Macrocyclic PAD4 inhibitors useful as immunosuppressive agents

Abstract

The present invention provides compounds of formula (I) useful as inhibitors of PAD4, compositions thereof, and methods for treating PAD4-related disorders, wherein rings A, A1, A2, A3, A4, Q, R1, R2, R3, R4, R5, and R6 in formula (I), together with other variables, are as defined herein. TIFF2023512557000326.tif38150

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 970,832, filed on February 6, 2020, the entire contents of which are hereby incorporated by reference herein.

Background Art

[0002] PAD4 is a member of the peptidylarginine deiminase (PAD) family of enzymes that has the ability to catalyze the citrullination of arginine to citrulline within the range of a peptide sequence. PAD4 is involved in the deimination or citrullination of various proteins in vitro and in vivo, resulting in multifunctional responses in various diseases (Jones J.E. et al., Curr. Opin. Drug Discov. Devel., 12(5)(2009), 616 - 627). Examples of typical diseases include, in addition to oncology indications, rheumatoid arthritis, diseases with a neutrophil contribution to the etiology (e.g., vasculitis, systemic lupus erythematosus, ulcerative colitis). PAD4 inhibitors also have broad applicability as tools and therapeutic agents for human diseases through epigenetic mechanisms.

[0003] Inhibitors of PAD4 are useful against rheumatoid arthritis (RA). RA is an autoimmune disease that affects approximately 1% of the population (Wegner N. et al., Immunol. Rev., 233(1)(2010), 34-54). RA is characterized by joint inflammation leading to the erosive destruction of bone and cartilage. Although not consistent, a weak genetic association between PAD4 polymorphisms and susceptibility to RA has been suggested in many population studies (Kochi Y. et al., Ann. Rheum. Dis., 70(2011),512-515). PAD4 (along with family member PAD2) was detected in synovial tissue where it is involved in the deimination of various joint proteins. This process is presumed to lead to the disruption of resistance to citrullinated substrates such as fibrinogen, vimentin and collagen, and the initiation of an immune response against these substrates in RA joints. These anti-citrullinated protein antibodies (ACPA) contribute to the etiology of the disease and may be used as a diagnostic test for RA (e.g., commercially available CCP2 or cyclic citrullinated protein 2 test). In addition, increased citrullination may also confer a further direct contribution to the etiology of the disease through its ability to directly affect the function of several joint and inflammatory mediators (e.g., fibrinogen, antithrombin, multiple chemokines). Anti-PAD4 antibodies can be measured in a subset of RA patients and may be correlated with a more erosive form of the disease.

[0004] PAD4 inhibitors are also useful for reducing the activity of pathological neutrophils in various diseases. According to research, the process of neutrophil extracellular trap (NET) formation, which is an innate defense mechanism by which neutrophils can immobilize and kill pathogenic bacteria, is associated with the citrullination of histones and is defective 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 the pathology of the disease. 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), deep vein thrombosis (Fuchs T. et al., Proc. Natl. Acad. Sci. USA, 107(36)(2010), 15880-5), periodontitis (Vitkov L. et al., Ultrastructural Pathol., 34(1)(2010), 25-30), sepsis (Clark S.R. et al., Nat. Med., 13(4)(2007), 463-9), appendicitis (Brinkmann V. et al., Science, 303(2004), 1532-5), and stroke.In addition, there is evidence indicating the potential contribution of NETs to lesions in skin diseases where NETs affect the skin, such as cutaneous lupus erythematosus (Villanueva E. et al., J. Immunol., 187(1)(2011), 538 - 52) and psoriasis (Lin A.M. et al., J. Immunol., 187(1)(2011), 490 - 500). Therefore, PAD4 inhibitors may be beneficial in addressing NET skin diseases when administered via the systemic or skin routes. PAD4 inhibitors may further affect additional functions within neutrophils and may have broader applicability to neutrophil diseases.

[0005] Studies have demonstrated the efficacy of PAD inhibitors (e.g., chloramidine) as tools in numerous animal model diseases, including collagen - induced arthritis (Willis V.C. et al., J. Immunol., 186(7)(2011), 4396 - 4404), dextran sulfate sodium (DSS) - induced experimental colitis (Chumanevich A.A. et al., Am. J. Physiol. Gastrointest. Liver Physiol., 300(6)(2011), G929 - G938), spinal cord repair (Lange S. et al., Dev. Biol., 355(2)(2011), 205 - 14), and experimental autoimmune encephalomyelitis (EAE). Reports on DSS colitis have also demonstrated that chloramidine promotes apoptosis of inflammatory cells both in vitro and in vivo, suggesting that PAD4 inhibitors may be more generally effective in a broad range of inflammatory diseases.

[0006] PAD4 inhibitors are also useful in the treatment of cancer (Slack J.L. et al., Cell. Mol. Life Sci., 68(4)(2011), 709-720). Overexpression of PAD4 has been demonstrated in many cancers (Chang X. et al., BMC Cancer, 9(2009), 40). An antiproliferative role for PAD4 inhibitors is suggested by the observation that PAD4 citrullinates arginine residues in histones at the promoters of p53 target genes such as p21, which are involved in cell cycle arrest and induction of apoptosis (Li P. et al., Mol. Cell Biol., 28(15)(2008), 4745-4758).

[0007] The above-described role of PAD4 in deiminating arginine residues in histones may indicate the role of PAD4 in the epigenetic regulation of gene expression. PAD4 is the major PAD family member observed to be endogenous in the nucleus as well as in the cytoplasm. Initial evidence that PAD4 may act as a histone demethyliminase has been inconclusive and unproven. However, it may indirectly reduce histone arginine methylation (and thus the epigenetic regulation associated with this mark) through depletion of available arginine residues by conversion to citrulline. PAD4 inhibitors are useful as epigenetic tools or therapeutic agents that affect the expression of various target genes in additional disease settings. Through such mechanisms, PAD4 inhibitors may also be effective in controlling citrullination levels in stem cells and thus may therapeutically affect the pluripotent state and differentiation potential of a variety of stem cells, including, but not limited to, embryonic stem cells, neural stem cells, hematopoietic stem cells, and cancer stem cells. Accordingly, there remains an unmet need to identify and develop PAD4 inhibitors for the treatment of PAD4-mediated disorders. SUMMARY OF THE INVENTION

[0008] Formula (I):

CHEMICAL

[0009] In some embodiments, the provided compound exhibits selectivity for PAD4 in relation to PAD2. The present invention also provides a pharmaceutically acceptable composition comprising the provided compound. The provided compound is useful for treating various disorders associated with PAD4. Such disorders are described in detail herein and include, for example, rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, and psoriasis. **DETAILED DESCRIPTION OF THE INVENTION**

