable compositions provided in this disclosure can also be administered via nasal aerosol or inhalation. Such compositions can be prepared as saline solutions using techniques well known in the field of pharmaceutical formulation, employing benzyl alcohol or other suitable preservatives, adsorption enhancers to improve bioavailability, fluorocarbons, and / or other conventional stabilizers or dispersants.

[0094] 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.

[0095] As needed, the pharmaceutically acceptable compositions provided in this disclosure may be administered to humans and other animals orally, rectally, parenterally, intracerebrospinally, vaginally, intraperitoneally, topically (e.g., by powder, ointment, or drops), buccally, as an oral or nasal spray, etc. In some embodiments, the compounds provided in this disclosure may be administered orally or parenterally once or more daily at dose levels of about 0.01 mg / kg to about 50 mg / kg, and preferably from about 1 mg / kg to about 25 mg / kg of the subject's body weight, to achieve the desired therapeutic effect.

[0096] 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, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitol fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0097] Injectable formulations, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile fixing oils are routinely used as solvents or suspending media. For this purpose, any mild fixing oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids (such as oleic acid) can also be used in the preparation of injectable formulations.

[0098] Injectable preparations can be sterilized, for example, by filtering through a bacterial retention filter or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0099] To prolong the effects of the compounds provided in this disclosure, it is generally desirable to slow the absorption of compounds injected subcutaneously or intramuscularly. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of the compound then depends on its dissolution rate, which in turn can depend on crystal size and crystal form. Alternatively, delayed absorption of parenteral-administered compounds can be achieved by dissolving or suspending the compound in an oily medium. Injectable depot forms are prepared by forming microcapsule matrices of the compound in a biodegradable polymer such as polylactide-polyglycolic acid. The rate of compound release can be controlled depending on the ratio of compound to polymer and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Depot injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

[0100] Compositions for rectal or vaginal application are preferably suppositories, which can be prepared by mixing the compounds provided in this disclosure with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and thus melts in the rectal or vaginal cavity and releases the active compound.

[0101] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; (e) solution blockers, such as paraffin; (f) absorption enhancers, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) absorbents, such as kaolin and bentonite; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

[0102] Similar solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or toffee and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. They may optionally contain light-blocking agents and may also have compositions that release only one or more active ingredients, or preferentially in a portion of the intestine, preferably in a delayed manner. Examples of encapsulation compositions that can be used include polymeric substances and waxes. Similar solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or toffee and high molecular weight polyethylene glycol.

[0103] The active compound may also be in a microencapsulated form having one or more excipients as described above. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells, such as enteric coatings, release-controlled coatings, and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. These dosage forms may also contain (as is common practice) additional substances besides inert diluents such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage form may also contain a buffer.

[0104] Dosage forms of the compounds provided in this disclosure for topical or transdermal application include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is mixed under aseptic conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, if required. Ophthalmic preparations, ear drops, and eye drops are also contemplated within the scope of this disclosure. Additionally, this disclosure considers the use of transdermal patches, which offer the added advantage of controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0105] Depending on the intended mode of administration, the disclosed compositions may be in solid, semi-solid, or liquid dosage forms, such as, for example, injections, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, etc., sometimes in unit doses and consistent with conventional pharmaceutical practice. Similarly, they may be administered intravenously (push and infusion), intraperitoneally, subcutaneously, or intramuscularly, all in forms well known to those skilled in the art of pharmaceutical science.

[0106] The amount of compounds in this disclosure that can be combined with carrier materials to produce compositions in a single dosage form will vary depending on the host being treated and the specific administration method. Preferably, the provided compositions should be formulated such that inhibitors can be administered to patients receiving these compositions at doses between 0.01 and 100 mg / kg body weight / day.

[0107] The compounds of this disclosure may be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies may take the form of a fixed combination, or the compounds of this disclosure and one or more other therapeutic compounds administered alternately or independently of each other, or a fixed combination and one or more other therapeutic compounds administered together. Examples of other such therapeutic agents include corticosteroids, cyclophosphamide, carvirstatin, cytokine-suppressing anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyguanidine (DSG); nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, celecoxib, and rofecoxib; steroids, such as prednisone or dexamethasone; antiviral agents, such as abacavir; antiproliferative agents, such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf); cytotoxic drugs, such as azathioprine and cyclophosphamide; TNF-α inhibitors, such as tenidap, anti-TNF antibodies or soluble TNF receptors, and rapamycin (sirolimus or rapamune) or their derivatives. Furthermore, or additionally, the compounds of this disclosure may be administered in combination with chemotherapy, radiotherapy, immunotherapy, light therapy, surgical intervention, or combinations thereof, particularly for cancer therapy. As mentioned above, in the context of other treatment strategies, long-term therapy is equally possible as adjuvant therapy. Other possible treatments include therapies to maintain the patient's condition after tumor regression, or even chemopreventive therapy (e.g., in patients at risk).

[0108] These additional agents can be administered separately from the composition containing the compounds of the present invention as part of a multiple-dosing regimen. Alternatively, these agents can be part of a single dosage form, mixed together with the compounds of this disclosure in a single composition. If administered as part of a multiple-dosing regimen, the two active agents can be taken simultaneously, sequentially, or at intervals between each other (typically within five hours).

[0109] As used herein, the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of a therapeutic agent according to this disclosure. For example, a compound of this disclosure may be administered simultaneously or sequentially with another therapeutic agent in an independent unit dosage form or together in a single unit dosage form. Thus, this disclosure provides a single unit dosage form comprising a compound of this disclosure, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or mediator.

[0110] The amounts of the provided compound and additional therapeutic agents (in those compositions containing additional therapeutic agents as described above) that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific method of administration. Preferably, the compositions of this disclosure are formulated such that the provided compound can be administered at a dose between 0.01 and 100 mg / kg body weight / day.

[0111] In those compositions that include additional therapeutic agents, the additional therapeutic agents and the compounds of this disclosure can act synergistically. Therefore, the amount of the additional therapeutic agent in such compositions will be less than the amount required in a single therapy using only said therapeutic agent.

[0112] The amount of additional therapeutic agent present in the compositions disclosed herein will not exceed the amount typically applied in compositions containing said therapeutic agent as the sole active pharmaceutical ingredient. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will be in the range of about 50% to 100% of the amount typically present in compositions containing said pharmaceutical agent as the sole active pharmaceutical ingredient.

[0113] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, timing of administration, excretion rate, drug combination, as well as the judgment of the treating physician and the severity of the specific disease or disorder being treated. The amount of the compounds of this disclosure in the composition will also depend on the specific compounds in the composition. Methods for synthesizing compounds

[0114] The compounds disclosed herein can be prepared by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the schemes given below.

[0115] Compounds of formula (I) can be prepared by methods known in the field of organic synthesis, as described in the following synthetic schemes section. In the schemes described below, it is readily understood that protecting groups, which are sensitive or reactive, are used where necessary, according to general principles or chemistry. Protecting groups are operated according to standard methods of organic synthesis (TW Greene and P. GM Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods readily apparent to those skilled in the art. Those skilled in the art will recognize the presence of a stereocenter in compounds of formula (I) depending on the chosen method and the reaction conditions and sequence. Therefore, this disclosure includes two possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but also their respective enantiomers and / or diastereomers. When a compound is required as a single enantiomer or diastereomer, it can be obtained by stereooriented synthesis or by resolving the final product or any convenient intermediate. The resolving of the final product, intermediate, or starting material may be influenced by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E.L. Eliel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994).

[0116] The compounds described herein can be obtained from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.

[0117] For example, the compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry, or variations thereof as understood by those skilled in the art. Illustrative methods include, but are not limited to, those described below. The compounds of the present invention can be synthesized according to the steps outlined in general schemes A, B, C, and D, which include different sequences of assembling intermediates. Starting materials can be commercially available or prepared using known procedures reported in the literature or as shown in the figures. Where X1, X2, Y, R1, R2, R3, R4, R5, R6, R7, and L are as defined above (or their protected forms), LG is fluorine, chlorine, bromine, iodine, halogen, -OH, -OTs, or another suitable leaving group, LG2 is fluorine, chlorine, bromine, iodine, halogen, or another suitable leaving group, and R 13 It is H or OH. How to use

[0118] The compounds and compositions described herein are generally used to inhibit PAD4.

[0119] The activity of the compounds used as PAD4 inhibitors in this disclosure can be determined in vitro, in vivo, or in cell lines. In vitro assays include determinations to confirm PAD4 inhibition. Detailed conditions for determining the compounds used as PAD4 inhibitors in this disclosure are illustrated in the following examples. In some embodiments, the provided compounds selectively inhibit PAD4 compared to PAD2.

[0120] As used herein, the terms "treatment" (treatment, treat, and treating) refer to reversing, alleviating, delaying the onset of a disease or disorder or one or more symptoms thereof, or inhibiting its progression, as described herein. In some embodiments, treatment may be administered after one or more symptoms have appeared. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also continue after symptoms have subsided, for example, to prevent or delay their recurrence.

[0121] The provided compounds are inhibitors of PAD4 and are therefore useful for treating one or more diseases or disorders associated with PAD4 enzyme activity. Accordingly, in some embodiments, this disclosure provides a method for treating diseases or disorders associated with PAD4 enzyme activity, the method comprising the step of administering a compound of this disclosure or a pharmaceutically acceptable composition thereof to a patient in need.

[0122] In one embodiment, the disease or disorder associated with PAD4 enzyme activity is a disease, condition, or disorder mediated by inappropriate PAD4 activity. In some embodiments, the disease or disorder associated with PAD4 enzyme activity is selected from rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, and psoriasis. In other embodiments, the disease or disorder associated with PAD4 enzyme activity is rheumatoid arthritis. In other embodiments, the disease or disorder associated with PAD4 enzyme activity is systemic lupus erythematosus. In other embodiments, the disease or disorder associated with PAD4 enzyme activity is vasculitis. In other embodiments, the disease or disorder associated with PAD4 enzyme activity is cutaneous lupus erythematosus. In other embodiments, the disease or disorder associated with PAD4 enzyme activity is psoriasis.

[0123] In one embodiment, a method for treating rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis is provided, the method comprising administering to a human subject in need a therapeutically effective amount of the provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.

[0124] In one embodiment, a method for treating rheumatoid arthritis is provided, the method comprising administering to a subject in need a therapeutically effective amount of a provided compound, its stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt. In one embodiment, a method for treating systemic lupus erythematosus is provided, the method comprising administering to a subject in need a therapeutically effective amount of a provided compound, its stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt. In one embodiment, a method for treating vasculitis is provided, the method comprising administering to a subject in need a therapeutically effective amount of a provided compound, its stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt. In one embodiment, a method for treating cutaneous lupus erythematosus is provided, the method comprising administering to a subject in need a therapeutically effective amount of a provided compound, its stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt. In one embodiment, a method for treating psoriasis is provided, the method comprising administering to a human subject in need a therapeutically effective amount of the provided compound, its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts.

[0125] In some implementations, diseases or disorders associated with PAD4 enzyme activity are selected from acid-induced lung injury, acne vulgaris (PAPA), acute lymphoblastic leukemia, acute respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenal insufficiency, aging, HIV / AIDS, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary disease, aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, weight loss, angina pectoris, angioedema, anhidrotic ectodermal dysplasia with immunodeficiency, ankylosing spondylitis, anterior segmental inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, asthma, atherosclerosis, atopic dermatitis, and autoimmune diseases. Autoimmune hepatitis, bee sting-induced inflammation, Behçet's disease, Behçet's syndrome, Bell's palsy, beryllium poisoning, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiomegaly, carpal tunnel syndrome, catabolism, cataracts, cerebral aneurysms, chemically 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, cryoinflammatory hormone-related periodic syndrome, cryptococcosis, cystic fibrosis, interleukin-1 receptor antagonist deficiency (DIRA), dermatitis, dermatitis endotoxemia, dermatomyositis, diffuse endogenous pontine glioma, etc. Endometriosis, endotoxemia, epicondylitis, erythroblastopenia, familial amyloid polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth retardation, glaucoma, glomerular diseases, glomerulonephritis, gout, gouty arthritis, graft-versus-host disease, intestinal diseases, head injury, headache, hearing loss, heart disease, hemolytic anemia, allergic purpura, hepatitis, hereditary periodic fever syndrome, herpes zoster and herpes simplex, HIV-1, Hodgkin's disease, Huntington's disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulin D with periodic fever (HIDS), aplastic anemia and other anemias, aplastic anemia, idiopathic thrombocytopenic purpura. Pigmentary disorders, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, iritis, irritant-induced inflammation, ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, nephropathy, kidney injury caused by parasitic infection, prevention of kidney transplant rejection, leptospirosis, leukemia, Leffler's syndrome, lung injury, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, Muller-Weil syndrome (urticaria, deafness, amyloidosis), multiple sclerosis, muscle wasting, muscle atrophy, myasthenia gravis, myocarditis, mycosis fungoides, myelodysplastic syndrome, myositis, sinusitis.Necrotizing enterocolitis, Neonatal multisystem inflammatory disease (NOMID), Nephrotic syndrome, neuritis, neuropathological diseases, non-allergen-induced asthma, obesity, ocular 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), phytoiritis-induced inflammation, pneumonia, lung inflammation, Pneumocystis infection, toxic ivy / urushiol oil-induced inflammation, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyositis, psoriasis, psychological stress disorders, lung diseases, pulmonary hypertension, pulmonary fibrosis, pyoderma gangrenosa, suppurative aseptic arthritis, kidney disease, retinal diseases, rheumatic carditis, rheumatic diseases, rheumatoid arthritis, sarcoidosis. Seborrheic dermatitis, sepsis, severe pain, sickle cell lung disease, sickle cell anemia, silica-induced disease, Sjögren's syndrome, skin diseases, sleep apnea, solid tumors, spinal cord injury, Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplantation, TNF receptor-related periodic syndrome (TRAPS), toxoplasmosis, transplantation, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticaria, uveitis, Wechsler granulomatosis, interstitial lung disease, psoriatic arthritis, juvenile idiopathic arthritis, Sjögren's syndrome, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, antiphospholipid antibody syndrome, sepsis, deep vein thrombosis, fibrosis, Alzheimer's disease, scleroderma, and CREST syndrome.