[0010] 1. General Description of Certain Embodiments of the Invention In some embodiments, such a compound comprises a compound represented by the formula described herein or a pharmaceutically acceptable salt thereof, wherein each variable group is defined herein and is as described in the embodiment. Such a compound has the formula (I): **CHEMICAL FORMULA** [Wherein: Q is selected from the group consisting of N and CH; A is a 4- to 15-membered heterocyclyl containing a carbon atom and 1 to 4 heteroatoms selected from N, O, and S(O) p ; A1 is C 1-4 alkylene substituted with 0 to 3 R1s; optionally, one or more methylene units of the C 1-4 alkylene may be replaced with O, S(O) p , NH, N(C 1-4 alkyl), and C(=O); A2 is selected from the group consisting of C 3-6 carbocyclic, and 4- to 6-membered heterocyclyl containing a carbon atom and 1 to 4 heteroatoms selected from N, O, and S(O) p and each is substituted with 0 to 4 R2s; A3 is selected from the group consisting of C 3-6 carbocyclic, and 4- to 6-membered heterocyclyl containing a carbon atom and 1 to 4 heteroatoms selected from N, O, and S(O) p and each is substituted with 0 to 4 R2s; A4 is selected from the group consisting of C 3-8 alkylene and C 3-8 alkenylene, and each is substituted with 0 to 5 R1s; optionally, one or more methylene units of the C 3-8 alkylene, except those directly bonded to the nitrogen atom of the indole or pyrrolopyridine moiety, may be replaced by O, S(O) p , NH, N(C 1-4 alkyl), and C(=O); provided that when A2 is absent, A1 is directly bonded to A3; when A3 is absent, A2 is directly bonded to A4; when both A2 and A3 are absent, A1 is directly bonded to A4, and at least two methylene units of A4 are replaced by O, S(O) p , NH, N(C 1-4 alkyl), and C(=O); R1 is selected from the group consisting of F, Cl, -OR b , and C 1-3 alkyl (substituted with 0 to 5 R c ); R2 is selected from the group consisting of F, Cl, CN, =O, C(=O)NR a R a , and C 1-3 alkyl (substituted with 0 to 5 R c ); R3 is selected from the group consisting of F, Cl, Br, -OR b , and C 1-3 alkyl (substituted with 0 to 5 R c ); R4 is selected from the group consisting of F, Cl, Br, C 1-6 alkyl (substituted with 0 to 5 Rs c ); R5 is selected from the group consisting of F, Cl, CN, C 1-3 alkyl, =N-OR b , -(CH2) r OR b , -OC(=O)NR a R a , -(CH2) r NR a R a , -NR a C(=NH)C 1-3 alkyl, -C(=O)OR b , -NR a C(=O)OR b , carbocyclilyl (substituted with 0 to 5 Rs c ), and heterocyclilyl (substituted with 0 to 5 Rs c ); or alternatively, two R5 groups together form a carbocyclic or heterocyclic ring; R6, in each occurrence, is independently selected from the group consisting of F, Cl, Br, and C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 hydroxyalkyl; R a , in each occurrence, is independently selected from the group consisting of H, C 1-6 alkyl (substituted with 0 to 5 Rs c ), C 2-6 alkenyl (substituted with 0 to 5 Rs c ), C 2-6 alkynyl (substituted with 0 to 5 Rs c ), -(CH2) r -C 3-10 carbocyclic (substituted with 0 to 5 Rs c ), and (CH2) r -heterocyclic (substituted with 0 to 5 Rs c ); or alternatively, R a and R a , together with the nitrogen atom to which both are attached, form a heterocyclic ring (substituted with 0 to 5 Rs cforms a replacement (replaced by); R b is, in each occurrence, H, C 1-6 alkyl (0 - 5 R c substituted), C 2-6 alkenyl (0 - 5 R c substituted), C 2-6 alkynyl (0 - 5 R c substituted), (CH2) r -C 3-10 carbocyclic (0 - 5 R c substituted), and (CH2) r -heterocyclic (0 - 5 R c substituted) and is independently selected from the group consisting of; R c is, in each occurrence, F, Cl, Br, CN, =O, OH, OC 1-4 alkyl, CO2H, C 1-6 alkyl (0 - 5 R d substituted), (CH2) r -C 3-6 cycloalkyl (0 - 5 R d substituted), (CH2) r -aryl (0 - 5 R d substituted), (CH2) r -heterocyclic (0 - 5 R d substituted) and is independently selected from the group consisting of, R d is, in each occurrence, F, Cl, Br, CN, OH, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl, and phenyl and is independently selected from the group consisting of; p is, in each occurrence, an integer selected from 0, 1, and 2; and r is, in each occurrence, an integer selected from 0, 1, 2, 3, and 4) is a compound having the structure represented by, or a pharmaceutically acceptable salt thereof.

[0011] 2. Definitions Throughout this specification and the appended claims, a given chemical formula or name, where isomers exist, includes all stereoisomers and optical isomers and their racemates. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the invention. A number of geometric isomers such as C=C double bonds, C=N double bonds, ring systems, etc. can also exist in compounds, and all such stable isomers are included in the present invention. The cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or in the form of separated isomers. The compounds of the present invention may be isolated in optically active form or in racemic form. The optically active form may be produced by resolving the racemate or by synthesizing from an optically active starting material. All methods used to produce the compounds of the present invention and the intermediates produced in those methods are considered to be part of the present invention. When enantiomeric or diastereomeric products are produced, they may be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the conditions of the method, the final product of the present invention may be obtained in either free (neutral) or salt form. Both the free and salt forms of these final products are within the scope of the present invention. If desired, one form of the compound may be converted to another. The free base or acid may be converted to a salt; the salt may be converted to the free compound or to another salt; a mixture of isomeric compounds of the present invention may be separated into the individual isomers. The compounds of the present invention, their free forms and salts may exist in the form of a plurality of tautomers in which a hydrogen atom is rearranged to another part of the molecule and the chemical bonds between the atoms of the molecule are rearranged accordingly. It should be understood that as long as they exist, all tautomeric forms are included in the present invention.

[0012] As used herein, the terms "alkyl" or "alkylene" shall include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C 12 alkyl" or "C 1-12"Alkyl" (or alkylene) includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 and C 11 and C 12 alkyl groups; "C4-C 18 alkyl" or "C 4-18 alkyl" (or alkylene) includes C4, C5, C6, C7, C8, C9, C 10 and C 11 and C 12 and C 13 and C 14 and C 15 and C 16 and C 17 and C 18 alkyl groups. Also, for example, "C1-C6 alkyl" or "C 1-6 alkyl" means an alkyl having 1 to 6 carbon atoms. The alkyl group may be unsubstituted or substituted such that at least one hydrogen is replaced by another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When "C0 alkyl" or "C0 alkylene" is used, it shall mean a direct bond.

[0013] "Alkenyl" or "alkenylene" includes a hydrocarbon chain of any linear or branched arrangement having a specific number of carbon atoms and one or more, preferably 1 to 2, carbon-carbon double bonds that can be present at any stable position along the chain. For example, "C2-C6 alkenyl" or "C 2-6"Alkenyl" (or "alkenylene") shall include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl.

[0014] "Alkynyl" or "alkynylene" shall include a hydrocarbon chain of any linear or branched configuration having one or more, preferably 1 to 3 carbon-carbon triple bonds that may be present at any stable position along the chain. For example, "C2-C6 alkynyl" or "C 2-6 alkynyl" (or "alkynylene") shall include C2, C3, C4, C5, and C6 alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0015] The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. For example, "C1-C6 alkoxy" or "C 1-6 alkoxy" (or "alkyloxy") shall include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group as described above in which the indicated number of carbon atoms are bonded via a sulfur bridge, e.g., methyl-S- and ethyl-S-.

[0016] The term "halo" or "halogen" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" shall include both branched and straight-chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms and substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" which shall include both branched and straight-chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms and substituted with one or more fluorine atoms.

[0017] The term "cycloalkyl" refers to a cyclic alkyl group containing a mono-, bi- or poly-cyclic ring system. For example, "C3-C6 cycloalkyl" or "C 3-6 cycloalkyl" shall include C3, C4, C5, and C6 cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". The term "cycloalkenyl" refers to a cyclic alkenyl group. C 4-6 cycloalkenyl shall include C4, C5, and C6 cycloalkenyl groups. Examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl.

[0018] As used herein, "carbocyclic", "carboscyclic", or "carbocyclic residue" means any stable 3-, 4-, 5-, 6-, 7- or 8-membered monocyclic or bicyclic, or 7-, 8-, 9-, 10-, 11-, 12- or 13-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, unsaturated, or aromatic. Examples of such "carbocyclic rings" include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As noted above, bridged rings are also included in the definition of carbocyclic rings (e.g., [2.2.2]bicyclooctane). Preferred carbocyclic rings are, unless otherwise indicated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, indanyl, and tetrahydronaphthyl. The term "carbocyclic" shall include "aryl" when used. Bridged rings occur when one or more, preferably 1 to 3, carbon atoms connect two non-adjacent carbon atoms. Preferred bridges are 1 or 2 carbon atoms. Note that a bridge always converts a monocyclic ring to a tricyclic ring. When a ring is bridged, substituents on that ring may also be present on the bridge.

[0019] As used herein, the terms "bicyclic carbocyclic" or "bicyclic carbocyclic group" shall mean a stable 9- or 10-membered carbocyclic ring system containing two fused rings and consisting of carbon atoms. One of the two fused rings is a benzo ring fused to the second ring; the second ring is a saturated, partially unsaturated, or unsaturated 5- or 6-membered carbocyclic ring. The bicyclic carbocyclic group may be attached to its pendant group at any carbon atom and may have a stable structure. The bicyclic carbocyclic groups described herein may be substituted on any carbon provided that the resulting compound is stable. Examples of bicyclic carbocyclic groups include, but are not limited to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.

[0020] The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbons, including, for example, phenyl and naphthyl. Aryl moieties are well known and are described, for example, in Lewis, R.J., ed., Hawley’s Condensed Chemical Dictionary, 15th Edition, John Wiley & Sons, Inc., New York (2007). "C 6-10 aryl" refers to phenyl and naphthyl.

[0021] As used herein, the terms "heterocycle", "heterocyclyl", or "heterocyclic group" shall mean a saturated, partially unsaturated, or fully unsaturated stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic, or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic heterocyclic ring containing carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; any polycyclic group in which any of the above-described heterocyclic rings is fused to a benzene ring is also included. Nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O) pwhere p is 0, 1 or 2). The nitrogen atom may or may not be substituted (i.e., is N or NR, where R, if defined, is H or another substituent). The heterocyclic ring may be attached to its pendant group by any heteroatom or carbon atom, provided a stable structure results. The heterocyclic rings described herein may be substituted on a carbon atom or on a nitrogen atom, provided the resulting compound is stable. The nitrogen of the heterocycle may optionally be quaternized. When the total number of S and O atoms in the heterocycle exceeds 1, it is preferred that these heteroatoms are not adjacent to each other. The total number of S and O atoms in the heterocycle is preferably 1 or less. When the term "heterocycle" is used, it is intended to include heteroaryl.

[0022] Examples of heterocycles include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiadinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxyindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-Thiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thieno[2,3-d]thiazolyl, thieno[2,3-d]oxazolyl, thieno[2,3-d]imidazolyl, phenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. For example, condensed rings and spiro compounds containing the above heterocycles are also included.,

[0023] Examples of 5- to 10-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiophenyl, benzotetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxyindolyl, benzoxazolinyl, benzothiazolyl, benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl. For example, condensed rings and spiro compounds containing the above heterocycles are also included.,

[0024] Bridged rings are also included in the definition of heterocycles. Bridged rings occur when one or more, preferably 1 to 3 atoms (i.e., C, O, N, or S) connect two non-adjacent carbon or nitrogen atoms. Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and carbon-nitrogen groups. Note that bridging always converts a monocyclic ring to a tricyclic ring. When the ring is bridged, substituents shown on the ring may also be present on the bridge.,

[0025] As used herein, the terms "bicyclic heterocycle" or "bicyclic heterocyclic group" mean a stable 9- or 10-membered heterocyclic ring system containing two fused rings and composed of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S. Of the two fused rings, one ring is a 5- or 6-membered monocyclic aromatic ring containing a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, or a benzo ring, each of which is fused to a second ring. The second ring is saturated, partially unsaturated, or unsaturated and is a 5- or 6-membered monocyclic ring containing a 5-membered heterocycle, a 6-membered heterocycle, or a carbocycle (provided that when the second ring is a carbocycle, the first ring is a ring other than benzo).

[0026] The bicyclic heterocyclic group may be bonded to its pendant group at any heteroatom or carbon atom, provided that a stable structure is provided. The bicyclic heterocyclic groups described herein may be substituted at a carbon or nitrogen atom, provided that the resulting compound is stable. When the total number of S and O atoms in the heterocycle exceeds 1, it is preferred that these heteroatoms are not adjacent to each other. The total number of S and O atoms in the heterocycle preferably does not exceed 1.

[0027] Examples of bicyclic heterocyclic groups include, but are not limited to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 2,3-dihydrobenzofuranyl, chromanyl, 1,2,3,4-tetrahydroquinoxalinyl, and 1,2,3,4-tetrahydroquinazolinyl.

[0028] As used herein, the terms "aromatic heterocyclic group" or "heteroaryl" shall mean stable monocyclic and polycyclic aromatic hydrocarbons containing ring members of at least one heteroatom such as sulfur, oxygen or nitrogen. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane. The heteroaryl group may or may not be substituted. The nitrogen atom may or may not be substituted (i.e., if defined, it is N or NR, where R is H or another substituent). The heteroatoms of nitrogen and sulfur may optionally be oxidized (i.e., N→O and S(O) p where p is 0, 1 or 2).

[0029] Examples of 5- to 6-membered heteroaryl include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, imidazolyl, imidazolidinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl. The term "counterion" is used to represent negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate, or positively charged species such as sodium (Na + ), potassium (K + ), ammonium (R n NH m + (n = 0-4, m = 0-4), etc. When a dotted ring is used within the ring structure, this indicates that the ring structure may be saturated, partially saturated or unsaturated.

[0030] As used herein, the term "amine protecting group" means any group known in the art of organic synthesis for the protection of an amine group that is stable to ester reducing agents, disubstituted hydrazines, R4-M and R7-M, nucleophilic reagents, hydrazine reducing agents, activators, strong bases, hindered amine bases, and cyclizing agents. Such amine protecting groups that meet these criteria include those listed in Wuts, P.G.M. et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007) and The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981) (the contents of which are hereby incorporated by reference as part of this specification). Examples of amine protecting groups include, but are not limited to, the following: (1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyl, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; (5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilanes such as trimethylsilane; (7) thiol-containing types such as phenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such as triphenylmethyl, methyl, and benzyl; and substituted alkyl types such as 2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilane types such as trimethylsilane.