[0126] In one embodiment, this disclosure provides a compound or a pharmaceutically acceptable salt thereof for use in a therapeutic manner. In another embodiment, this disclosure provides a compound or a pharmaceutically acceptable salt thereof for treating a disease or disorder mediated by inappropriate PAD4 activity. In yet another embodiment, this disclosure provides a compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof for treating rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis. In another embodiment, this disclosure provides a compound or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts for the treatment of rheumatoid arthritis. In another embodiment, this disclosure provides a compound or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts for the treatment of systemic lupus erythematosus. In yet another embodiment, this disclosure provides a compound or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts for the treatment of vasculitis. In another embodiment, this disclosure provides a compound or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof for the treatment of cutaneous lupus erythematosus. In another embodiment, this disclosure provides a compound or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof for the treatment of psoriasis. In another embodiment, this 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 treating a disorder mediated by inappropriate PAD4 activity.In another embodiment, this disclosure provides the use of a compound or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts in the manufacture of an agent for treating rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis. In another embodiment, this disclosure provides the use of a compound or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts in the manufacture of an agent for treating rheumatoid arthritis. In another embodiment, this disclosure provides the use of a compound or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts in the manufacture of an agent for treating systemic lupus erythematosus. In another embodiment, this disclosure provides the use of a compound or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts in the manufacture of an agent for treating vasculitis. In another embodiment, this disclosure provides the use of a compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cutaneous lupus erythematosus. In another embodiment, this disclosure provides the use of a compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating psoriasis. In other embodiments, this disclosure provides a pharmaceutical composition for treating or preventing diseases or disorders mediated by inappropriate PAD4 activity, said pharmaceutical composition comprising the provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In other embodiments, this disclosure provides a pharmaceutical composition for treating or preventing rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis, said pharmaceutical composition comprising the provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In other embodiments, this disclosure provides a pharmaceutical composition for treating or preventing rheumatoid arthritis, said pharmaceutical composition comprising the provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In other embodiments, this disclosure provides a pharmaceutical composition for treating or preventing systemic lupus erythematosus, said pharmaceutical composition comprising the provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.In other embodiments, this disclosure provides a pharmaceutical composition for treating or preventing vasculitis, the pharmaceutical composition comprising the provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In other embodiments, this disclosure provides a pharmaceutical composition for treating or preventing cutaneous lupus erythematosus, the pharmaceutical composition comprising the provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In other embodiments, this disclosure provides a pharmaceutical composition for treating or preventing psoriasis, the pharmaceutical composition comprising the provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. Example

[0127] The following examples have been prepared, separated, and characterized using the methods disclosed herein. These examples illustrate a portion of the scope of this disclosure and are not intended to limit its scope. abbreviation Analysis procedures and methods Description of preparative HPLC and analytical LCMS methods:

[0128] Method A: Column: XBridge preparative Shield RP C18, 30*150 mm, 5 μm; Mobile phase A: 0.05% TFA in water; Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 24% B to 37% B over 8 min; Wavelength: 254 nm / 220 nm.

[0129] Method B: Column: HALO 90A C18, 3.0*30 mm, 2.0 μm; Mobile phase A: 0.05% TFA in water, Mobile phase B: ACN + 0.05% TFA; Flow rate: 1.5 mL / min; [gradient]; Wavelength: 254 nm. Method B variation:

[0130] Method C: Column: SunFire C18 OBD preparative, 19*250 mm, 5 μm; Mobile phase A: 0.05% TFA in water; Mobile phase B: ACN; Flow rate: 25 mL / min; 32% B to 36% B in 6.5 min; Wavelength: 254 / 210 nm.

[0131] Method D: Column: Shim-pack Scepter C18, 3.0*33 mm, 3.0 μm; Mobile phase A: 5 mMNH4HCO3 in water; Mobile phase B: ACN; Flow rate: 1.5 mL / min; [gradient]; Wavelength: 254 nm. Method D variant:

[0132] Method E: Column: Xselect CSH preparative C18, 30*150 mm, 5 μm; Mobile phase A: 0.05% TFA in water; Mobile phase B: ACN; [Flow rate]; [Gradient]; Wavelength: 254 nm / 220 nm. Method E variant:

[0133] Method F: Column: XBridge preparative OBD C18, 30*150 mm, 5 μm; Mobile phase A: 10 mM NH4HCO3 in water; Mobile phase B: ACN; Flow rate: 60 mL / min; 22% B to 52% B over 10 min; Wavelength: 254 nm / 220 nm

[0134] Method G: Column: XBridge preparative phenyl OBD C18, 19*250 mm, 5 μm; Mobile phase A: 0.05% TFA in water; Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 22% B to 52% B over 10 min; Wavelength: 254 nm / 220 nm.

[0135] Method H: Column: HALO C18, 4.6*100 mm, 2.7 μm; Mobile phase A: 0.05% TFA in water, Mobile phase B: ACN + 0.05% TFA; Flow rate: 1.5 mL / min; Gradient: 10% B to 95% B in 6 min, hold at 95% for 2 min, then 95% B to 5% B in 2 min; Wavelength: 254 nm.

[0136] Method I: Column: XBridge C18, 19*200 mm, 5 µm; Mobile phase A: 0.05% TFA / ACN 95: 5 in water, Mobile phase B: 0.05% TFA / ACN 5: 95 in water; Flow rate: 20 mL / min; [gradient]; Wavelength: 220 nm. Method I variant:

[0137] Method J: Column: XBridge C18, 2.1*50, 1.7 µm; Mobile phase A: 0.05% TFA / ACN 95:5 in water; Mobile phase B: 0.05% TFA / ACN 5:95 in water; Flow rate: 1.0 mL / min; Gradient: 0% B to 100% B in 3 min, held at 100% B for 0.5 min; Wavelength: 220 nm.

[0138] Method K: Column: HALO C18, 3.0*30 mm, 3.0 μm; Mobile phase A: 0.05% TFA in water, Mobile phase B: 0.05% TFA in ACN; Flow rate: 1.5 mL / min; [gradient]; Wavelength: 254 nm. Method K variation: Synthesis Examples

[0139] The compounds of the present invention can be prepared by various methods well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry, or variations thereof as understood by those skilled in the art. Illustrative methods include, but are not limited to, those described below. The compounds of the present invention can be synthesized according to the steps outlined in general schemes A, B, C, and D, which include different sequences of assembling intermediates. Starting materials can be commercially available or prepared by known procedures reported in the literature or as shown in the figures. 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]naphthid-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinecycloundecan-4-one Synthesis of intermediate 1I: Synthesis of intermediate 1A

[0140] NaH (60% w / w, 5.6 g, 233 mmol) was added dropwise to a solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (10.0 g, 47.5 mmol) in DMF (500 mL) at 0ºC under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was cooled to 0ºC, and (2-(chloromethoxy)ethyl)trimethylsilane (16.0 g, 96.0 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 5 h, then diluted with water (2 L) and extracted with ethyl acetate (2 L). The combined organic extracts were washed with water (2 x 2 L) and brine (2 x 2 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 5:1) to give intermediate 1A (12 g) as a white oil. LCMS (ESI, m / z): 341 [M+H] + . Synthesis of intermediate 1B

[0141] Tributyl(1-ethoxyvinyl)stanane (20 g, 55 mmol), DavePhos (3.0 g, 7.6 mmol), and Pd(dppf)Cl2 (3.0 g, 3.7 mmol) were added to a solution of intermediate 1A (12 g, 35.2 mmol) in 1,4-dioxane (400 mL) under nitrogen atmosphere, and the resulting mixture was stirred overnight at 90ºC in a sealed container. The reaction mixture was acidified with aqueous HCl (1 M, 100 mL), stirred at room temperature for 0.5 h, diluted with water (1 L), and extracted with ethyl acetate (2 x 1 L). The combined organic extracts were washed with water (2 x 2 L) and brine (2 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 4:1) to give intermediate 1B (10 g) as a yellow solid. LCMS (ESI, m / z): 349 [M+H] + . Synthesis of intermediate 1C

[0142] (S)-2-methylpropane-2-sulfinamide (14 g, 115 mmol) and Ti(OiPr)4 (65 g, 230 mmol) were added to a solution of intermediate 1B (10.0 g, 28.7 mmol) in THF (200 mL) under nitrogen atmosphere, and the resulting mixture was stirred overnight at 60ºC. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (1 L). The solid was filtered off, and the filtrate was diluted with water (1 L) and extracted with ethyl acetate (2 x 2 L). The combined organic extracts were washed with water (3 L) and brine (3 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 2:1) to give intermediate 1C (8 g) as a yellow solid. LCMS (ESI, m / z): 480 [M+H] + . Synthesis of intermediate 1D

[0143] Trisec-butyllithium borohydride (2 M in THF, 20 mL) was added fractionally to a solution of intermediate 1C (8.0 g, 16.7 mmol) in THF (200 mL) at -78ºC under nitrogen atmosphere, and the resulting mixture was stirred at -78ºC for 6 h. The reaction was then quenched at 0ºC with saturated aqueous NH4Cl solution (500 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organic extracts were washed with brine (1000 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 1:1) to give intermediate 1D (7 g) as a yellow solid. LCMS (ESI, m / z): 482 [M+H] + . Synthesis of intermediate 1E

[0144] Intermediate 1D (6.0 g, 12.5 mmol) was stirred in HCl (4 M in EtOAc, 150 mL) at room temperature for 3 h, 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 h, then extracted with ethyl acetate (2 x 1 L), washed with water (2 L) and brine (2 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by rapid column chromatography on silica (petroleum ether / ethyl acetate = 3:1). The resulting substance was further purified by rapid column chromatography on C18 silica (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 30% B to 100% B). The pure fraction was concentrated under vacuum to remove the organic solvent, and the remaining aqueous solution was lyophilized to give intermediate 1E (3.5 g) as a white solid. LCMS (ESI, m / z): 348 [M+H] + . Synthesis of intermediate 1F

[0145] Cs₂CO₃ (4.8 g, 14.6 mmol) and intermediate 1E (1.7 g, 4.9 mmol) were added to a solution of tert-butyl 8-bromo-2,2-dimethyloctanoate (1.5 g, 4.9 mmol, WO 2021222353) in DMF (50 mL) under nitrogen atmosphere, and the resulting mixture was stirred at 65ºC for 1 h. The reaction mixture was then diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were washed with water (2 x 400 mL) and brine (2 x 400 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 5:1) to give intermediate 1F (1.8 g) as a yellow solid. LCMS (ESI, m / z): 574 [M+H] + . Synthesis of intermediate 1G

[0146] TFA (6 mL) was added to a solution of intermediate 1F (1.8 g, 3.1 mmol) in DCM (30 mL). The resulting mixture was stirred at room temperature for 3 h, and then concentrated under vacuum to give crude intermediate 1G (1.2 g) as a yellow oil. LCMS (ESI, m / z): 418 [M+H] + . Synthesis of intermediate 1H

[0147] DIPEA (1.5 mL, 19.2 mmol) was added to a solution of intermediate 1G (1.6 g, 3.8 mmol) and HATU (1.8 g, 4.6 mmol) in DMF (30 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h, then diluted with water (150 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic extracts were washed with water (2 x 300 mL) and brine (2 x 300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 3:1) to give intermediate 1H (700 mg) as a white solid. LCMS (ESI, m / z): 400 [M+H] + . Synthesis of intermediate 1I

[0148] NaOH (200 mg, 5 mmol) was added to a solution of intermediate 1H (400 mg, 1 mmol) in methanol (10 mL) and water (5 mL) at room temperature, and the resulting mixture was stirred at 50ºC for 2 h. The reaction mixture was acidified to pH 2 with aqueous HCl (1 M), stirred at room temperature for 0.5 h, and then extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were washed with brine (2 x 60 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give intermediate 1I (350 mg) as a white solid. LCMS (ESI, m / z): 358 [M+H] + . Synthesis of intermediate 1J

[0149] A solution of tert-butyl 2-chloro-7,8-dihydro-5H-1,6-naphthyl-6-carboxylate (20.0 g, 74.4 mmol) in ethyl acetate (500 mL) was added to a solution of NaIO4 (47.8 g, 223 mmol) in water (250 mL) under nitrogen atmosphere at 0°C, and the resulting mixture was stirred at 0°C for 10 min, followed by fractional addition of RuCl3 (2.31 g, 11.2 mmol). The resulting mixture was stirred overnight at 15°C, diluted with a saturated aqueous solution of Na2SO3 (1 L), and extracted with ethyl acetate (2 x 1 L). The combined organic extracts were washed with brine (2.5 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by rapid column chromatography on silica (petroleum ether / ethyl acetate = 4:1) to give intermediate 1J (20 g) as a brown solid. LCMS (ESI, m / z): 283 [M+H] + . Synthesis of intermediate 1K

[0150] TFA (6 mL) was added to a solution of intermediate 1J (1 g, 3.54 mmol) in DCM (30 mL). The resulting mixture was stirred at room temperature for 1 h, and then concentrated under vacuum to give crude intermediate 1K (1.2 g). LCMS (ESI, m / z): 183 [M+H] + . Synthesis of intermediate 1L

[0151] NaH (60% w / w, 789 mg, 32.9 mmol) was added in portions to a solution of crude intermediate 1K (1.2 g) in THF (60 mL) at 0ºC under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was cooled to 0ºC, and (R)-tetrahydro-3H-[1,2,3]oxazolo[4,3-c][1,4]oxazine 1,1-dioxide (1.77 g, 9.86 mmol, J. Med. Chem. 2019, 62, 18, 8609) was added. The resulting mixture was stirred at room temperature for 2 h, then diluted with water (300 mL) and extracted with ethyl acetate (2 x 300 mL). The combined organic extracts were washed with brine (600 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by rapid column chromatography on C18 silica (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 0% B to 50% B) to give 1 L (3 g) of the intermediate as a yellow oil. LCMS (ESI, m / z): 382 [M+H] + . Synthesis of intermediate 1M

[0152] A solution of intermediate 1 L (2.5 g, 6.91 mmol) in methanol (15 mL) and HCl (2 M in EtOAc, 15 mL) was stirred at 50ºC for 2 h in a sealed container. The solid was filtered off and the filtrate was concentrated under vacuum. The crude product was purified by rapid column chromatography on C18 silica (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 0% B to 50% B) to give intermediate 1M (830 mg) as a yellow solid. LCMS (ESI, m / z): 282 [M+H] + . Synthesis of intermediate 1N

[0153] A mixture of intermediate 1M (600 mg, 2.13 mmol), NaHCO3 (1.08 g, 10.6 mmol), and Boc2O (930 mg, 4.26 mmol) in THF (20 mL) and water (20 mL) was stirred overnight at room temperature. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by rapid silica column chromatography (petroleum ether / ethyl acetate = 1:1) to give intermediate 1N (620 mg) as a white solid. LCMS (ESI, m / z): 382 [M+H] + . Synthesis of intermediate 1O

[0154] N-methyl-1-phenyl-methylamine (1.97 g, 16.2 mmol) was added to a solution of intermediate 1N (620 mg, 1.62 mmol) in ethylene glycol (8 mL, 1.62 mmol) and t-BuOH (8 mL, 1.62 mmol), and the resulting mixture was stirred at 50ºC for 2 days. The solid was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by rapid silica column chromatography (petroleum ether / ethyl acetate = 5:1) to give intermediate 1O (400 mg) as a white solid. LCMS (ESI, m / z): 467 [M+H] + . Synthesis of intermediate 1P

[0155] KNO3 (260 mg, 2.57 mmol) was added fractionally to a solution of intermediate 1O (400 mg, 0.86 mmol) in H2SO4 (5 mL, 93.9 mmol) at 0°C, and the resulting mixture was stirred at 20°C for 3 h. The reaction mixture was poured into ice water (100 mL) and washed with ethyl acetate (2 x 100 mL). The remaining aqueous phase proceeded directly to the next step without further treatment. LCMS (ESI, m / z): 322 [M+H] + . Synthesis of intermediate 1Q