[0031] As used herein, the term "substituted" means that at least one hydrogen atom is replaced with a group other than hydrogen, provided that normal valency is maintained and the substitution results in a stable compound. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). When the compounds of the present invention contain nitrogen atoms (e.g., when they are amines), these atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide), and other compounds of the present invention can be obtained. Thus, the specified nitrogen atoms are considered to cover both the specified nitrogen and its N-oxide (N→O) derivatives.

[0032] When any variable group is shown two or more times in the construction of a compound or in a formula, its definition is independent of its definition in all other cases. Thus, for example, if a group is substituted with 0 to 3 R groups, then in that case, the group may optionally be substituted with up to 3 R groups, and each R is independently selected from the definition of R. When a bond to a substituent is shown across a bond connecting two atoms of a ring, then in that case, such a substituent may be bonded to any atom of the ring. When a substituent is listed without indicating the atom to which such a substituent is bonded to the residue of a compound of a given formula, then in that case, such a substituent may be bonded through any atom in such a substituent.

[0033] Combinations of substituents and / or variable groups are permitted only if such combinations result in a stable compound. As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of normal medical judgment, are free of excessive toxicity, irritation, allergic response, and / or other problems or complications, and, considering a reasonable benefit / risk ratio, are suitable for use in contact with human and animal tissues.

[0034] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, wherein the parent compound is modified by producing its acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of inorganic or organic acids with basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or formed by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, maleate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts and the like.

[0035] Salts derived from appropriate bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4It includes (alkyl) 4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts, where appropriate, are non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0036] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free form of the acid or base of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two solvents; generally, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred. A list of suitable salts is described in Allen, Jr., L.V. ed., Remington: The Science and Practice of Pharmacy, 22th Edition, Pharmaceutical Press, London, UK (2012), the disclosure of which is incorporated herein by reference.

[0037] In addition, the compounds of formula (I) may be in the form of prodrugs. Any compound that will be converted in vivo to provide a bioactive agent (i.e., a compound of formula I) is a prodrug within the scope and spirit of the present invention. Various forms of prodrugs are well known in the art. Examples of such prodrug derivatives are: a) Bundgaard, H. ed., Design of Prodrugs, Elsevier (1985), and Widder, K. et al. eds., Methods in Enzymology, 112:309 - 396, Academic Press (1985); b) Bundgaard, H., Chapter 5, "Design and Application of Prodrugs", edited by Krosgaard-Larsen, P. et al., A Textbook of Drug Design and Development, pp. 113-191, Harwood Academic Publishers (1991); c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992); d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and f) Rautio, J., ed., Prodrugs and Targeted Delivery (Methods and Principles in Medicinal Chemistry), Vol. 47, Wiley-VCH (2011) See also.

[0038] Compounds containing a carboxy group can form physiologically hydrolysable esters that, upon hydrolysis in the body, provide the compound of formula I itself and are used as prodrugs. Such prodrugs are often preferably administered orally since hydrolysis mainly occurs under the influence of digestive enzymes. If the ester itself is active or in such cases where hydrolysis occurs in the blood, parenteral administration may also be utilized. Examples of physiologically hydrolysable esters of the compound of formula I include C 1-6 alkyl, C 1-6 alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C 1-6 alkanoyloxy C 1-6 alkyl (e.g., acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), C 1-6 alkoxycarbonyloxy C 1-6Alkyl (e.g., methoxycarbonyloxymethyl or ethoxycarbonyloxymethyl, glycilyloxymethyl, phenylglycilyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl), and other well-known physiologically hydrolysable esters such as those used in the fields of penicillins and cephalosporins. Such esters can be prepared by conventional techniques known in the art.

[0039] The production of prodrugs is well-known in the art and is described, for example, in King, F.D. (ed.), Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (2nd Edition, reprint (2006)); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G. (ed.), The Practice of Medicinal Chemistry, 3rd Edition, Academic Press, San Diego, CA (2008).

[0040] The present invention is intended to encompass all isotopes of the atoms present in the compound. Isotopes include those atoms having the same atomic number but different mass numbers. General examples, without limitation, of isotopes of hydrogen are deuterium (symbol D or 2 H) and tritium (symbol T or 3 H). For example, a methyl group can be represented as CH3 or CD3. Isotopes of carbon are 13 C and 14It includes C. The isotope-labeled compounds of the present invention can generally be prepared by general techniques known to those skilled in the art or, alternatively, by using appropriately isotope-labeled reagents instead of the unlabeled reagents used, by methods similar to the methods described herein.

[0041] The term "solvate" means a physical association of a compound of the invention with one or more solvent molecules, either organic or inorganic. This physical association includes hydrogen bonding. In certain cases, the solvate will be isolable, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The solvent molecules in the solvate can be present in a regular arrangement and / or a disordered arrangement. The solvate can contain solvent molecules in either a stoichiometric or non-stoichiometric amount. "Solvate" includes both solvates separable from the liquid phase. Examples of solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.

[0042] As used herein, the terms "measurable affinity" and "inhibit measurably" mean a measurable change in the activity of PAD4 between a compound or composition thereof of the invention and a sample containing PAD4, and an equivalent sample containing PAD4 without the compound or composition thereof.

[0043] The abbreviations used in this specification are defined as follows: "1x" means once, "2x" means twice, "3x" means three times, "°C" means Celsius temperature, "eq" means equivalent, "g" means gram, "mg" means milligram, "L" means liter, "mL" means milliliter, "μL" means microliter, "N" means normality, "M" means mole, "mmol" means millimole, "min" means minute, "h" means hour, "rt" means room temperature, "RT" means retention time, "atm" means atmospheric pressure, "psi" means pounds per square inch, "conc." means concentration, "aq" means "aqueous", "sat" or "sat’d" means saturated, "MW" means molecular weight, "mp" means melting point, "MS" or "Mass Spec" means mass spectrometry, "ESI" means electrospray ionization mass spectrometry, "HR" means high resolution, "HRMS" means high resolution mass spectrometry, "LCMS" means liquid chromatography mass spectrometry, "HPLC" means high performance liquid chromatography, "RP HPLC" means reverse phase HPLC, "TLC" or "tlc" means thin layer chromatography, "NMR" means nuclear magnetic resonance spectroscopy, "nOe" means nuclear Overhauser effect spectroscopy, " 1 "H" means proton, "δ" means delta, "s" means singlet, "d" means doublet, "t" means triplet, "q" means quartet, "m" means multiplet, "br" means broad, "Hz" is defined as Hertz, and "α", "β", "R", "S", "E", "Z" and "ee" are stereochemical notations well known to those skilled in the art. As used herein, the term "pharmaceutically acceptable salt" refers to salts that are within the scope of normal medical judgment, are without excessive toxicity, irritation, allergic reaction, etc., and are suitable for use in contact with the tissues of humans and lower animals, taking into account a reasonable benefit / risk ratio.

[0044] [Table 1] [Table 2] [Table 3]

[0045] 3. Description of the compound In a first aspect, the present invention relates to formula (I):

Chemical formula

[0046] In a second aspect, the present invention, within the scope of the first aspect, provides a compound of formula (II): [Chemical formula: [wherein: [Chemical formula: is [Chemical formula: selected from the group consisting of; A1 is C 1-4 alkyl (substituted with 0 to 2 R1), and optionally, one or more methylene units of the C 1-4 alkylene may be replaced with NH, N(C 1-4 alkyl), and C(=O); A2 is selected from the group consisting of C6 aryl and a 4- to 6-membered heterocyclyl containing a carbon atom and 1 to 4 heteroatoms selected from N, O, and S(O) p ), each being substituted with 0 to 2 R2; A3 is C 3-6Selected from the group consisting of 4- to 6-membered heterocyclyl containing cycloalkyl, C6 aryl, and carbon atoms and 1 to 4 heteroatoms selected from N, O, and S(O); each is substituted with 0 to 2 R2; p and optionally, one to three methylene units of the C alkylene are replaced by O, S(O), NH, N(C alkyl), and C(═O), except those directly bonded to the nitrogen atom of the indole or pyrrolopyridine moiety; A4 is selected from the group consisting of C alkylene and C alkenylene; each is substituted with 0 to 5 R1; 3-7 C alkylene and C alkenylene; each is substituted with 0 to 5 R1; 3-7 and optionally, one to three methylene units of the C alkylene are replaced by O, S(O), NH, N(C alkyl), and C(═O), except those directly bonded to the nitrogen atom of the indole or pyrrolopyridine moiety; 3-7 Selected from the group consisting of F, Cl, and -OR; p Selected from the group consisting of F, Cl, CN, ═O, and C(═O)NR; 1-4 Selected from the group consisting of F, Cl, Br, and -OC alkyl; R1 is selected from the group consisting of F, Cl, and -OR; b and optionally, one to three methylene units of the C alkylene are replaced by O, S(O), NH, N(C alkyl), and C(═O), except those directly bonded to the nitrogen atom of the indole or pyrrolopyridine moiety; R2 is selected from the group consisting of F, Cl, CN, ═O, and C(═O)NR; a R; a and each occurrence is independently selected from the group consisting of H and C alkyl; and R3 is selected from the group consisting of F, Cl, Br, and -OC alkyl; 1-4 R4 is selected from the group consisting of F, Cl, C alkyl, C haloalkyl, and C hydroxyalkyl; R; 1-5 C alkyl; 1-5 C haloalkyl; 1-5 C hydroxyalkyl; R; a and each occurrence is independently selected from the group consisting of H and C alkyl; and 1-5 R; and each occurrence is independently selected from the group consisting of H and C alkyl;] b H and C alkyl; 1-5 To provide a compound represented by or a pharmaceutically acceptable salt thereof. In a third aspect, the present invention provides, within the scope of the second aspect, a compound of formula (III):

[0047] In a third aspect, the present invention provides, within the scope of the second aspect, a compound of formula (III):

Chemical formula

Chemical formula

Chem.

[0048] In a fourth aspect, the present invention, within the scope of the third aspect, provides a compound of formula (IV):

Chemical formula

Chemical formula

Chemical formula

[0049] In a fifth aspect, the present invention, within the scope of the fourth aspect, provides a compound of formula (V): [Chemical formula] [wherein: A4 is selected from the group consisting of C 3-7 alkylene and C 3-7 alkenylene, each optionally substituted with 0 to 5 R1; optionally, one or more methylene units of said C 3-7 alkylene may be replaced with O and NH, except those directly bonded to the nitrogen atom of the indole or pyrrolopyridine moiety; R1 is selected from the group consisting of F and -OH; R2 is selected from the group consisting of F, CN, and C(=O)NH2; and R4 is selected from the group consisting of C 1-4 haloalkyl and C 1-4 hydroxyalkyl] or a pharmaceutically acceptable salt thereof.

[0050] In a sixth aspect, the present invention, within the scope of the fifth aspect, provides a compound, or a pharmaceutically acceptable salt thereof, wherein A4 is selected from the group consisting of C 3-7 alkylene, -OC 4-7 alkylene, and C 3-7 alkenylene. or a pharmaceutically acceptable salt thereof.

[0051] In a seventh aspect, the present invention, within the scope of the fourth aspect, provides a compound of formula (VI): [Chemical formula] [wherein: A4 is selected from the group consisting of C 3-7 alkylene, -OC 4-7 alkylene, and C 3-7 alkenylene, each optionally substituted with 0 to 5 R1; R1 is -OR b and C 1-3selected from the group consisting of alkyl; R2 is selected from the group consisting of F and CN; R3 is -OC 1-4 alkyl; R4 is selected from the group consisting of C 1-3 haloalkyl and C 1-3 hydroxyalkyl; and R b is, in each occurrence, independently selected from the group consisting of H and C 1-3 alkyl] provides a compound represented by, or a pharmaceutically acceptable salt thereof.

[0052] In an eighth aspect, the present invention is within the scope of the seventh aspect, where

Chemical formula

Chemical formula

[0053] In a ninth aspect, the present invention is within the scope of the fourth aspect, formula (VII):

Chemical formula

Chemical formula

[0054] In a tenth aspect, the present invention, within the scope of the third aspect, provides a compound of formula (VIII):

Chemical formula

Chemical formula

Chemical formula

[0055] In an eleventh aspect, the present invention is within the scope of the tenth aspect, A3 is cyclopropyl (substituted with 0 to 2 R2) and

Chemical formula

[0056] In a twelfth aspect, the present invention is within the scope of the second aspect, formula (IX):

Chemical formula

Chemical formula

Chemical formula

[0057] In a thirteenth aspect, the present invention, within the scope of the twelfth aspect, provides a compound of formula (X):

Chemical formula

Chemical formula

Chemical formula

[0058] In a fourteenth aspect, the present invention, within the scope of the twelfth aspect, herein: A2 is

Chemical formula

[0059] In a fifteenth aspect, the present invention, within the scope of the twelfth aspect, provides a compound of formula (XI):

Chem.

Chem.

Chem.

[0060] In a sixteenth aspect, the present invention, within the scope of the second aspect, provides a compound of formula (XII):

Chem.

Chem.

Chem.

[0061] In a 17th aspect, the present invention relates to formula (XIII):

Chemical formula

Chemical formula

Chemical formula

[0062] In an 18th aspect, the present invention, within the scope of the 4th aspect, relates to formula (XIV):

Chemical formula

Chemical formula

[0063] In a 19th aspect, the invention provides, within the scope of the 4th aspect, a compound of formula (XV): [Chem.] [wherein: Q is selected from the group consisting of N and CH; [Chem.] is [Chem.] selected from the group consisting of; A4 is C 3-7 alkylene and C 3-7 alkenylene, each optionally substituted with 0 - 5 R1s; R1 is selected from the group consisting of F and -OH; and R3 is -OC 1-4 alkyl] provides a compound represented by, or a pharmaceutically acceptable salt thereof.

[0064] In a 20th aspect, the invention provides, within the scope of the 4th aspect, a compound of formula (XVI): [Chem.] [wherein: Q is selected from the group consisting of N and CH;

Chemical formula

Chemical formula

[0065] In a 21st aspect, the present invention, within the scope of the 20th aspect, where

Chemical formula

Chemical formula

Chemical formula

[0066] In a 22nd aspect, the present invention, within the scope of the 17th aspect, where

Chemical formula

[0067] In one embodiment, the present invention uses the RFMS PAD4 functional assay disclosed herein to determine the IC 50 value is < 4.000 μM, preferably the IC 50 value is < 1.000 μM, preferably the IC 50 value is < 0.500 μM, preferably the IC 50 value is < 0.100 μM, more preferably the IC 50 value is < 0.050 μM, more preferably the IC 50 value is < 0.03 μM, more preferably the IC 50 value is < 0.02 μM, even more preferably the IC 50 value is < 0.01 μM, and provides a compound.