[0156] Add NaHCO3 (1.45 g, 14.3 mmol), Boc2O (392 mg, 1.79 mmol), and THF (50 mL) to the aqueous solution from the preceding steps. Stir the resulting mixture overnight at room temperature, then dilute with water (50 mL) and extract with ethyl acetate (2 x 150 mL). Wash the combined organic extracts with water (300 mL) and brine (300 mL), dry to anhydrous sodium sulfate, and concentrate under vacuum. Purify the crude product by silica rapid column chromatography (petroleum ether / ethyl acetate = 2:3) to give intermediate 1Q (260 mg). LCMS (ESI, m / z): 422 [M+H] + . Synthesis of intermediate 1R

[0157] A solution of NH4Cl (330 mg, 6.17 mmol) in water (3 mL) was added dropwise to a solution of intermediate 1Q (260 mg, 0.62 mmol) in methanol (3 mL), followed by the addition of zinc powder (403 mg, 6.17 mmol) fractionally. The resulting mixture was stirred at room temperature for 3 h. The solid was filtered off and the filtrate was concentrated under vacuum. The residue was diluted with water (50 mL) and ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (100% ethyl acetate) to give intermediate 1R (200 mg) as a yellow solid. LCMS (ESI, m / z): 392 [M+H] + . Synthesis of intermediate 1S

[0158] HATU (128 mg, 0.3 mmol) was added to a solution of intermediate 1I (100 mg, 0.3 mmol) and DIPEA (109 mg, 0.8 mmol) in DMF (3 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 min, and then added dropwise to a solution of intermediate 1R (110 mg, 0.3 mmol) in DMF (1 mL) at room temperature. The resulting mixture was stirred overnight at 40ºC, diluted with water (20 mL), and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with water (2 x 40 mL) and brine (2 x 40 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 3:1) to give intermediate 1S (150 mg) as a yellow solid. LCMS (ESI, m / z): 731 [M+H] + . Synthesis of intermediate 1T

[0159] The solution of intermediate 1S (130 mg, 0.2 mmol) in acetic acid (3 mL) was stirred overnight at 100ºC. The resulting solution was concentrated under vacuum to give intermediate 1T (120 mg), a yellow oil, which proceeded directly to the next step without further processing. LCMS (ESI, m / z): 713 [M+H] + . Synthesis of Example 1

[0160] TFA (1 mL) was added to a solution of intermediate 1T (120 mg, 0.17 mmol) in DCM (4 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method A, RT: 7.8 min). The purified fraction was concentrated under vacuum to remove the organic solvent and the residual aqueous solution was lyophilized to give Example 1 (43.6 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, br, 1H), 8.92 (s,br, 1H), 8.52 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.26 (s, 1H), 7.21 (d, J = 8.0 Hz, 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)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinecycloundecan-4-one Synthesis of intermediate 2A

[0161] NaH (60% w / w, 0.90 g, 36.3 mmol) was added in portions to a solution of 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (5.0 g, 30.2 mmol) in THF (300 mL) at 0ºC under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 0.5 h. The reaction was cooled to 0ºC, and (R)-tetrahydro-3H-[1,2,3]oxazolo[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 h, then cooled to 0ºC, quenched with water (5 mL), and concentrated under vacuum. The crude product was purified by rapid column chromatography on C18 silica (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 0% B to 100% B) to give intermediate 2A (9 g) as a yellow solid. LCMS (ESI, m / z): 345 [M+H] + . Synthesis of intermediate 2B

[0162] Aqueous HCl (2 M, 30 mL) was added to a solution of intermediate 2A (9.0 g, 26.1 mmol) in methanol (200 mL). The resulting mixture was stirred at room temperature for 2 h and then concentrated under vacuum. The crude product was purified by rapid column chromatography on C18 silica (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 0% B to 100% B) to give intermediate 2B (6 g) as a yellow solid. LCMS (ESI, m / z): 256 [M+H] + . Synthesis of intermediate 2C

[0163] KNO3 (6.9 g, 68.1 mmol) was added fractionally to a solution of intermediate 2B (6.0 g, 22.7 mmol) in H2SO4 (60 mL) at 0ºC, and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was poured into ice water (500 mL) and washed with ethyl acetate (2 x 500 mL). The remaining aqueous phase proceeded directly to the next step without further treatment. LCMS (ESI, m / z): 310 [M+H] + . Synthesis of intermediate 2D

[0164] Add Na₂CO₃ (19.6 g, 185 mmol), THF (100 mL), and Boc₂O (4.2 g, 19.4 mmol) to the aqueous solution from the preceding steps. Stir the resulting mixture overnight at room temperature, then extract with ethyl acetate (2 x 500 mL). Wash the combined organic extracts with water (1 L) and brine (1 L), dry to anhydrous sodium sulfate, and concentrate under vacuum. Purify the crude product by rapid silica column chromatography (petroleum ether / ethyl acetate = 2:3) to give intermediate 2D (2 g) as a yellow solid. LCMS (ESI, m / z): 410 [M+H] + . Synthesis of intermediate 2E

[0165] DIPEA (1.9 g, 14.7 mmol) was added to a solution of intermediate 2D (2.0 g, 4.89 mmol) and methylamine hydrochloride (0.7 g, 9.77 mmol) in MeCN (50 mL) at room temperature, and the resulting mixture was stirred at room temperature for 2 h. The solid was filtered off, and the filtrate was concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 1:5) to give intermediate 2E (1 g) as a yellow solid. LCMS (ESI, m / z): 421 [M+H] + . Synthesis of intermediate 2F

[0166] A solution of NH4Cl (1.27 g, 23.8 mmol) in water (6 mL) was added to a solution of intermediate 2E (1.0 g, 2.38 mmol) in methanol (24 mL), followed by the sequential addition of zinc powder (1.55 g, 23.8 mmol), and the resulting mixture was stirred at room temperature for 3 h. The solid was filtered off and the filtrate was concentrated under vacuum. The residue was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (100% ethyl acetate) to give intermediate 2F (700 mg) as a yellow solid. LCMS (ESI, m / z): 391 [M+H] + . Synthesis of intermediate 2G

[0167] HATU (128 mg, 0.34 mmol) and DIPEA (0.05 mL, 0.67 mmol) were added to a solution of intermediate 1I (80 mg, 0.22 mmol) in DMF (4 mL) at room temperature under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 10 min, followed by the addition of intermediate 2F (105 mg, 0.27 mmol). The resulting mixture was stirred at room temperature overnight and then purified directly on C18 silica by rapid column chromatography (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 0% B to 100% B) to give intermediate 2G (140 mg) as a yellow solid. LCMS (ESI, m / z): 730 [M+H] + . Synthesis of intermediate 2H

[0168] A solution of intermediate 2G (180 mg, 0.24 mmol) in AcOH (10 mL, 174 mmol) was stirred at 70ºC for 3 h. The mixture was concentrated under vacuum to give crude intermediate 2H (150 mg) as a yellow solid. LCMS (ESI, m / z): 712 [M+H] + . Synthesis of Example 2

[0169] TFA (1 mL) was added to a solution of intermediate 2H (150 mg, 0.21 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method C, RT: 5.17 min). The purified fraction was concentrated under vacuum to remove the organic solvent and the residual aqueous solution was lyophilized to give Example 2 (117 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6+D2O) δ 8.27 (s, 1H), 8.06 (d, J= 8.0 Hz, 1H), 7.61 (s, 1H), 7.20 (d, J = 8.0 Hz, 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] + . LCMSRT: 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]naphthid-2-yl)-2,5,5-trimethyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinecycloundecan-4-one Synthesis of Example 3 from Intermediate 1J: Synthesis of 3G from methyl (2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropionate: Synthesis of intermediate 3A

[0170] TBSCl (80.4 g, 534 mmol) was added to a solution of (2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropionate (90 g, 410 mmol) and imidazole (30.7 g, 452 mmol) in DCM (900 mL) at 0°C. The resulting mixture was stirred at 20°C for 2 h, then diluted with water (1 L) at 0°C and extracted with DCM (3 x 800 mL). The combined organic extracts were washed with brine (2 x 1 L), dried over anhydrous Na2SO4, filtered, and concentrated to give crude intermediate 3A (140 g) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ: 5.34 (d, J = 8.4 Hz, 1H), 4.36 (d, J = 8.8 Hz, 1H), 4.06 (d, J = 2.4 Hz, 1H), 4.03 (d, J = 2.4 Hz, 1H), 3.75(s, 3H), 1.46 (s, 9H), 0.87 (s, 9H), 0.03 (d, J = 5.2 Hz, 6H). Synthesis of intermediate 3B

[0171] A solution of intermediate 3A (144 g, 432 mmol) in THF (300 mL) was added to a suspension of LiAlH4 (27.9 g, 734 mmol) in THF (1.2 L) at 0°C, and the resulting mixture was stirred at 0°C for 1 h. The reaction was then quenched with a saturated aqueous solution of NH4Cl (800 mL), the solid was filtered off, and the filtrate was extracted with ethyl acetate (2 x 800 mL). The combined organic extracts were washed with brine (800 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give crude intermediate 3B (110 g) as a pale yellow oil. 1 H NMR (400 MHz, 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). Synthesis of intermediate 3C

[0172] A solution of SOCl2 (77.1 g, 648 mmol) in DCM (400 mL) was added to a solution of imidazole (147 g, 2.16 mol) in DCM (700 mL) at 0°C, and the resulting mixture was stirred at 18°C ​​for 1 h. The reaction was cooled to -10°C, and a solution of intermediate 3B (110 g, 360 mmol) in DCM (600 mL) was added. The resulting mixture was stirred at 18°C ​​for 1 h, then diluted with aqueous citric acid (10%, 800 mL) and extracted with DCM (2 x 1 L). The combined organic extracts were washed with water (2 x 1 L), dried over anhydrous Na2SO4, filtered, and concentrated to give crude intermediate 3C (104 g) as a pale yellow oil. 1 H NMR (400 MHz, 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). Synthesis of intermediate 3D

[0173] Two batches were performed in parallel. A solution of RuCl3 (30.7 mg, 148 µmol) and NaIO4 (31.6 g, 148 mmol) in H2O (500 mL) was added to a solution of intermediate 3C (52 g, 148 mmol) in MeCN (1000 mL) at 18ºC. The resulting mixture was stirred at 18ºC for 1 h, then the two batches were combined, diluted with water (1 L), and extracted with DCM (2 x 1 L). The combined organic extracts were washed with water (2 x 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give crude intermediate 3D (80 g) as a pale yellow solid. 1 H NMR (400 MHz, 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). Synthesis of intermediate 3E

[0174] TBAF (1 M, 277 mL) was added to a solution of intermediate 3D (85 g, 231 mmol) in THF (850 mL). The resulting mixture was stirred at 20ºC for 1 h, then diluted with saturated NH4Cl aqueous solution (100 mL) and extracted with ethyl acetate (2 x 800 mL). The combined organic extracts were washed with water (2 x 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid silica column chromatography (petroleum ether / ethyl acetate = 2:1) to give intermediate 3E (20 g) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ: 5.05 (d, J = 7.6 Hz, 2H), 4.57 - 4.44 (m, 2H), 3.81 - 3.73 (m, 3H), 1.45 (s, 9H). Synthesis of intermediate 3F

[0175] A solution of SOCl2 (22.2 g, 186 mmol) in DCM (200 mL) was added dropwise to a solution of imidazole (42.3 g, 621 mmol) in DCM (200 mL) at 0°C, and the resulting mixture was stirred at 20°C for 1 h. The reaction was cooled to -10°C, and a solution of intermediate 3E (20 g, 103 mmol) in DCM (200 mL) was added dropwise. The resulting mixture was stirred at 20°C for 1 h, then diluted to pH = 5 with aqueous citric acid (10%) and extracted with DCM (3 x 300 mL). The combined organic extracts were washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude intermediate 3F (22 g) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ: 5.29 - 4.97 (m, 2H), 4.86 - 4.57 (m, 2H), 4.42 - 4.10 (m, 3H), 1.52 (s, 9H). Synthesis of intermediate 3G

[0176] Under nitrogen atmosphere, a solution of RuCl3 (191 mg, 919 μmol) and NaIO4 (19.7 g, 91.9 mmol) in water (220 mL) was added dropwise to a solution of intermediate 3F (22 g, 91.9 mmol) in MeCN (440 mL). The resulting mixture was stirred at 20ºC for 1 h, then filtered, and the filter cake was washed with DCM (300 mL). The filtrate was diluted with water (300 mL) and extracted with DCM (800 mL). The combined organic extracts were washed with water (2 x 300 mL) and brine (2 x 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give crude intermediate 3G (17.5 g) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ: 4.73-4.53 (m, 5H), 1.57 (s, 9H). Synthesis of intermediate 3H

[0177] Two batches were performed in parallel. N-methyl-1-phenyl-methylamine (42.9 g, 354 mmol) was added to a solution of intermediate 1J (20.0 g, 70.7 mmol) in tert-butanol (400 mL) and ethylene glycol (400 mL). The resulting mixture was stirred at 50ºC for 16 h and then concentrated to remove t-BuOH. The residue was purified by rapid silica column chromatography (petroleum ether: ethyl acetate = 30:1 to 5:1) to give intermediate 3H (40 g) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ: 7.40 (d, J = 9.2 Hz, 1H), 7.35-7.21 (m, 5H), 6.67 (d, J = 9.2 Hz, 1H), 4.87 (s, 2H), 3.87 (t, J = 6.0 Hz, 2H), 3.11 (s, 3H), 2.91 (t, J = 6.0Hz, 2H), 1.48 (s, 9H). Synthesis of intermediate 3I

[0178] TFA (158 g, 1.39 mol) was added dropwise to a solution of intermediate 3H (28.0 g, 76.2 mmol) in DCM (300 mL) at 0°C. The resulting mixture was stirred at 20°C for 1 h and then concentrated. The residue was diluted with DCM (200 mL), adjusted to pH 8 with a saturated aqueous solution of Na₂CO₃, and extracted with DCM (2 x 200 mL). The combined organic extracts were washed with brine (400 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give intermediate 3I (17.5 g) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ: 7.83 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.33-7.20 (m, 5H), 6.58 (d, J = 8.8 Hz, 1H), 4.84 (s, 2H), 3.38-3.35 (m, 2H), 3.07(s, 3H), 2.81 (t, J = 6.8 Hz, 2H). Synthesis of intermediate 3J

[0179] NaH (60% w / w, 2.30 g, 57.4 mmol) was added in portions to a solution of intermediate 3G (11.0 g, 43.1 mmol) in DMF (220 mL) at 0ºC, and the resulting mixture was stirred at 0ºC for 30 min. Then, intermediate 3I (7.68 g, 28.7 mmol) was added in portions. The resulting mixture was stirred at 20ºC for 2 h, then quenched at 0ºC with a saturated aqueous solution of NH4Cl (80 mL), diluted with water (300 mL) and ethyl acetate (100 mL), and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were washed with water (2 x 200 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica rapid column chromatography (DCM / MeOH = 50:1 to 20:1) to give intermediate 3J (9.7 g), which was a yellow oil. 1H NMR (400 MHz, 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 = 8.8 Hz, 1H), 6.25(d, J = 8.8 Hz, 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). Synthesis of intermediate 3K

[0180] Two batches were performed in parallel. KNO3 (5.50 g, 54.4 mmol) was added fractionally to a solution of intermediate 3J (6 g, 13.6 mmol) in H2SO4 (60 mL) at 0°C, and the resulting mixture was stirred at 20°C for 3 h. Both batches were poured into ice water (1 L) and washed with ethyl acetate (2 x 300 mL). The aqueous phase was slowly alkalized to pH 9–10 using Na2CO3, and 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 h and then extracted with ethyl acetate (2 x 2 L). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by rapid silica column chromatography (petroleum ether / ethyl acetate = 10:1 to 1:1) to give intermediate 3K (4.13 g) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ: 8.86 (d, J= 4.8 Hz, 1H), 8.65 (s, 1H), 6.98 (d, J = 8.8 Hz, 1H), 4.45 (d, J = 5.6 Hz,1H), 4.35 (d, J = 5.2 Hz, 1H), 3.68-3.32 (m, 4H), 3.08 (s, 3H), 3.07-3.02 (m, 2H), 1.31 (s, 9H). Synthesis of intermediate 3L

[0181] A solution of NH4Cl (12.1 g, 226 mmol) in water (50 mL) was added to a solution of intermediate 3K (10.0 g, 22.6 mmol) in methanol (200 mL), followed by the sequential addition of zinc powder (14.5 g, 226 mmol), and the resulting mixture was stirred at room temperature for 2 h. The solid was filtered off and the filtrate was concentrated under vacuum. The crude product was purified by rapid column chromatography on C18 silica (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 0% B to 50% B) to give intermediate 3L (7.6 g) as a pale yellow solid. LCMS (ESI, m / z): 368 [M+H] + . Synthesis of Example 3

[0182] Example 3 (88.6 mg) was prepared from intermediate 3L and intermediate 1I as a white solid using a synthesis scheme similar to that of Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.31 (s, br, 3H), 8.07 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.29 (s, 1H), 7.23 (d, J= 8.0 Hz, 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]pyridinecycloundecan-4-one Synthesis of intermediate 4A

[0183] NaH (600 mg, 15 mmol) was added fractionally to a solution of 6-fluoro-3,4-dihydro-2H-isoquinoline-1-one (1.6 g, 10 mmol) in DMF (100 mL) at 0ºC under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 0.5 h. The reaction was cooled to 0ºC, and intermediate 3G (3.1 g, 12 mmol) was added fractionally. The resulting mixture was stirred at room temperature for 2 h, quenched with water (300 mL), and extracted with ethyl acetate (300 mL). The combined organic extracts were washed with water (2 x 300 mL) and brine (2 x 300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 1:1) to give intermediate 4A (1.0 g) as a yellow solid. LCMS (ESI, m / z): 341 [M+H] + . Synthesis of intermediate 4B

[0184] Methylamine (2 M in THF, 1.5 equivalences) was added to a solution of intermediate 4A (1.0 g, 2.9 mmol) in MeCN (30 mL) at room temperature, and the resulting mixture was stirred at room temperature for 2 h. The solution was concentrated under vacuum, and the crude product was purified by silica rapid column chromatography (DCM / MeOH = 10:1) to give intermediate 4B (1.0 g) as a pale yellow solid. LCMS (ESI, m / z): 352 [M+H] + . Synthesis of intermediate 4C

[0185] KNO3 (1.17 g, 11.6 mmol) was added fractionally to a solution of intermediate 4B (1.0 g, 2.9 mmol) in H2SO4 (10 mL) at 0ºC, and the resulting mixture was stirred at room temperature for 3 h. The mixture was poured into ice water (50 mL) and washed with ethyl acetate (2 x 30 mL). The aqueous phase was alkalized to pH 9–10 with saturated Na2CO3 aqueous solution, and then THF (50 mL) and Boc2O (759 mg, 3.5 mmol) were added. The resulting mixture was stirred at room temperature for 16 h, then extracted with ethyl acetate (2 x 150 mL), and the combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 1:2) to give intermediate 4C (800 mg) as a yellow solid. LCMS (ESI, m / z): 397 [M+H] + . Synthesis of intermediate 4D

[0186] Zinc powder (620 mg, 9.48 mmol) was added fractionally 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), and the resulting mixture was stirred at room temperature for 2 h. The solid was filtered off and the filtrate was concentrated under vacuum. The residue was purified by rapid column chromatography on C18 silica (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 0% B to 50% B) to give intermediate 4D (400 mg) as a white solid. LCMS (ESI, m / z): 367 [M+H] + . Synthesis of Example 4

[0187] Example 4 was prepared from intermediate 4D and intermediate 1I as a white solid using a synthesis scheme similar to that of Example 2. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 3H), 8.27 (s, 1H), 8.05 (d, J =8.4 Hz, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.60 (s, 1H), 7.19 (d, J = 8.4 Hz,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]isoquinolin-2-yl)-2,5,5-trimethyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinecycloundecan-4-one Synthesis of intermediate 5A

[0188] LiAlH4 (2.5 M in THF, 1.1 mL, 2.8 mmol) was added dropwise to a solution of intermediate 1I (200 mg, 0.56 mmol) in THF (8 mL) at 0ºC under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 2 h. The reaction 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 min. The mixture was then dried over anhydrous sodium sulfate, the solid was filtered off, and the filtrate was concentrated under vacuum. The crude product was purified by rapid column chromatography on C18 silica (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 0% B to 100% B) to give intermediate 5A (150 mg) as a yellow solid. LCMS (ESI, m / z): 344 [M+H]+ . Synthesis of intermediate 5B

[0189] MnO2 (380 mg, 4.37 mmol) was added to a solution of intermediate 5A (150 mg, 0.44 mmol) in DCM (5 mL) at room temperature, and the resulting mixture was stirred at room temperature for 2 h. The solid was filtered off, and the filtrate was concentrated under vacuum. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 3:1) to give intermediate 5B (120 mg) as a yellow solid. LCMS (ESI, m / z): 342 [M+H] + . Synthesis of intermediate 5C

[0190] Under nitrogen atmosphere, Cs₂CO₃ (5.72 g, 17.6 mmol) and cyclopropylamine (670 mg, 11.7 mmol) were added to a solution of intermediate 2D (2.4 g, 5.86 mmol) in DMF (60 mL), and the resulting mixture was stirred at room temperature for 1 h. The reaction was then quenched with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were washed with water (2 x 400 mL) and brine (2 x 400 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 1:2) to give intermediate 5C (1.6 g) as a yellow solid. LCMS (ESI, m / z): 447 [M+H] + . Synthesis of intermediate 5D

[0191] Pd / C (480 mg, 4.53 mmol) was added to the reaction flask under nitrogen atmosphere, followed by ethyl acetate (100 mL), DCM (5 mL), and intermediate 5C (1.6 g, 3.58 mmol). The flask was degassed and refilled with nitrogen (3x) followed by hydrogen (3x). The resulting mixture was stirred under hydrogen atmosphere at room temperature for 4 h, and the solid was filtered off and the filtrate concentrated under vacuum. The crude product was purified by rapid column chromatography on C18 silica (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 0% B to 60% B) to give intermediate 5D (600 mg) as a yellow solid. LCMS (ESI, m / z): 417 [M+H] + . Synthesis of intermediate 5E

[0192] Potassium persulfate complex salt (oxone) (144 mg, 0.23 mmol) was added to a solution of intermediate 5B (80 mg, 0.23 mmol) in DMF (1.5 mL) and water (0.05 mL). The resulting solution was stirred at room temperature for 2 h, then diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were washed with water (2 x 20 mL) and brine (2 x 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 1:2) to give intermediate 5E (80 mg) as a white solid. LCMS (ESI, m / z): 738 [M+H] + . Synthesis of Example 5

[0193] TFA (1 mL) was added to a solution of intermediate 5D (100 mg, 0.14 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method A, RT: 7.8 min). The purified fraction was concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to give Example 5 (69.1 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6+D2O) δ 8.26 (s, 1H), 8.06 (d,J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.28 (s, 1H), 7.19 (d, J = 8.0 Hz, 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] + LCMSRT: 1.004 min (Method D1). Example 6. (R)-1 2 -(9-fluoro-1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-2,5,5-trimethyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinecycloundecan-4-one Synthesis of intermediate 6A

[0194] BH3 (1 M in THF, 134 mL, 134 mmol) was added to a solution of 2-(3-chloro-2-fluoro-phenyl)acetonitrile (10.0 g, 58.9 mmol) in THF (134 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70ºC for 2 h in a sealed container, then added dropwise to methanol at 0ºC and stirred at 0ºC for 20 min. The mixture was concentrated under vacuum to give crude intermediate 6A (5.7 g) as a yellow oil. LCMS (ESI, m / z): 174, 176 [M+H] + . Synthesis of intermediate 6B

[0195] Intermediate 6A (1.1 g, 6.50 mmol) and Et3N (22.6 mL, 13.0 mmol) in DCM (24 mL) were added to a solution of triphosgene (5.7 g, 19.5 mmol) in DCM (48 mL) at 0ºC under nitrogen, and the resulting mixture was stirred at room temperature for 2 h. The solid was filtered off, and the filtrate was added dropwise to a solution of AlCl3 (5.2 g, 39.0 mmol) in DCM (50 mL) at 0ºC under nitrogen. The resulting mixture was stirred at room temperature overnight, then quenched with water (200 mL), acidified with aqueous HCl (4 M) until the mixture became a clear solution, and extracted with DCM (2 x 200 mL). The combined organic extracts were washed with brine (400 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by rapid silica column chromatography (100% ethyl acetate) to obtain intermediate 6B (2 g), a yellow oil. LCMS (ESI, m / z): 200, 202 [M+H] + . Synthesis of intermediate 6C

[0196] NaH (60% w / w, 90 mg, 3.76 mmol) was added in portions to a solution of intermediate 6B (500 mg, 2.50 mmol) in THF (25 mL) at 0ºC under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was cooled to 0ºC, and (R)-tetrahydro-3H-[1,2,3]oxazolo[4,3-c][1,4]oxazine 1,1-dioxide (673 mg, 3.76 mmol) was added in portions. The resulting mixture was stirred at room temperature for 0.5 h, then quenched with a saturated aqueous NH4Cl solution (1 mL) and purified directly on C18 silica by rapid column chromatography (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 15% B to 90% B) to give a yellow solid sulfonic acid intermediate, which was added to HCl (4 M in MeOH, 10 mL) and stirred in a sealed container at 50ºC for 1 h. The reaction was concentrated under vacuum to give intermediate 6C (400 mg) as a yellow oil. LCMS (ESI, m / z): 299, 301 [M+H] + . Synthesis of intermediate 6D

[0197] KNO3 (202 mg, 2.01 mmol) was added fractionally to a solution of intermediate 6C (150 mg, 0.5 mmol) in H2SO4 (2 mL) at 0ºC, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was added dropwise to ice water, stirred for 10 min, and washed with ethyl acetate (2 x 10 mL). The remaining aqueous phase proceeded directly to the next step without further treatment. LCMS (ESI, m / z): 344, 346 [M+H] + . Synthesis of intermediate 6E

[0198] The aqueous solution from the preceding steps was adjusted to pH 8 with saturated NaHCO3 aqueous solution (10 mL), followed by the addition of Boc2O (76.4 mg, 0.35 mmol) in THF (5 mL). The resulting mixture was stirred overnight at room temperature and then extracted with ethyl acetate (2 x 40 mL). The combined organic extracts were washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 5:1) to give intermediate 6E (120 mg) as a pale yellow solid. LCMS (ESI, m / z): 444, 446 [M+H] + . Synthesis of intermediate 6F

[0199] Methylamine (2 M in THF, 0.81 mL) was added to a solution of intermediate 6E (120 mg, 0.27 mmol) and DIPEA (104 mg, 0.81 mmol) in MeCN (3 mL), and the resulting mixture was stirred overnight at 50ºC in a sealed container. The reaction mixture was purified by rapid column chromatography on C18 silica (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 5% B to 85% B over 25 min) to give intermediate 6F (100 mg) as a white solid. LCMS (ESI, m / z): 439 [M+H] + . Synthesis of intermediate 6G

[0200] A solution of NH4Cl (122 mg, 2.28 mmol) in water (2 mL) was added to a solution of intermediate 6F (100 mg, 0.23 mmol) in methanol (4 mL), followed by the addition of zinc powder (119 mg, 1.82 mmol) fractionally. The resulting mixture was stirred at room temperature for 3 h. The solid was filtered off and the filtrate was concentrated under vacuum. The residue was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by rapid column chromatography on C18 silica (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 0% B to 60% B) to give intermediate 6G (75 mg) as a white solid. LCMS (ESI, m / z): 409 [M+H] + . Synthesis of Example 6

[0201] Example 6 (37.8 mg) was prepared as a white solid by using a synthesis scheme similar to that of Example 2, from intermediate 6G (75 mg, 0.18 mmol) and intermediate 1I. 1 H NMR (400 MHz, DMSO-d6+D2O) δ 8.12 (s, 1H),8.06 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 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 = 6.8 Hz, 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]isoquinolin-2-yl)-2,5,5-trimethyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinecycloundecan-4-one Synthesis of intermediate 7A

[0202] NBS (698 mg, 3.92 mmol) was added to a solution of intermediate 2E (1.1 g, 2.62 mmol) in DMF (26 mL) under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature, then diluted with water (130 mL) and extracted with ethyl acetate (2 x 130 mL). The combined organic layers were washed with water (2 x 260 mL) and brine (2 x 260 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (100% ethyl acetate) to give intermediate 7A (1.05 g) as a yellow solid. LCMS (ESI, m / z): 499, 501 [M+H] + . Synthesis of intermediate 7B

[0203] Na₂S₂O₄ (97 mg, 0.56 mmol) was added 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). The resulting mixture was stirred at room temperature for 6 h, then diluted with water (5 mL) and extracted with ethyl acetate (2 x 5 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (DCM / MeOH = 20:1) to give intermediate 7B (80 mg) as a pale yellow solid. LCMS (ESI, m / z): 790, 792 [M+H] + . Synthesis of intermediate 7C

[0204] Pd2(dba)3 (18 mg, 0.02 mmol) and t-BuBrettPhos (33 mg, 0.04 mmol) were added to a solution of intermediate 7B (80 mg, 0.10 mmol) and KOH (39 mg, 0.30 mmol) in methanol (2.5 mL) and 1,4-dioxane (2.5 mL) under nitrogen atmosphere. The resulting mixture was stirred at 100ºC for 2 h in a sealed container, then diluted with water (15 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 4:1) to give intermediate 7C (14 mg) as a pale yellow solid. LCMS (ESI, m / z): 742 [M+H] + . Synthesis of Example 7

[0205] TFA (0.5 mL) was added to a solution of intermediate 7C (14 mg, 0.02 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method E1, RT: 8.63 min). The purified fraction was concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to give Example 7 (6.2 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.15 - 8.82 (m, 2H),8.07 - 8.05 (m, 2H), 7.83 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 8.0 Hz, 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)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-2,5,5-trimethyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinecycloundecan-4-one Synthesis of intermediate 8A