[0068] As defined and described above herein, Q is N or CH. In some embodiments, Q is N. In some embodiments, Q is CH. As defined and described above herein, A1 is a C 1-4 alkylene which may optionally be substituted with one or two R1s. For example, in some embodiments, A1 is -CH2-. In some embodiments, A1 is -CH2CH2-. In some embodiments, A1 is -CH2CH2CH2-. Optionally, the C of A11-4 One or more methylene units of the alkylene may be replaced by O, S(O) p , NH, N(C 1-4 alkyl), and C(=O). For example, in some embodiments, A1 is -C(=O)NHCH2CH2CH2-. In certain embodiments, A1 is selected from those functional groups described in the examples below.

[0069] As defined and described above herein, A2 is a C 3-6 carbocyclic ring substituted with 0 to 4 R2s, and a 4- to 6-membered heterocyclyl containing a carbon atom and 1 to 4 heteroatoms selected from N, O, and S(O) p . In some embodiments, A2 is a C6 aryl substituted with 0 to 2 R2s. In some embodiments, A2 is a 4- to 6-membered heterocyclyl containing a carbon atom and 1 to 3 heteroatoms selected from N and O. In some embodiments, A2 is pyridyl. In some embodiments, A2 is a 5-membered heteroaryl containing a carbon atom and 1 to 2 N atoms. In some embodiments, A2 is pyrazole, and one of its nitrogen atoms is bonded to A3. In certain embodiments, A2 is selected from those functional groups described in the examples below.

[0070] As defined and described above herein, A3 is a C 3-6 carbocyclic ring substituted with 0 to 4 R2s, and a 4- to 6-membered heterocyclyl containing a carbon atom and 1 to 4 heteroatoms selected from N, O, and S(O) p . In some embodiments, A3 is a C6 aryl substituted with 0 to 2 R2s. In some embodiments, A3 is a C 3-6It is cycloalkyl. In some embodiments, A3 is a 4- to 6-membered heterocyclyl containing a carbon atom and 1 to 3 heteroatoms selected from N and O. In some embodiments, A3 is cyclopropyl substituted with 2 Fs. In some embodiments, A3 is a 5-membered heterocyclyl containing a carbon atom and 1 or 2 N atoms. In certain embodiments, A3 is selected from those functional groups described in the following examples.

[0071] As defined and described above herein, A4 is C 3-8 It is alkylene. In some embodiments, A4 is -CH2CH2CH2-. In some embodiments, A4 is -CH2CH2CH2CH2-. In some embodiments, A4 is -CH2CH2CH2CH2CH2-. In some embodiments, A4 is -CH2CH2CH2CH2CH2CH2-. In some embodiments, A4 is -CH2CH2CH2CH2CH2CH2CH2-. In some embodiments, A4 is C 3-8 It is alkenylene. For example, in some embodiments, A4 is -CH2=CH2CH2CH2-. In some embodiments, A4 is -CH2=CH2CH2CH2CH2-. In some embodiments, A4 is -CH2=CH2CH2CH2CH2CH2-.

[0072] In some embodiments, A4 is C 3-8 It is alkylene and C 3-8 It is alkenylene, each substituted with 1 to 5 R1s. For example, in some embodiments, A4 is -CH2(OH)CH2(OH)CH2CH2CH2CH2-. In some embodiments, A4 is -CH2(OH)CH2(OH)CH2CH2-. Optionally, one or more methylene units of the C 3-8 alkylene of A4, except those directly bonded to the nitrogen atom of the indole or pyrrolopyridine moiety, are O, S(O) p , NH, N(C 1-4(alkyl), and may be replaced by C(=O). In some embodiments, A4 is -OCH2CH2CH2-. In some embodiments, A4 is -OCH2CH2CH2CH2-. In some embodiments, A4 is -OCH2CH2CH2CH2CH2-. In certain embodiments, A4 is selected from those functional groups described in the examples below.

[0073] As defined and described above herein, R1 is halogen, -OR b , and C 1-3 alkyl. In some embodiments, R1 is F. In some embodiments, R1 is Cl. In some embodiments, R1 is OH. In certain embodiments, R1 is selected from those functional groups described in the examples below. As defined and described above herein, R2 is F, Cl, CN, =O, C(=O)NR a R a , and C 1-3 alkyl. In some embodiments, R2 is F. In some embodiments, R2 is Cl. In some embodiments, R2 is CN. In some embodiments, R2 is =O. In some embodiments, R2 is C(=O)NH2. In certain embodiments, R2 is selected from those functional groups described in the examples below.

[0074] As defined and described above herein, R3 is F, Cl, Br, -OR b , and C 1-3 alkyl. In some embodiments, R3 is F, Cl or Br. In some embodiments, R3 is -OC 1-4 alkyl. In some embodiments, R3 is -OCH3. In some embodiments, R3 is -OCH2CH3. In certain embodiments, R3 is selected from those functional groups described in the examples below. As defined and described above in this specification, R4 is F, Cl, Br, C 1-6 alkyl (substituted with 0 - 5 Rs c ). In certain embodiments, R4 is C 1-5 alkyl substituted with 1 - 4 F, Cl, Br, and OH.

[0075] In some embodiments, R4 is

Chemical formula

[0076] As defined and described above in this specification, R5 is F, Cl, CN, C 1-3 alkyl, =N - OR b , -(CH2) r OR b , -OC(=O)NR a R a , -(CH2) r NR a R a , -NR a C(=NH)C 1-3 alkyl, -C(=O)OR b , -NR a C(=O)OR b , carbocyclilyl (substituted with 0 - 5 Rs c ), and heterocyclilyl (substituted with 0 - 5 Rs c ). Alternatively, two R5 groups together form a carbocyclic or heterocyclic ring. As defined and described above in this specification, R6 is F, Cl, Br, and C 1-4 alkyl. In some embodiments, R6 is absent.

[0077] As defined and described above in this specification, ring A and R5 are, that is,

Chemical formula

Chem.

[0078] In some embodiments,

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0079] In some embodiments, [Chemistry] is [Chemistry] is. In some embodiments, [Chemistry] is [Chemistry] is. In some embodiments, [Chemistry] is [Chemistry] is. In some embodiments, [Chemistry] is [Chemistry] is. In some embodiments, [Chemistry] is [Chemistry] It is. In some embodiments,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0080] In some embodiments, [Chem.] is [Chem.] In some embodiments, [Chem.] is [Chem.] In some embodiments, [Chem.] is [Chem.] In some embodiments, [Chem.] is [Chem.] In some embodiments, [Chem.] is

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0081] In some embodiments,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0082] In some embodiments, [Chemistry] is [Chemistry] In some embodiments, [Chemistry] is [Chemistry] In some embodiments, [Chemistry] is

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0083] In some embodiments,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0084] In some embodiments,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0085] ​In some embodiments, the compounds of formula (I) are selected from the following examples. In certain embodiments, the present invention also provides any of the compounds described above and herein for use in therapy, or a pharmaceutically acceptable salt or composition thereof. In some embodiments, the present invention also provides any of the compounds in isolated form described above and herein. In some embodiments, the present invention provides a compound according to any one of claims 1 to 16.

[0086] 4. Pharmaceutically acceptable compositions According to another alternative embodiment, the invention provides a composition comprising a compound of the invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound incorporated into the composition of the invention is an amount effective to inhibit PAD4 appreciably in a biological sample or patient. In certain embodiments, the amount of the compound in the composition of the invention is an amount effective to inhibit PAD4 visibly in a biological sample or patient. In certain embodiments, the composition of the invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the invention is formulated for oral administration to a patient.

[0087] As used herein, the term "subject" is used interchangeably with the term "patient" and means an animal, preferably a mammal. In some embodiments, the subject or patient is human. In other embodiments, the subject (or patient) is a veterinary subject (or patient). In some embodiments, the veterinary subject (or patient) is a dog, cat, or horse.

[0088] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound being formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compounds of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, polyethylene glycol, and lanolin.

[0089] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenterally" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intramedullary, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions of the present invention may be an aqueous or oily suspension. These suspensions may be formulated according to techniques known in the art using appropriate dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent such as, for example, a solution of 1,3-butanediol. Among the acceptable vehicles and solvents that can be utilized are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly employed as a solvent or suspending medium.

[0090] For this purpose, any sterile fixed oil containing synthetic monoglycerides or diglycerides may be utilized. Fatty acids such as oleic acid and its glyceride derivatives are useful for preparing injectables, especially in their polyoxyethylated versions, as are natural medically acceptable oils such as olive oil or castor oil. These oily solutions or suspensions may also contain diluents or dispersants of long-chain alcohols, such as carboxymethyl cellulose or similar dispersants, which are commonly used to formulate pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0091] The pharmaceutically acceptable compositions of the present invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful 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 an anti-precipitant. Optionally, certain sweetening, flavoring, or coloring agents may also be added.

[0092] Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These can be manufactured by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0093] The pharmaceutically acceptable compositions of the present invention may also be administered topically, particularly when the target of treatment includes areas or organs that can be easily addressed by topical application, including diseases of the eye, skin or lower intestinal tract. Suitable topical formulations are readily manufactured for each of these areas or organs. Topical application to the lower intestinal tract can be effected with rectal suppository formulations (see above) or suitable enema formulations. Topical transdermal patches can also be used.

[0094] For topical application, the pharmaceutically acceptable compositions provided may be formulated as suitable ointments containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions provided may be formulated as suitable lotions or creams containing the active ingredient suspended or dissolved in one or more carriers. Suitable carriers include, but are not limited to, mineral oil,, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0095] When used ophthalmically, the pharmaceutically acceptable compositions provided may be formulated as a micro-suspension in isotonic pH-adjusted sterile saline, with or without a preservative such as benzalkonium chloride, or preferably as a solution in isotonic pH-adjusted sterile saline. Alternatively, when used ophthalmically, the pharmaceutically acceptable compositions may be formulated as an ointment such as petrolatum.

[0096] The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are manufactured according to techniques well known in the field of pharmaceutical formulations and may be manufactured as a solution in saline using benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0097] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0098] The pharmaceutically acceptable compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intracapsularly, vaginally, intraperitoneally, topically (such as by powder, ointment or drops), buccally, as an oral or nasal spray, etc., depending on the severity of the infectious disease to be treated. In certain embodiments, the compounds of the present invention may be administered orally or parenterally at a dosage level of about 0.01 mg to about 50 mg, preferably about 1 mg to about 25 mg, per kg of body weight of the subject per day, once or several times a day, to obtain the desired therapeutic effect.

[0099] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, the oral composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring and odor - masking agents, and perfumes.

[0100] Injectable preparations, for example, sterile injectable aqueous or oily suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable formulations may also be sterile injectable solutions, suspensions, or emulsions in a non - toxic parenterally acceptable diluent or solvent such as, for example, a solution in 1,3 - butanediol. Among the acceptable vehicles and solvents that may be utilized are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any sterile fixed oil containing synthetic monoglycerides or diglycerides may be utilized. In addition, fatty acids such as oleic acid are used in the manufacture of injectable preparations.

[0101] Injectable preparations may be sterilized, for example, by filtration through a bacteria - retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0102] In order to extend the effect of the compounds of the present invention, it is often desirable to delay the absorption from subcutaneous or intramuscular injection of the compounds. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. In that case, the absorption rate of the compound depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Alternatively, the delayed absorption of the form of the compound administered parenterally is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are produced by forming a microcapsule-type matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the properties of the particular polymer utilized, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injection formulations are also produced by encapsulating the compound in liposomes or microemulsions that can be compatible with body tissues.

[0103] Compositions for rectal or vaginal administration are preferably suppositories, which can be produced by mixing the compounds of the present invention 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 to release the active compound.

[0104] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is combined 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 silicic acid, b) binders such as, for example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrants such as agar - agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution retardants such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, 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 buffering agents.

[0105] Solid compositions of the same type may also be used as fillers in soft and hard - filled gelatin capsules using excipients such as lactose or milk sugar, as well as high - molecular - weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be manufactured using coating agents and shells such as enteric - coating agents and other coating agents well - known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may be compositions that release only the active ingredient or, preferentially, release the active ingredient in a particular part of the intestinal tract, optionally in a delayed manner. Examples of implantable compositions that can be used include polymeric substances and waxes. Solid compositions of the same type may also be used as fillers in soft and hard - filled gelatin capsules using excipients such as lactose or milk sugar, as well as high - molecular - weight polyethylene glycols and the like.

[0106] The active compound can also be in microencapsulated form with one or more of the excipients described above. Solid pharmaceutical forms such as tablets, dragees, capsules, pills, and granules can be manufactured using coating agents and shells such as enteric coating agents, release control coating agents, and other coating agents well known in the field of pharmaceutical formulations. In such solid pharmaceutical forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such pharmaceutical forms may also contain, as is normal current practice, additives other than inert diluents, for example lubricants for tablets such as magnesium stearate and microcrystalline cellulose and other tablet auxiliaries. In the case of capsules, tablets and pills, the pharmaceutical forms may also contain buffering agents. They may, if desired, contain opacifying agents and may be compositions which release only the active ingredient or, preferentially, release the active ingredient in a particular part of the intestinal tract, if desired in a delayed manner. Examples of implantable compositions which can be used are polymeric substances and waxes.

[0107] Pharmaceutical forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, with the preservatives or buffering agents required. Ophthalmic preparations, ear drops, and eye drops are also considered to be within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches which have the additional advantage of providing controlled delivery of the compound to the body. Such pharmaceutical forms can be manufactured by dissolving or dispensing the compound in a suitable medium. The rate of flow of the compound across the skin can be increased using absorption promoters. The rate can be controlled either by providing a rate controlling membrane or by dispersing the compound in a polymeric matrix or gel.

[0108] The amount of the compounds of the present invention that can be combined with a carrier material to produce a single dosage form composition will vary depending on the host being treated and the particular method of administration. Preferably, the compositions provided should be formulated so that an inhibitor can be administered to a patient receiving these compositions at a dosage of 0.01 - 100 mg / kg body weight / day.