[0206] Under nitrogen atmosphere, PEPPSI-IPr (12 mg, 0.09 mmol) and K₂CO₃ (36 mg, 0.27 mmol) were added to a solution of intermediate 7B (70 mg, 0.09 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborane (11 mg, 0.09 mmol) in 1,4-dioxane (3 mL). The resulting mixture was stirred at 80ºC for 10 h, then diluted with water (9 mL) and extracted with ethyl acetate (2 x 9 mL). The combined organic extracts were washed with water (18 mL) and brine (18 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 1:2) to give intermediate 8A (40 mg) as a pale yellow solid. LCMS (ESI, m / z): 726 [M+H] + . Synthesis of Example 8

[0207] TFA (0.5 mL) was added to a solution of intermediate 8A (40 mg, 0.05 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method F, RT: 8.7 min). The purified fraction was concentrated under vacuum to remove the organic solvent and the residual aqueous solution was lyophilized to give Example 8 (15.2 mg) as a white solid. LCMS (ESI, m / z): 626 [M+H] + LCMS RT: 1.377 min (Method B2). Example 9. (R)-2-methyl-1 2 -(1-Methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridazine-5(1,2)-diphenylcyclodecafen-4-one Synthesis of intermediate 9A

[0208] LiAlH4 (2.5 M in THF, 29 mL) was added dropwise to a solution of intermediate 1E (5 g, 14.4 mmol) in THF (150 mL) at 0ºC under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 2 h. The reaction 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 min. The mixture was then dried over anhydrous sodium sulfate, the solid was filtered off, and the filtrate was concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 1:1) to give intermediate 9A (4 g) as a white solid. LCMS (ESI, m / z): 292 [M+H] + . Synthesis of intermediate 9B

[0209] MnO2 (11.9 g, 137 mmol) was added to a solution of intermediate 9A (4 g, 13.7 mmol) in DCM (150 mL) at room temperature, and the resulting mixture was stirred for 2 h. The solid was filtered off, and the filtrate was concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 3:1) to give intermediate 9B (3.5 g) as a pale yellow solid. LCMS (ESI, m / z): 290 [M+H] + . Synthesis of intermediate 9C

[0210] Na₂S₂O₄ (2.1 g, 24.2 mmol) was added 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). The resulting mixture was stirred overnight at 90ºC, then diluted with water (150 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic extracts were washed with water (300 mL) and brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (DCM / MeOH = 15:1) to give intermediate 9C (1.5 g) as a yellow solid. LCMS (ESI, m / z): 660 [M+H] + . Synthesis of intermediate 9D

[0211] Under nitrogen atmosphere, Cs₂CO₃ (177 mg, 0.55 mmol) and tert-butyl 2-(5-(toluenesulfonyloxy)pentyl)benzoate* (91 mg, 0.22 mmol) were added to a solution of intermediate 9C (120 mg, 0.18 mmol) in DMF (2 mL). The resulting mixture was stirred at 50ºC for 2 h, then diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with water (2 x 10 mL) and brine (2 x 10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 4:1) to give intermediate 9D (100 mg) as a pale yellow solid. LCMS (ESI, m / z): 907 [M+H] + *Prepared according to a similar synthesis scheme as described in WO 2021222353. Synthesis of intermediate 9E

[0212] TFA (0.5 mL) was added to a solution of intermediate 9D (100 mg, 0.11 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 16 h, and then concentrated under vacuum to give intermediate 9E (70 mg) as a white solid. LCMS (ESI, m / z): 650 [M+H] + . Synthesis of Example 9

[0213] HATU (62 mg, 0.16 mmol) was added to a solution of intermediate 9E (70 mg, 0.11 mmol) and DIPEA (42 mg, 0.32 mmol) in DMF (2 mL) at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 1 h and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method G, RT: 8.57 min). The purified fraction was concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to give Example 9 (35 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.09 - 9.03 (m, 1H), 9.00 - 8.84 (m, 2H), 8.26 (s, 1H), 8.08 (d, J = 8.0 Hz, 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). Example 10. (R)-2-methyl-1 2 -(1-Methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-6-oxa-3-aza-1(6,1)-pyrrolo[2,3-b]pyridazine-5(1,2)-diphenylcyclodecafen-4-one Synthesis of Example 10

[0214] Example 10, a white solid, was prepared from intermediate 9C and tert-butyl 2-(4-bromobutoxy)benzoate (WO 2021222353) using a synthesis scheme similar to that of Example 9. 1H NMR (400 MHz, DMSO-d6) δ 9.75 (d,J = 6.8 Hz, 1H), 9.13 (s, br, 1H), 8.96 (s, br, 1H), 8.31 (s, 1H), 8.15 (d, J= 8.0 Hz, 1H), 8.11 - 8.08 (m, 1H), 7.64 (s, 1H), 7.56 - 7.48 (m, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 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 =6.4 Hz, 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)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinecycloundecan-4-one Synthesis of intermediate 11A

[0215] Et3N (1.15 g, 11.4 mmol), DMAP (60 mg, 0.49 mmol), and TsCl (1.30 g, 6.81 mmol) were added fractionally to a solution of tert-butyl 8-hydroxyoctanoate (500 mg, 2.31 mmol) in DCM (20 mL) at 0ºC under nitrogen. The resulting mixture was stirred overnight at room temperature, then diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic extracts were washed with brine (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 give intermediate 11A (600 mg) as a colorless oil. LCMS (ESI, m / z): 371 [M+H] + . Synthesis of Example 11

[0216] Example 11, a white solid, was prepared from intermediates 9C and 11A using a synthesis scheme similar to that of Example 9. 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (s, br, 1H), 8.88 (s, br, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.27 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H),7.19 (d, J = 8.0 Hz, 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), 2.10 - 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)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridazine-5(2,3)-pyrazinecyclodecafen-4-one Synthesis of intermediate 12A

[0217] A mixture of (Z)-N,N'-diisopropylaminoiminocyanate tert-butyl ester (329 µL, 1.478 mmol) and 3-bromopyrazine-2-carboxylic acid (100 mg, 0.493 mmol) in THF (2.2 mL) was adjusted to 60ºC and stirred overnight. The reaction mixture was then diluted with EtOAc, washed with water (2X) and brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica column chromatography (0 to 100% EtOAc in hexane) to give intermediate 12A (112.7 mg). 1 HNMR (400 MHz, DMSO-d6) δ 8.79 - 8.71 (m, 1H), 8.70 - 8.63 (m, 1H), 1.59 (s,9H). Synthesis of intermediate 12B

[0218] Intermediate 12B was synthesized from intermediate 12A according to a similar synthetic protocol described in WO 2021222353 regarding the chloride variant of intermediate 12A. LCMS (ESI, m / z): 421 [M+H] + . Synthesis of intermediate 12C

[0219] 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) in DMF (997 µL) was adjusted to 65ºC and stirred overnight. After reaching near room temperature, the reaction mixture was diluted with ethyl acetate, washed with water (2X) and brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (DCM / MeOH) to give intermediate 12C (65.5 mg). LCMS (ESI, m / z): 908 [M+H] + . Synthesis of intermediate 12D

[0220] HCl (4.0 M in dioxane, 721 µL, 2.89 mmol) was added to a solution of intermediate 12C (65.5 mg, 0.072 mmol) in DCM (160 µL). The resulting mixture was stirred at room temperature for 1 h and then concentrated to dryness under a nitrogen stream to give crude intermediate 12D. LCMS (ESI, m / z): 652 [M+H] + . Synthesis of Example 12

[0221] DIPEA (63 µL, 0.36 mmol) was added to a mixture of intermediate 12D and HATU (82 mg, 0.216 mmol) in DMF (2.9 mL). The resulting mixture was stirred at room temperature for 1 h, and then concentrated to approximately 2 mL total volume under a nitrogen stream. The remaining mixture was filtered, and the filtrate was purified by preparative HPLC (Method I1). The fraction containing the desired product was dried under vacuum. The purified material was then diluted with 3 mL of a 1:1 mixture of dichloroethane and methanol, treated with Si-pyridine, and shaken for at least 2 h. The resulting mixture was filtered and dried under vacuum to give 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)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-7,10-dioxa-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinecyclododecano-4-one Synthesis of Example 13

[0222] Example 13 was prepared from intermediate 9C and tert-butyl 3-(2-(2-bromoethoxy)ethoxy)propionate using a synthetic protocol similar to that of 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]naphthid-2-yl)-5 5-Fluoro-2-methyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridaza-5(4,3)-pyridinium cyclodecafen-4-one Synthesis of intermediate 14A

[0223] Et3N (273 mg, 2.12 mmol) was added to a solution of tert-butyl 3-fluoro-5-(5-hydroxypentyl)pyridine-4-carboxylate* (200 mg, 0.71 mmol) in DCM (6 mL). The resulting mixture was cooled to 0ºC under nitrogen. TsCl (202 mg, 1.06 mmol) and DMAP (17 mg, 0.14 mmol) were then added fractionally, and the resulting mixture was stirred overnight at room temperature. The reaction was diluted with saturated aqueous NH4Cl solution (15 mL) at 0ºC and extracted with DCM (3 x 15 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum at 0ºC. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 3:1) to give intermediate 14A (225 mg) as a colorless oil. LCMS (ESI, m / z): 438 [M+H] + *Prepared according to a similar synthesis scheme as described in WO 2021222353. Synthesis of intermediate 14B

[0224] Under nitrogen atmosphere, Cs₂CO₃ (2.8 g, 8.59 mmol) and intermediate 14A (1.3 g, 2.97 mmol) were added to a solution of intermediate 1E (1.0 g, 2.88 mmol) in DMF (20 mL). The resulting mixture was stirred at 50ºC for 3 h, then diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with water (2 x 200 mL) and brine (2 x 200 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 2:1) to give intermediate 14B (1.3 g) as a yellow oil. LCMS (ESI, m / z): 613 [M+H] + . Synthesis of intermediate 14C

[0225] TFA (5 mL) was added to a solution of intermediate 14B (1.0 g, 1.63 mmol) in DCM (20 mL). The resulting mixture was stirred overnight at room temperature and then concentrated under vacuum to give crude intermediate 14C (600 mg) as a yellow oil. LCMS (ESI, m / z): 457 [M+H] + . Synthesis of intermediate 14D

[0226] HATU (1.4 g, 3.68 mmol) was added to a solution of intermediate 14C (1.1 g, 2.41 mmol) and DIPEA (5 g, 38.5 mmol) in DCM (20 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h, then diluted with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 3:1) to give intermediate 14D (400 mg) as a white solid. LCMS (ESI, m / z): 439 [M+H] + . Synthesis of intermediate 14E

[0227] NaOH (250 mg, 6.25 mmol) was added to a solution of intermediate 14D (350 mg, 0.80 mmol) in methanol (6 mL) and water (3 mL), and the resulting mixture was stirred at 50ºC for 0.5 h. The reaction mixture was acidified to pH 2 with aqueous HCl (1 M), stirred at room temperature for 0.5 h, diluted with water (20 mL), and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with water (2 x 40 mL) and brine (2 x 40 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give crude intermediate 14E (300 mg) as a white solid. LCMS (ESI, m / z): 397 [M+H] + . Synthesis of Example 14

[0228] Example 14 was prepared from intermediates 14E and 3L as a white solid using a synthesis scheme similar to that of Example 1. 1H NMR (400 MHz, DMSO-d6) δ 9.48 (d, J = 7.6 Hz, 1H), 8.50 (d, J =9.2 Hz, 2H), 8.34 (s, 1H), 8.29 - 8.24 (m, 3H), 8.13 (d, J = 8.0 Hz, 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 - 2.33 (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 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridaza-5(4,3)-pyridinium cyclodecafen-4-one Synthesis of Example 15

[0229] Example 15 was prepared from intermediates 14E and 4D as a white solid using a synthesis scheme similar to that of Example 2. 1H NMR (400 MHz, DMSO-d6) δ 9.48 (d, J = 7.2 Hz, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 8.28 - 8.23 ​​(m, 4H), 8.11 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H),7.27 (d, J = 8.0 Hz, 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 - 2.39 (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]isoquinolin-2-yl)-5 5 -Fluoro-2-methyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridaza-5(4,3)-pyridinium cyclodecafen-4-one Synthesis of Example 16

[0230] Example 16 was prepared from intermediates 14D and 5D as a white solid using a synthesis scheme similar to that of Example 5. 1H NMR (400 MHz, DMSO-d6) δ 9.46 (d, J = 8.0 Hz, 1H), 9.16 - 8.89 (m,2H), 8.48 (s, 1H), 8.33 (s, 1H), 8.23 ​​(s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.62(s, 1H), 7.35 (s, 1H), 7.26 (d, J = 8.0 Hz, 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 = 7.2 Hz, 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)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridaza-5(4,3)-pyridinium cyclodecafen-4-one Synthesis of Example 17

[0231] Example 17 was prepared from intermediates 14E and 2F as a white solid using a synthesis scheme similar to that of Example 2. 1H NMR (400 MHz, DMSO-d6+D2O) δ 9.49 (d, J = 8.0 Hz 1H), 8.48 (s,1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.11 (d, J = 8.0 Hz 1H), 7.62 (s, 1H), 7.28(d, J = 8.0 Hz 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)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridaza-5(1,2)-cyclopropanecyclodecafen-4-one Synthesis of intermediate 18A

[0232] To (5) 1 R,5 2 R,2R,Z)-2-methyl-4-oxo-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridazine-5(1,2)-cyclopropanecyclodecaban-7-ene-1 2Formaldehyde* (80 mg, 0.25 mmol, WO 2021222353) and intermediate 2F (110 mg, 0.28 mmol) were reacted with Na2S2O4 (160 mg, 0.92 mmol) in a solution of ethanol (2 mL) and water (1 mL). The resulting mixture was stirred at 90ºC for 2 h, then cooled to room temperature and purified directly onto C18 silica by rapid column chromatography (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 0% B to 100% B) to give intermediate 18A (120 mg) as a yellow solid. *Note: cis / trans composition not determined. LCMS (ESI, m / z): 694 [M+H] + . Synthesis of intermediate 18B

[0233] Pd / C (40 mg) was added to the reaction flask under nitrogen atmosphere, followed by ethanol (5 mL) and intermediate 18A (120 mg, 0.17 mmol). The flask was degassed and refilled with nitrogen (3x) followed by hydrogen (3x). The mixture was stirred overnight under hydrogen atmosphere at room temperature, and the solids were filtered off. The filtrate was concentrated under vacuum to give crude intermediate 18B (80 mg) as a yellow oil. LCMS (ESI, m / z): 696 [M+H] + . Synthesis of Example 18

[0234] TFA (0.5 mL) was added to a solution of intermediate 18B (80 mg, 0.11 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method E2, RT: 8.68 min). The purified fraction was concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to give Example 18 (41.1 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, br, 1H), 8.91 (s, br , 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.28 (s, 1H), 8.00 (d, J = 8.0Hz, 1H), 7.62 (s, 1H), 7.14 (d, J = 8.4 Hz, 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)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)spiro[cyclopropane-1,5'-3-aza-1(6,1)-pyrrolo[2,3-b]pyridiniumcycloundecanone]-4'-one Synthesis of Example 19

[0235] Example 19, a white solid, was prepared from intermediate 1E, tert-butyl 1-(6-bromohexyl)cyclopropane-1-carboxylate (WO 2021222353), and intermediate 2F using a synthetic scheme similar to that of Example 14. 1H NMR (400 MHz, DMSO-d6+D2O) δ 8.30 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.25 (d,J = 8.0 Hz, 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)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinecyclodecafen-4-one Synthesis of Example 20

[0236] Example 20, a white solid, was prepared from intermediate 1E, tert-butyl 7-bromo-2,2-dimethylheptanoate (WO 2021222353), and intermediate 2F using a synthesis scheme similar to that of Example 14. 1H NMR (400 MHz, DMSO-d6+D2O) δ 8.28 (s, 1H), 8.06 (d, J = 8.0 Hz, 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)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinecyclododecano-4-one Synthesis of intermediate 21A

[0237] LDA (2 M in THF, 3.5 mL, 6.93 mmol) was added dropwise to a solution of tert-butyl 2-methylpropionate (500 mg, 3.47 mmol) in THF (30 mL) at 0ºC under nitrogen atmosphere, and the resulting mixture was stirred at 0ºC for 1 h, followed by dropwise addition of 1,7-dibromoheptane (2.68 g, 10.4 mmol). The resulting mixture was stirred at 0ºC for 0.5 h and then at room temperature for 2 h, followed by quenching with saturated NH4Cl aqueous solution (50 mL) at 0ºC, stirring at room temperature for 20 min, and extraction with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 20:1) to give intermediate 21A (650 mg) as a pale yellow solid. Synthesis of Example 21

[0238] Example 21, a white solid, was prepared from intermediates 1E, 21A, and 2F using a synthesis scheme similar to that of Example 14. 1 H NMR (400 MHz, DMSO-d6+D2O) δ 8.29 (s, 1H), 8.07 (d, J =8.0 Hz, 1H), 7.62 (s, 1H), 7.23 (d, J = 8.0 Hz, 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)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-6-oxa-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinecycloundecan-4-one Synthesis of intermediate 22A

[0239] Intermediate 1E (300 mg, 0.86 mmol) was dissolved in DMF (6 mL) with 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). The resulting mixture was stirred overnight at 70ºC, then allowed to cool to room temperature and purified directly on C18 silica by rapid column chromatography (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 10% B to 80% B) to give intermediate 22A (240 mg) as a yellow oil. LCMS (ESI, m / z): 520 [M+H] + . Synthesis of intermediate 22B

[0240] TFA (1 mL) was added to a solution of intermediate 22A (240 mg, 0.46 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 1 h, and then concentrated under vacuum to give crude intermediate 22B (190 mg) as a yellow oil. LCMS (ESI, m / z): 420 [M+H] + . Synthesis of intermediate 22C

[0241] NaOH (108 mg, 2.7 mmol) was added to a solution of intermediate 22B (190 mg, 0.45 mmol) in methanol (2.5 mL) and water (2.5 mL) at room temperature. The resulting mixture was stirred at 50ºC under nitrogen for 1 h, then neutralized with aqueous HCl (4 M) and purified directly on C18 silica by rapid column chromatography (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 0% B to 60% B) to give intermediate 22C (130 mg) as a yellow oil. LCMS (ESI, m / z): 350 [M+H] + . Synthesis of intermediate 22D

[0242] HATU (245 mg, 0.64 mmol) and DIPEA (147 mg, 1.29 mmol) were added to a solution of intermediate 22C (150 mg, 0.43 mmol) in DMF (4 mL). The resulting solution was stirred at room temperature for 1 h and then used directly in the next step without further purification. LCMS (ESI, m / z): 450 [M+H]+. Synthesis of Example 22

[0243] Example 22 was prepared from intermediates 22D and 2F as a white solid using a synthesis scheme similar to that of Example 2. 1 H NMR (400 MHz, DMSO-d6+D2O) δ 8.30 (s, 1H), 8.14 (d, J = 8.0 Hz,1H), 7.62 (s, 1H), 7.29 (d, J = 8.0 Hz, 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)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-6,9-dioxa-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinecycloundecan-4-one Synthesis of intermediate 23A

[0244] Potassium tert-butoxide (782 mg, 6.97 mmol) was added to a mixture of tert-butyl 2-bromo-2-methylpropionate (1 mL, 5.36 mmol) and diethylene glycol (1.018 mL, 10.72 mmol) in DMSO (17.87 mL). The resulting mixture was adjusted to 60ºC and stirred overnight, then cooled to room temperature, diluted with EtOAc, washed with water (3X) and brine, dried over MgSO4, filtered, and concentrated under vacuum to give crude intermediate 23A (192 mg), which was used for the next step without further purification. Synthesis of intermediate 23B

[0245] Tert-butyl formate (221 mg, 1.160 mmol) and DMAP (9.45 mg, 0.077 mmol) were added to a mixture of intermediate 23A (192 mg, 0.773 mmol) and triethylamine (323 µL, 2.320 mmol) in DCM (7.0 mL) at 0ºC. The resulting mixture was stirred at room temperature for 1 h, then diluted with DCM, washed with water (2X) and brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica column chromatography (15% to 40% ethyl acetate in hexane) to give intermediate 23B (37 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.90 - 8.89 (m, 1H),7.79 (br d, J=8.0 Hz, 2H), 7.49 (br d, J=8.1 Hz, 2H), 4.17 - 4.07 (m, 2H),3.63 - 3.55 (m, 2H), 3.47 - 3.41 (m, 2H), 3.40 - 3.34 (m, 2H), 2.46 - 2.40 (m, 3H), 1.41 (s, 9H), 1.27 (s, 6H). Synthesis of Example 23

[0246] Example 23 was prepared from intermediates 9C and 23B using a synthesis scheme similar to that of 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)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridaza-5(1,2)-cyclopropanecyclononafen-4-one Synthesis of intermediate 24A

[0247] 2-(4-((tert-butyldiphenylsilyl)oxy)butyl)cyclopropane-1-carboxylic acid tert-butyl ester* was purified by SFC (column: (R,R) WHELK-O 14.6*50 mm, 3 µm; mobile phase B: 1% 2 M NH3-MeOH in IPA / hexane = 1:10; flow rate: 4 mL / min; gradient: isocratic B). The purified fraction was concentrated under vacuum to give the first eluted stereoisomer (280 mg) and intermediate 24A (300 mg, the second eluted stereoisomer) as a pale yellow oil. Note: cis / trans composition was not determined. LCMS (ESI, m / z): 453 [M+H] + *Prepared from 5-hydroxypentanal according to a similar synthetic scheme as described in WO 2021222353. Synthesis of intermediate 24B

[0248] TBAF (5 mL) was added to a solution of intermediate 24A (260 mg, 0.57 mmol) in THF (5 mL) at 0ºC. The resulting mixture was stirred at room temperature for 1 h, then diluted with water (30 mL) and extracted with ethyl acetate (30 mL). The organic extract was washed with water (5 x 30 mL) and brine (5 x 30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 1:1) to give intermediate 24B (110 mg) as a pale yellow oil. LCMS (ESI, m / z): 215 [M+H] + . Synthesis of intermediate 24C

[0249] Et3N (0.2 mL, 1.12 mmol), DMAP (4 mg, 0.04 mmol), and TsCl (106 mg, 0.56 mmol) were added fractionally to a solution of intermediate 24B (85 mg, 0.38 mmol) in DCM (4 mL) at 0ºC under nitrogen. The resulting mixture was stirred overnight at room temperature, then diluted with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 5:1) to give intermediate 24C (120 mg) as a pale yellow oil. LCMS (ESI, m / z): 369 [M+H] + . Synthesis of intermediate 24D

[0250] Intermediate 24C (120 mg, 0.33 mmol) and Cs₂CO₃ (344 mg, 1.05 mmol) were added to a solution of intermediate 1E (120 mg, 0.35 mmol) in DMF (4 mL). The resulting mixture was stirred overnight at 50ºC, then allowed to cool to room temperature and purified directly on C₁₈ silica by rapid column chromatography (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 10% B to 100% B) to give intermediate 24D (110 mg) as a yellow solid. LCMS (ESI, m / z): 544 [M+H] + . Synthesis of intermediate 24E

[0251] A solution of intermediate 24D (90 mg, 0.16 mmol) in HCl (4 M in EtOAc, 1 mL) was stirred at room temperature under nitrogen for 3 h. The mixture was concentrated under vacuum, and the resulting crude product was purified by rapid column chromatography on C18 silica (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 50% B to 100% B) to give intermediate 24E (60 mg) as a yellow oil. LCMS (ESI, m / z): 388 [M+H] + . Synthesis of Example 24

[0252] Example 24 was prepared from intermediates 24E and 2F using a synthesis scheme similar to that of Example 14, resulting in a light yellow oily substance. 1H NMR (400 MHz, DMSO-d6+D2O) δ 8.28 (s, 1H), 8.03 (d, J = 8.0Hz, 1H), 7.60 (s, 1H), 7.17 (d, J = 8.0 Hz, 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 = 7.2 Hz, 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)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-6-oxa-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinecycloundecan-4-one Synthesis of Example 25

[0253] Example 25 was prepared from intermediate 9C and tert-butyl 2-methyl-2-((5-(toluenesulfonyloxy)pentyl)oxy)propionate* using a synthetic protocol similar to that of Example 12. LCMS (ESI, m / z): 614 [M+H] + LCMS RT: 1.46 min (Method J). *Prepared according to a similar synthesis scheme as described in WO 2021222353. Examples 26 and 27. (2R)-5-fluoro-2-methyl-1 2-(1-Methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-5-(pyridin-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinecycloundecan-4-one Synthesis of intermediate 26A

[0254] Intermediate 26A was prepared from 2-(pyridin-2-yl)acetic acid tert-butyl and ((6-bromohexyl)oxy)(tert-butyl)dimethylsilane according to a similar synthetic scheme as described in WO 2021222353. LCMS (ESI, m / z): 466 [M+H] + . Synthesis of Examples 26 and 27

[0255] The mixtures of Examples 26 and 27 were prepared from intermediates 9C and 26A using a synthetic protocol similar to that of Example 12. The mixtures were then separated by preparative HPLC (Method I2) to obtain two pure chiral diastereomers. Example 26 (Diastereomeric 1, First elution: 1H NMR (500 MHz, 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, 1H), 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 = 7.1 Hz, 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).

[0256] Example 27 (diastereomer 2, second elution): 1H NMR (500 MHz, 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,1H), 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]pyridinecycloundecan-4-one Synthesis of intermediate 28A

[0257] H₂SO₄ (200 mL) was added dropwise to solid 6-fluoro-3,4-dihydroisoquinoline-1(2H)-one (15.0 g, 90.8 mmol) at 0ºC, followed by fractional addition of KNO₃ (36.7 g, 364 mmol). The resulting mixture was stirred at room temperature for 3 h, then added dropwise to ice water (1 L) and extracted with ethyl acetate (2 x 1 L). The combined organic extracts were washed with brine (2 L), dried over anhydrous sodium sulfate, and concentrated under vacuum to give crude intermediate 28A (22.5 g) as a yellow solid. LCMS (ESI, m / z): 211 [M+H] + . Synthesis of intermediate 28B

[0258] Methylamine hydrochloride (12.8 g, 190 mmol) and DIPEA (36.8 g, 285 mmol) were added to a solution of intermediate 28A (20.0 g, 94.8 mmol) in MeCN (200 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h, then diluted with water (1 L) and extracted with DCM (2 x 1 L). The combined organic extracts were washed with water (2 L) and brine (2 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (100% ethyl acetate) to give intermediate 28B (15 g) as a yellow solid. LCMS (ESI, m / z): 222 [M+H] + . Synthesis of intermediate 28C

[0259] A solution of intermediate 28B (10 g, 45 mmol) in methanol (210 mL) was added to a solution of saturated NH4Cl aqueous solution (70 mL), followed by the addition of zinc powder (29.3 g, 450 mmol) fractionally, and the resulting mixture was stirred at room temperature for 2 h. The solid was filtered off and the filtrate was concentrated under vacuum. The residue was diluted with water (500 mL) and extracted with DCM (2 x 500 mL). The combined organic extracts were washed with water (1 L) and brine (1 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (DCM / MeOH = 10:1) to give intermediate 28C (4.6 g) as a gray solid. LCMS (ESI, m / z): 192 [M+H] + . Synthesis of intermediate 28D

[0260] HATU (4.8 g, 12.7 mmol) was added to a solution of intermediate 1I (3.5 g, 9.7 mmol) and DIPEA (3.82 g, 28.6 mmol) in DMF (100 mL) at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 10 min, and then added dropwise to a solution of intermediate 28C (2.8 g, 14.6 mmol) in DMF (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 h, then diluted with water (500 mL) and extracted with ethyl acetate (500 mL). The combined organic extracts were washed with water (2 x 500 mL) and brine (2 x 500 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by rapid column chromatography on C18 silica (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 0% B to 100% B) to give intermediate 28D (4.6 g) as a yellow solid. LCMS (ESI, m / z): 531 [M+H] + . Synthesis of intermediate 28E

[0261] A solution of intermediate 28D (1.3 g, 2.5 mmol) in acetic acid (25 mL) was stirred at 70ºC for 3 h and then concentrated under vacuum. The crude product was purified by rapid column chromatography on C18 silica (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 0% B to 100% B) to give intermediate 28E (1.06 g) as a yellow solid. LCMS (ESI, m / z): 513 [M+H] + . Synthesis of intermediate 28F

[0262] NaH (60% w / w, 16 mg, 0.67 mmol) was added fractionally to a solution of intermediate 28E (50 mg, 0.10 mmol) in THF (3 mL) at 0ºC under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was cooled to 0ºC, and (S)-tetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (32 mg, 0.20 mmol) was added fractionally. The resulting mixture was stirred at room temperature overnight, then quenched with saturated aqueous NH4Cl solution (0.5 mL), and purified directly on C18 silica by rapid column chromatography (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 0% B to 100% B) to give intermediate 28F (40 mg) as a yellow solid. LCMS (ESI, m / z): 676 [M+H] + . Synthesis of Example 28

[0263] A solution of intermediate 28F (25 mg, 0.04 mmol) in HCl (4 M in MeOH, 2 mL) was stirred overnight at 70ºC in a sealed container and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method E4, RT: 8.5 min). The purified fraction was concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to give Example 28 (15.6 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, br 1H), 8.40 (s, br1H), 8.26 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.62(s, 1H), 7.19 (d, J = 8.0 Hz, 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]isoquinolin-2-yl)-11H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinecycloundecanone-4-one Synthesis of Example 29

[0264] Example 29, a white solid, was prepared from intermediate 28E and (R)-tetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide using a synthesis scheme similar to that of Example 28. 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, br, 1H), 8.41 (s, br, 1H), 8.26 (s, 1H), 8.05 (d, J = 8.0 Hz,1H), 7.84 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.19 (d, J = 8.0 Hz, 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 = 8.0 Hz, 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-difluoropiperidin-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]pyridinecycloundecan-4-one Synthesis of intermediate 30A

[0265] BH3 (1 M in THF, 3.8 mL, 3.8 mmol) was added to a solution of (R)-1-(tert-butoxycarbonyl)-4,4-difluoropiperidine-2-carboxylic acid (500 mg, 1.89 mmol) in 20 mL of THF at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature, then added to methanol at 0°C, stirred for 20 min at 0°C, and concentrated under vacuum. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 2:1) to give intermediate 30A (300 mg) as a white solid. LCMS (ESI, m / z): 252 [M+H] + . Synthesis of intermediate 30B

[0266] HCl (4 M in EtOAc, 4 mL, 16 mmol) was added to a solution of intermediate 30A (150 mg, 0.6 mmol) in ethyl acetate (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h and then concentrated under vacuum to give intermediate 30B (80 mg) as a white solid. LCMS (ESI, m / z): 152 [M+H] + . Synthesis of intermediate 30C

[0267] A solution of SOCl2 (108 mg, 0.95 mmol) in DCM (2 mL) was added dropwise to a solution of imidazole (216 mg, 3.18 mmol) in DCM (2 mL) under nitrogen atmosphere at 0ºC. The resulting mixture was stirred at room temperature for 1 h, then cooled to -10ºC, and a solution of intermediate 30B (80 mg, 0.53 mmol) in DCM (2 mL) was added dropwise under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h, then diluted with water (10 mL), acidified to pH 6 with citric acid, and extracted with DCM (3 x 10 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give intermediate 30C (80 mg) as a white solid. LCMS (ESI, m / z): 198 [M+H] + . Synthesis of intermediate 30D

[0268] A solution of NaIO4 (88 mg, 0.41 mmol) and RuCl3 (10.3 mg, 0.04 mmol) in H2O (1 mL) was added to a solution of intermediate 30C (80 mg, 0.41 mmol) in MeCN (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h, then diluted with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give intermediate 30D (80 mg) as a white solid. LCMS (ESI, m / z): 214 [M+H] + . Synthesis of intermediate 30E

[0269] NaH (60% w / w, 7.0 mg, 0.20 mmol) was added to a solution of intermediate 28E (50 mg, 0.10 mmol) in THF (2 mL) at 0ºC under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was cooled to 0ºC, 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 50ºC, then quenched with saturated aqueous NH4Cl solution (0.5 mL) and purified directly on C18 silica by rapid column chromatography (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 5% B to 80% B) to give intermediate 30E (60 mg) as a white solid. LCMS (ESI, m / z): 726 [M+H] + . Synthesis of Example 30

[0270] A solution of intermediate 30E (60 mg, 0.08 mmol) in HCl (4 M in MeOH, 4 mL) was stirred at 50ºC for 2 h in a sealed container, and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method E3, RT: 8.68 min). The purified fraction was concentrated under vacuum to remove organic solvents, and the residual aqueous solution was lyophilized to give Example 30 (53.4 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6+D2O) δ 8.27 (s, 1H), 8.05 (d, J =8.0 Hz, 1H), 7.58 (s, 1H), 7.18 (d, J = 8.0 Hz, 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), 3.23 - 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 =6.8 Hz, 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).

[0271] Examples 31-38 (see Table 1) were prepared from intermediate 28E and suitable commercially available precursors using a synthesis scheme similar to that of Example 30. Table 1. Characterization of Examples 31-38. 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]isoquinolin-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3-b]pyridinecycloundecan-4-one Synthesis of intermediate 39A

[0272] Ms₂O (905 mg, 3.4 mmol) and Et₃N (465 mg, 4.6 mmol) were added to a solution of (S)-2-(hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester (500 mg, 2.3 mmol) in DCM (23 mL) at 0ºC under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h, then diluted with saturated NH₄Cl aqueous solution (20 mL) at 0ºC and extracted with DCM (2 x 20 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 5:1) to give intermediate 39A (400 mg) as a pale yellow oil. LCMS (ESI, m / z): 296 [M+H] + . Synthesis of intermediate 39B

[0273] NaH (60% w / w, 14 mg, 0.35 mmol) was added dropwise to a solution of intermediate 28E (60 mg, 0.12 mmol) in DMF (3 mL) at 0ºC under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 0.5 h. The reaction was cooled to 0ºC, 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 50ºC for 2 h, then quenched with a saturated aqueous solution of NH4Cl (0.5 mL) and purified directly on C18 silica by rapid column chromatography (mobile phase A: 0.5% TFA in water, mobile phase B: ACN; gradient: 0% B to 100% B) to give intermediate 39B (29 mg) as a yellow solid. LCMS (ESI, m / z): 712 [M+H] + . Synthesis of Example 39

[0274] TFA (1 mL) was added to a solution of intermediate 39B (30 mg, 0.04 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method E5, RT: 8.5 min). The purified fraction was concentrated under vacuum to remove the organic solvent and the residual aqueous solution was lyophilized to give Example 39 (15.6 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6+D2O) δ 8.26 (s, 1H), 8.09 (d,J = 8.0 Hz, 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 = 12 Hz, 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]pyridinecycloundecan-4-one Synthesis of intermediate 40A

[0275] Et3N (0.84 mL, 4.81 mmol) and MsCl (219 mg, 1.92 mmol) were added to a solution of (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 1.60 mmol) in DCM (16 mL) at 0ºC under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h, then quenched with a saturated aqueous solution of NH4Cl (20 mL) at 0ºC and extracted with DCM (2 x 20 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum at 0ºC to give intermediate 40A (300 mg) as a pale yellow oil. LCMS (ESI, m / z): 266 [M+H]+ . Synthesis of Example 40

[0276] Example 40, a white solid, was prepared from intermediates 28E and 40A using a synthesis scheme similar to that of Example 39. 1 H NMR (400 MHz, DMSO-d6) δ 8.90 - 8.82 (m, 2H), 8.24 (s, 1H), 8.05(d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.2 Hz, 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 = 8.0 Hz, 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]pyridinecycloundecan-4-one Synthesis of intermediate 41A

[0277] BH3 (1 M in THF, 18 mL, 18 mmol) was added to a solution of N-(tert-butoxycarbonyl)-O-methyl-D-serine (2 g, 9.12 mmol) in THF (90 mL) at 0ºC. The resulting mixture was stirred at room temperature for 6 h, then quenched with methanol (0.6 mL) at 0ºC and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 3:1) to give intermediate 41A (1 g) as a white solid. LCMS (ESI, m / z): 206 [M+H] + . Synthesis of intermediate 41B

[0278] SOCl2 (626 mg, 5.26 mmol) was added dropwise to a solution of imidazole (1.19 g, 17.54 mmol) in DCM (5 mL) at 0ºC. The resulting mixture was stirred at room temperature for 1 h, then cooled to -10ºC, and a solution of intermediate 41A (600 mg, 2.92 mmol) in DCM (5 mL) was added. The resulting mixture was stirred at room temperature for 2 h, then diluted with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 4:1) to give intermediate 41B (300 mg) as a white solid. LCMS (ESI, m / z): 252 [M+H] + . Synthesis of intermediate 41C

[0279] A solution of NaIO4 (255 mg, 1.19 mmol) and RuCl3 (24 mg, 0.12 mmol) in water (4 mL) was added to a solution of intermediate 41B (300 mg, 1.19 mmol) in acetonitrile (8 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h and then concentrated under vacuum. The residue was diluted with water (30 mL) and extracted with DCM (3 x 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 4:1) to give intermediate 41C (200 mg) as a white solid. LCMS (ESI, m / z): 268 [M+H] + . Synthesis of intermediate 41D

[0280] NaH (60% w / w, 15 mg, 0.39 mmol) was added fractionally to a solution of intermediate 28E (100 mg, 0.20 mmol) in DMF (2 mL) at 0ºC under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 0.5 h, then cooled to 0ºC and intermediate 41C (62 mg, 0.23 mmol) was added. The resulting mixture was stirred at room temperature for 4 h, then quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 1:2) to give intermediate 41D (90 mg) as a colorless oil. LCMS (ESI, m / z): 700 [M+H] + . Synthesis of Example 41

[0281] TFA (0.5 mL) was added to a solution of intermediate 41D (35 mg, 0.05 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated under vacuum. The crude product was purified by preparative HPLC (method E5, RT: 8.5 min). The purified fraction was concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to give Example 41 (13.5 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.06 - 8.04(m, 4H), 7.83 (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.19 (d, J = 8.0 Hz, 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]pyridinecycloundecan-4-one Synthesis of intermediate 42A

[0282] NaH (60% w / w, 4 mg, 0.20 mmol) was added dropwise to a solution of intermediate 41D (60 mg, 0.10 mmol) in DMF (2 mL) at 0ºC under nitrogen. The resulting mixture was stirred at room temperature for 0.5 h, then cooled to 0ºC and MeI (28.4 mg, 0.20 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 2 h, then quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (petroleum ether / ethyl acetate = 1:2) to give intermediate 42A (35 mg) as a colorless oil. LCMS (ESI, m / z): 714 [M+H] + . Synthesis of Example 42

[0283] TFA (0.5 mL) was added to a solution of intermediate 42A (35 mg, 0.04 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated under vacuum. The crude product was purified by preparative HPLC (Method G, RT: 8.57 min). The purified fraction was concentrated under vacuum to remove the organic solvent and the residual aqueous solution was lyophilized to give Example 42 (20.5 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, br, 2H), 8.24 (s,1H), 8.05 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.2 Hz, 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]pyridinecycloundecan-4-one Synthesis of intermediate 43A

[0284] A pre-prepared solution of 4-toluenesulfonyl chloride (133 mg, 0.695 mmol) in DCM (2 mL) was added dropwise to a solution of (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) in DCM (5 mL). The resulting mixture was stirred overnight at room temperature, then diluted with water and extracted with DCM. The organic extract was washed with saturated aqueous NaHCO3 solution and brine, dried over magnesium sulfate, and concentrated under vacuum. The crude product was purified by silica rapid column chromatography (0 to 20% ethyl acetate in hexane) to give intermediate 43A as a colorless oil. LCMS (ESI, m / z): 291.8 [M+H-Boc] + . Synthesis of Example 43

[0285] Example 43 was prepared from intermediates 28E and 43A using a synthesis scheme similar to that of 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]pyridinecycloundecan-4-one Synthesis of Example 44

[0286] Example 44 was prepared from intermediate 28E (80 mg, 0.156 mmol) and (R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester using a synthetic protocol similar to that of Example 43. LCMS (ESI, m / z): 632 [M+H] + LCMS RT: 1.5 min (Method J). RFMS measurement

[0287] The compound was dissolved in 100% DMSO to achieve a concentration of 10 mM. The compound stock solution was stored at room temperature. A series of dilutions were prepared in DMSO and mixed eight times with a 20 µL mixing volume. The final highest 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 37ºC for 30 min, enzyme / substrate reaction for 90 min, reaction with phenylglyoxal at 37ºC for 30 min; stop solution: 40 µL of 5% trichloroacetic acid solution in ACN.

[0288] Assay protocol: 0.13 µL of the compound solution was added to a 10 nM PAD4 solution in assay buffer (13 µL). After 30 min, 500 µM BAEE solution in assay buffer (13 µL) was added, and the reaction was incubated at 37ºC for 90 min. The enzymatic reaction was quenched by adding 6.1 N trichloroacetic acid (15 µL, 100% w / v). Final concentration: 20%. Then, 35 µL of 8.5 mM phenylglyoxal solution was added to a final concentration of 4 mM, and the reaction was incubated at 37ºC for 30 min. After 30 min, the plate was centrifuged to remove all precipitate. The enzyme reaction was quenched with an equal volume of methanol containing the internal standard (modified citrulline). Samples were loaded onto a Rapid Fire RF300 system (Agilent), where they were first sipped for 1000 ms and then directly loaded into a C18 separation column for 3000 ms of desalting using a mixture of acetonitrile and 0.01% formic acid. The mobile phase flow rate was 1.5 mL / min. Once the sample was eluted from the column, it was transferred to the mass spectrometer at a flow rate of 1.25 mL / min using acetonitrile and 0.01% formic acid for 4000 ms. Peptidyl citrulline and the internal standard ion were analyzed using a Sciex API5500 triple quadrupole mass spectrometer (Applied Biosystems) equipped with ESI.

[0289] Multiple reaction monitoring (MRM) transitions of the product and internal standard were performed at m / z 424.5–350.4 and m / z 293–247, respectively. The residence time for each transition was set to 200 ms, and an ESI voltage of 5500 Ω and a source temperature of 400°C were used. The extracted ion peaks for each transition were integrated using RapidFire Integrator software. The peak areas of the analytes were normalized using the internal standard. For the given compound examples, the following shows the IC50 values ​​of human PAD4 (hPAD4) as determined by RapidFire mass spectrometry (RFMS). 50 .

[0290] Table 2 below shows the activities of the selected compounds of the present invention in the above PAD4 assay. Compounds with activities designated as "A" are provided with IC50. 50 ≤ 10 nM; compounds with activity designated as "B" provide IC50. 50 11-100 nM; compounds with activity designated as "C" provide IC50. 50 101-500 nM; compounds with activity designated as "D" provide IC50. 50 501-1000 nM; compounds with activity designated as "E" provide IC50. 50 > 1000 nM. Table 2. Bioactivity Data List of implementation plans Listed implementation scheme 1. A compound of formula I: (I), Or its pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer. in: X1 and X2 are each independently CR8 or N; Y is selected from -(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-; R1 is independently -CH(NHR7)-(C1-C3 alkyl) or a 4- to 8-membered heterocycle containing at least one heteroatom selected from N, O, or S, wherein the alkyl or heterocycle is optionally surrounded by one or more R 11 replace; R2 is independently H or C1-C4 alkyl; R3 is independently H, halogen, or C1-C4 alkyl; R4 is independently hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; R5 and R6 are independently selected from H, halogens, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, heteroaryl, and aryl; wherein the heteroaryl or aryl is optionally substituted with one or more halogens or C1-C6 alkoxy groups; or R5 and R6, together with the atoms in between, form C3-C6 cycloalkyl groups or 4- to 8-membered heterocyclic groups; or R5, R6, and R9, together with their intermediate and adjacent atoms, form a C3-C6 cycloalkyl, 4- to 8-membered heterocyclic, heteroaryl, or aryl group, wherein the cycloalkyl, heterocyclic, heteroaryl, or aryl group is optionally surrounded by one or more R... 12 replace; 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 carbocyclic group; Each R 10 It is independently H, halogen, or C1-C4 alkyl; Each R 11 Independently selected from H, halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups; Each R 12 Independently selected from H, halogens, -OH, -NH2, -CN, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl and C3-C4 cycloalkyl, 3 to 10 membered heterocyclic groups, heteroaryl groups and C6-C 10 Aryl; L represents 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. Example 2. The compound according to example 1, wherein the compound has formula (Ia): (Ia), Where X3 is CH2, NH, O or S, and r is an integer from 1 to 3. 3. A compound according to any one of the foregoing listed embodiments, wherein the compound has formula (Ia-1): (Ia-1) X3 is NH, O or S. (Ia-2) Where A is a C3-C8 cycloalkyl, aryl, or heteroaryl group; and X3 is NH, O or S. Example 5. The compound according to examples 1-3, wherein the compound has formula (Ia-3). (Ia-3), X3 is NH, O or S. 6. The compound according to embodiments 1, 2, or 4, wherein the compound has formula (Ia-4). (Ia-4), Where A is a C3-C8 cycloalkyl, aryl, or heteroaryl group; and X3 can be CH2, NH, O, or S. 7. The compound according to embodiment 1 or 2, wherein the compound has formula (Ia-5). (Ia-5), X3 can be CH2, NH, O, or S. 8. The compound according to embodiment 1, wherein the compound has formula (Ib): (Ib). 9. The compound according to embodiment 1 or 8, wherein the compound has the formula (Ib-1): (Ib-1). 10. The compound according to embodiment 1 or 8, wherein the compound has the formula (Ib-2): (Ib-2) Where A is a C3-C8 cycloalkyl, aryl, or heteroaryl group. Example 11. The compound according to example 1 or 8, wherein the compound has formula (Ib-3). (Ib-3). Example 12. The compound according to example 1 or 8, wherein the compound has the formula (Ib-4). (Ib-4), Where A is a C3-C8 cycloalkyl, aryl, or heteroaryl group. Example 13. The compound according to example 1 or 8, wherein the compound has the formula (Ib-5). (Ib-5). Example 14. The compound according to example 1 or 8, wherein the compound has the formula (Ib-6). (Ib-6). 15. The compound according to embodiment 1 or 2, wherein the compound has the formula (Ic): (Ic). Listed Embodiment 16. The compound according to listed Embodiment 1 or 15, wherein the compound has the formula (Ic-1): (Ic-1). 17. The compound according to embodiment 1 or 15, wherein the compound has formula (Ic-2): (Ic-2) Where A is a C3-C8 cycloalkyl, aryl, or heteroaryl group. Example 18. The compound according to example 1 or 15, wherein the compound has formula (Ic-3). (Ic-3). Example 19. The compound according to example 1 or 15, wherein the compound has formula (Ic-4). (Ic-4), Where A is a C3-C8 cycloalkyl, aryl, or heteroaryl group. Example 20. The compound according to example 1 or 15, wherein the compound has the formula (Ic-5): (Ic-5). Listed Embodiment 21. The compound according to Listed Embodiment 1, wherein the compound has the formula (Id): (Id), Where r is an integer from 0 to 2. Example 22. The compound according to example 1, wherein the compound has the formula (Ie): (Ie), Where r is an integer from 0 to 2. 23. The compound according to embodiment 1, wherein the compound has the formula (If): (If), Where A is a C3-C8 cycloalkyl, aryl, or heteroaryl group; and r is an integer from 0 to 2. Example 24. The compound according to any one of the foregoing examples, wherein R2 is H or a C1-C4 alkyl group. 25. The compound according to any one of the foregoing listed embodiments, wherein R2 is a methyl group. 26. The compound according to any one of the foregoing listed embodiments, wherein R3 is H. Example 27. The compound according to any one of the foregoing examples, wherein R4 is a C1-C4 alkyl group. 28. The compound according to any one of the foregoing listed embodiments, wherein R4 is a methyl group. Example 29. The compound according to any one of the foregoing examples, wherein R7 is a methyl group. 30. The compound according to any one of the foregoing listed embodiments, wherein R7 is cyclopropyl. 31. The compound according to any one of the foregoing listed embodiments, wherein at least one R 11 It is selected from halogens, C1-C6 alkoxy groups, or C1-C6 alkyl groups. 32. The compound according to any one of the foregoing listed embodiments, wherein at least one R 11 It is H. 33. The compound according to any one of the foregoing listed embodiments, wherein at least one R 11 It's fluorine. 34. The compound according to any one of the foregoing listed embodiments, wherein at least one R11 It is a C1-C6 alkoxy group. 35. The compound according to any one of the foregoing listed embodiments, wherein the compound is selected from: Or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof. Example 36. A pharmaceutically acceptable composition comprising a compound according to any one of examples 1-35 and a pharmaceutically acceptable carrier, adjuvant, or mediator. Example 37. A method for inhibiting PAD4 in a subject or biological sample, the method comprising the step of contacting the PAD4 with a compound according to any one of examples 1-35. Example 38. A method for treating a subject with a PAD4-mediated disease, disorder, or condition, the method comprising administering to the subject the composition according to example 36. Listed Implementation Scheme 39. The method according to Listed Implementation Scheme 38, wherein the PAD4-mediated disease, disorder, or condition is selected from 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 disease, aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, and weight loss, angina pectoris, angioedema, anhidrotic ectodermal dysplasia with immunodeficiency, ankylosing spondylitis, anterior segment inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, Arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, Behçet's disease, Behçet's syndrome, Bell's palsy, beryllium poisoning, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiomegaly, carpal tunnel syndrome, catabolism disorders, cataracts, cerebral aneurysms, chemical irritant-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 diseases, corneal ulcers, Crohn's disease, cryoinflammatory hormone-related periodic syndrome, cryptococcosis, cystic fibrosis, interleukin-1 receptor antagonist deficiency (DIRA), dermatitis. Dermatitis, endotoxemia, dermatomyositis, diffuse endogenous pontine glioma, endometriosis, endotoxemia, epicondylitis, erythroblastopenia, familial amyloid polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth retardation, glaucoma, glomerular diseases, glomerulonephritis, gout, gouty arthritis, graft-versus-host disease, intestinal diseases, head injury, headache, hearing loss, heart disease, hemolytic anemia, allergic purpura, hepatitis, hereditary periodic fever syndrome, herpes zoster and herpes simplex, HIV-1, Hodgkin's disease, Huntington's disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulin D with periodic fever (HIDS), aplastic anemia Blood and other anemias, aplastic anemia, idiopathic thrombocytopenic purpura, pigmentary disorders, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, iritis, irritant-induced inflammation, ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, nephropathy, kidney injury caused by parasitic infection, kidney transplant rejection prevention, leptospirosis, leukemia, Leffler syndrome, lung injury, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, Muller-Weil syndrome (urticaria, deafness, amyloidosis), multiple sclerosis, muscle wasting, muscle atrophy.Myasthenia gravis, myocarditis, mycosis fungoides, myelodysplastic syndrome, myositis, sinusitis, necrotizing enterocolitis, neonatal multiple system inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological diseases, non-allergen-induced asthma, obesity, ocular allergies, optic neuritis, organ transplantation, osteoarthritis, otitis media, Paget's disease, pain, pancreatitis, Parkinson's disease, pemphigus, pericarditis, periodic fever, periodontitis, peritoneometriosis, pertussis, pharyngitis and adenitis (PFAPA syndrome), phytoiritis-induced inflammation, pneumonia, lung inflammation, Pneumocystis infection, toxic ivy / urushiol oil-induced inflammation, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyositis, psoriasis, psoriasis, psoriasis, psoriasis Diseases, psychological stress-related illnesses, lung diseases, pulmonary hypertension, pulmonary fibrosis, pyoderma gangrene, pyogenic aseptic arthritis, kidney disease, retinal diseases, rheumatic heart disease, rheumatic diseases, rheumatoid arthritis, sarcoidosis, seborrheic dermatitis, sepsis, severe pain, sickle cell disease, sickle cell anemia, silica-induced diseases, Sjögren's syndrome, skin diseases, sleep apnea, solid tumors, spinal cord injury, Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplantation, TNF receptor-related periodic syndrome (TRAPS), toxoplasmosis, transplantation, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticaria, uveitis, and Wechsler's granulomatosis. Example 40. The method according to example 38, wherein the PAD4-mediated disease, disorder, or condition is selected from rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, and psoriasis. equivalent

[0291] While we have described many embodiments of this disclosure, it will be apparent that our basic embodiments can be modified to provide other embodiments utilizing the compounds and methods of this disclosure. Therefore, it should be understood that the scope of this disclosure will be defined by the appended claims, and not by the specific embodiments already illustrated by way of example.

[0292] Details of one or more embodiments of this disclosure are set forth in the accompanying description above. While any methods and materials similar to or equivalent to those described herein may be used in practicing or testing this disclosure, preferred methods and materials are now described. Other features, objectives, and advantages of this disclosure will become apparent from the specification and claims. In the specification and appended claims, the singular form includes the plural indicator unless the context clearly requires otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. All patents and publications referenced in this specification are incorporated herein by reference.

[0293] The foregoing description is presented for illustrative purposes only and is not intended to limit this disclosure to the precise form disclosed, but is limited by the appended claims.

Claims

1. A compound of formula I: (I)， Or its pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer. in: X1 and X2 are each independently CR8 or N; Y is selected from -(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-; R1 is independently -CH(NHR7)-(C1-C3 alkyl) or a 4- to 8-membered heterocycle containing at least one heteroatom selected from N, O, or S, wherein the alkyl or heterocycle is optionally surrounded by one or more R 11 replace; R2 is independently H or C1-C4 alkyl; R3 is independently H, halogen, or C1-C4 alkyl; R4 is independently hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; R5 and R6 are independently selected from H, halogens, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, heteroaryl, and aryl; wherein the heteroaryl or aryl is optionally substituted with one or more halogens or C1-C6 alkoxy groups; or R5 and R6, together with the atoms in between, form C3-C6 cycloalkyl groups or 4- to 8-membered heterocyclic groups; or R5, R6, and R9, together with their intermediate and adjacent atoms, form a C3-C6 cycloalkyl, 4- to 8-membered heterocyclic, heteroaryl, or aryl group, wherein the cycloalkyl, heterocyclic, heteroaryl, or aryl group is optionally surrounded by one or more R... 12 replace; 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 carbocyclic group; Each R 10 It is independently H, halogen, or C1-C4 alkyl; Each R 11 Independently selected from H, halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups; Each R 12 Independently selected from H, halogens, -OH, -NH2, -CN, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl and C3-C4 cycloalkyl, 3 to 10 membered heterocyclic groups, heteroaryl groups and C6-C 10 Aryl; L represents 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.

2. The compound according to claim 1, wherein the compound has formula (Ia): (I), Where X3 is CH2, NH, O or S, and r is an integer from 1 to 3.

3. The compound according to claim 1 or 2, wherein the compound has formula (Ia-1) (Ia-1)、Formula (Ia-2) (Ia-2)、Formula (Ia-3) (Ia-3)、Formula (Ia-4) (Ia-4) Or formula (Ia-5) (Ia-5), where X3 is NH, O, or S, and A is a C3-C8 cycloalkyl, aryl, or heteroaryl group.

4. The compound according to claim 1, wherein the compound has the formula (Ib): (Ib).

5. The compound according to claim 1 or 4, wherein the compound has the formula (Ib-1): (Ib-1), Formula (Ib-2): (Ib-2) Equation (Ib-3) (Ib-3), Equation (Ib-4) (Ib-4), Equation (Ib-5) (Ib-5) or Equation (Ib-6) (Ib-6), Where A is a C3-C8 cycloalkyl, aryl, or heteroaryl group.

6. The compound according to claim 1, wherein the compound has the formula (Ic): (Ic)。 7. The compound according to claim 1 or 6, wherein the compound has the formula (Ic-1): (Ic-1)、 Equation (Ic-2): (Ic-2) Equation (Ic-3) (Ic-3)、 Equation (Ic-4) (Ic-4), or Equation (Ic-5): (Ic-5), Where A is a C3-C8 cycloalkyl, aryl, or heteroaryl group.

8. The compound according to claim 1, wherein the compound has the formula (Id): (Id)、 Formula (Ie): (Ie), or Formula (If): (If), Where A is a C3-C8 cycloalkyl, aryl, or heteroaryl group; and r is an integer from 0 to 2.

9. The compound according to any one of the preceding claims, wherein R2 is H or a C1-C4 alkyl group.

10. The compound according to any one of the preceding claims, wherein R3 is H.

11. The compound according to any one of the preceding claims, wherein R4 is a C1-C4 alkyl group.

12. The compound according to any one of the preceding claims, wherein R7 is methyl or cyclopropyl.

13. The compound according to any one of the preceding claims, wherein at least one R 11 It is selected from H, halogen, fluorine, C1-C6 alkoxy or C1-C6 alkyl.

14. The compound according to any one of the preceding claims, wherein the compound is selected from: Or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof.

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

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

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

18. The method of claim 17, wherein the PAD4-mediated disease, disorder, or condition is selected from acid-induced lung injury, acne (PAPA), acute lymphoblastic leukemia, acute respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenocortical insufficiency, aging, AIDS, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary disease, aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, and weight loss, angina pectoris, angioedema, anhidrotic ectodermal dysplasia with immunodeficiency, ankylosing spondylitis, anterior segment inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, asthma, atherosclerosis. Sclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, Behçet's disease, Behçet's syndrome, Bell's palsy, beryllium poisoning, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiomegaly, carpal tunnel syndrome, catabolism, cataracts, cerebral aneurysms, chemical irritant-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 diseases, corneal ulcers, Crohn's disease, cryoinflammatory hormone-related periodic syndrome, cryptococcosis, cystic fibrosis, interleukin-1 receptor antagonist deficiency (DIRA), dermatitis, dermatitis endotoxemia, dermatomyositis Inflammation, diffuse endogenous pontine glioma, endometriosis, endotoxemia, epicondylitis, erythroblastopenia, familial amyloid polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth retardation, glaucoma, glomerular diseases, glomerulonephritis, gout, gouty arthritis, graft-versus-host disease, intestinal diseases, head injury, headache, hearing loss, heart disease, hemolytic anemia, allergic purpura, hepatitis, hereditary periodic fever syndrome, herpes zoster and herpes simplex, HIV-1, Hodgkin's disease, Huntington's disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulin D with periodic fever (HIDS), aplastic anemia and other anemias, aplastic anemia Benign anemia, idiopathic thrombocytopenic purpura, pigmentary disorders, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, iritis, irritant-induced inflammation, ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, nephropathy, kidney injury caused by parasitic infection, kidney transplant rejection prevention, leptospirosis, leukemia, Leffler syndrome, lung injury, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, Muller-Weil syndrome (urticaria, deafness, amyloidosis), multiple sclerosis, muscle wasting, muscle atrophy, myasthenia gravis, myocarditis.Mycosis fungoides, myelodysplastic syndrome, myositis, sinusitis, necrotizing enterocolitis, neonatal multisystem inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological diseases, non-allergen-induced asthma, obesity, ocular 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), phytoiritis-induced inflammation, pneumonia, lung inflammation, Pneumocystis infection, toxic ivy / urushiol oil-induced inflammation, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyositis, psoriasis, psoriasis, psoriasis, psoriasis, psychogenic Irritating diseases, lung diseases, pulmonary hypertension, pulmonary fibrosis, pyoderma gangrene, pyogenic aseptic arthritis, kidney disease, retinal diseases, rheumatic heart disease, rheumatic diseases, rheumatoid arthritis, sarcoidosis, seborrheic dermatitis, sepsis, severe pain, sickle cell disease, sickle cell anemia, silica-induced diseases, Sjögren's syndrome, skin diseases, sleep apnea, solid tumors, spinal cord injury, Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplantation, TNF receptor-related periodic syndrome (TRAPS), toxoplasmosis, transplantation, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticaria, uveitis, and Wechsler's granulomatosis.

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

20. The method of claim 19, wherein the PAD4-mediated disease, disorder, or condition is rheumatoid arthritis.

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