[0109] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapies can take the form of a fixed combination, or the administration of the compounds of the present invention and one or more other therapeutic compounds can be alternating, or administered independently of each other, or take the form of a combined administration of a fixed combination and one or more other therapeutic compounds. Examples of such other therapeutic agents include corticosteroids, loxipram, calphostin, cytokine-suppressive anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors such as deoxyspergualin (DSG); non-steroidal 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 tenizap, anti-TNF antibodies or soluble TNF receptors, and rapamycin (sirolimus or Rapamune) or its derivatives. The compounds of the present invention can, in addition or alternatively, be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or combinations thereof, particularly for tumor therapy. As noted above, long-term therapy is equally possible, as is adjuvant therapy in connection with other treatment methods. Other possible treatments are those for maintaining the patient's condition after the tumor has regressed, or even chemoprevention in patients, for example, at risk.

[0110] These additional agents may be administered separately from the compositions containing the compounds of the invention as part of a treatment regimen involving multiple administrations. Alternatively, these agents may be part of a single administration form and may be admixed with the compounds of the invention in a single composition. If administered as part of a treatment regimen involving multiple administrations, the two active agents may be administered simultaneously, sequentially, or within a defined period of time relative to each other, usually within 5 hours of each other.

[0111] As used herein, the terms "combination", "combined", and related terms refer to the simultaneous or sequential administration of the therapeutic agents according to the invention. For example, the compounds of the invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0112] The amounts of both the compounds of the invention and the additional therapeutic agents (the amounts in their compositions including the 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 to be treated and the particular route of administration. Preferably, the compositions of the invention should be formulated such that the compounds of the invention can be administered at a dosage between 0.01 - 100 mg / kg body weight / day.

[0113] In those compositions containing an additional therapeutic agent, the additional therapeutic agent and the compounds of the invention may act synergistically. Accordingly, the amount of the additional therapeutic agent in such compositions will likely be less than the amount required in a monotherapy utilizing only that therapeutic agent.

[0114] The amount of the additional therapeutic agent incorporated into the compositions of the invention will not exceed the amount that would normally be administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of the additional therapeutic agent in the compositions disclosed herein will be in the range of about 50% - 100% of the amount generally present in a composition containing that agent as the sole therapeutically active agent.

[0115] It should also be recognized that the individual dosage and treatment methods for a particular patient will depend on a variety of factors, including the activity of the individual compounds utilized, age, weight, general health, gender, diet, duration of administration, excretion rate, drug combinations, as well as the judgment of the attending physician and the severity of the particular disease being treated. The amount of the compound of the present invention in the composition will also depend on the individual compounds in the composition.

[0116] 5. Use, Formulation, and Administration The compounds and compositions described herein are generally useful for the inhibition of PAD4. The activity of the compounds utilized in the present invention as inhibitors of PAD4 can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that measure the inhibition of PAD4. The detailed conditions for assaying the compounds utilized as inhibitors of PAD4 in the present invention are described in the following examples. In some embodiments, the provided compounds selectively inhibit PAD4 as compared to PAD2.

[0117] As used herein, the terms “treating,” “treat,” and “treatment” refer to reversing, alleviating, delaying, or inhibiting the onset of a disease or disorder described herein, or one or more of its symptoms. In some embodiments, treatment may be administered after the onset of one or more symptoms. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account a medical history of symptoms and / or genetic or other susceptibility factors). Treatment may also continue after symptoms have resolved, for example, to prevent or delay recurrence.

[0118] The provided compound is an inhibitor of PAD4 and is thus useful for treating one or more disorders associated with PAD4 activity. Thus, in certain embodiments, the invention provides a method of treating a PAD4-mediated disorder, the method comprising administering to a patient in need thereof a compound of the invention or a pharmaceutically acceptable composition thereof.

[0119] In one embodiment, a PAD4-mediated disorder is a disease, condition or disorder mediated by inappropriate PAD4 activity. In some embodiments, a PAD4-mediated disorder is selected from the group consisting of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, and psoriasis. In further embodiments, the disorder mediated by inappropriate PAD4 activity is rheumatoid arthritis. In further embodiments, the disorder mediated by inappropriate PAD4 activity is systemic lupus erythematosus. In further embodiments, the disorder mediated by inappropriate PAD4 activity is vasculitis. In further embodiments, the disorder mediated by inappropriate PAD4 activity is cutaneous lupus erythematosus. In further embodiments, the disorder mediated by inappropriate PAD4 activity is psoriasis.

[0120] In one embodiment, a method of 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 thereof a therapeutically effective amount of the provided compound or a pharmaceutically acceptable salt thereof.

[0121] In one embodiment, there is provided a method of treating rheumatoid arthritis, comprising administering to a human subject in need thereof a therapeutically effective amount of a provided compound or a pharmaceutically acceptable salt thereof. In one embodiment, there is provided a method of treating systemic lupus erythematosus, comprising administering to a human subject in need thereof a therapeutically effective amount of a provided compound or a pharmaceutically acceptable salt thereof. In one embodiment, there is provided a method of treating vasculitis, comprising administering to a human subject in need thereof a therapeutically effective amount of a provided compound or a pharmaceutically acceptable salt thereof. In one embodiment, there is provided a method of treating cutaneous lupus erythematosus or psoriasis, comprising administering to a human subject in need thereof a therapeutically effective amount of a provided compound or a pharmaceutically acceptable salt thereof. In one embodiment, there is provided a method of treating psoriasis, comprising administering to a human subject in need thereof a therapeutically effective amount of a provided compound or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, PAD4-mediated disorders include acid-induced lung injury, pyogenic arthritis (PAPA), acute lymphocytic leukemia, acute respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenocortical insufficiency, aging, AIDS, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, and weight loss, angina, angioedema, anhidrotic ectodermal dysplasia with immunodeficiency, ankylosing spondylitis, anterior uveitis, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune pneumonia, bee sting-induced inflammation, Behçet's disease, Behçet's syndrome, Bell's palsy, beryllium poisoning, Braun syndrome, bone pain, bronchitis, burns, cystitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolism disorders, cataracts, cerebral aneurysms, chemical irritant-induced inflammation, choroiditis, chronic heart failure, chronic lung disease of prematurity, chronic lymphocytic leukemia, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue diseases, corneal ulcers, Crohn's disease, cryopyrin-associated periodic syndrome, cryptococcosis, cystic fibrosis, deficiency of interleukin-1 receptor antagonist (DIRA), dermatitis, dermatitis endotoxemia, dermatomyositis, diffuse glioblastoma, endometriosis, endotoxemia, ethmoiditis, erythroblastopenia, familial amyloidotic polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth retardation, glaucoma, glomerular diseases, glomerulonephritis, gout, gouty arthritis, graft-versus-host disease, intestinal diseases, head injuries, headaches, hearing loss, heart disease, hemolytic anemia, Henoch-Schönlein purpura, hepatitis, hereditary periodic fever syndromes, herpes zoster and herpes simplex, HIV-1, Hodgkin's disease, Huntington's disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulinemia D with recurrent fever (HIDS), hypoplasia and other anemias, aplastic anemia, idiopathic thrombocytopenic purpura, dyschromatosis, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, iris, irritant-induced inflammation, ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, kidney injury caused by parasitic infection, kidney transplant rejection prevention, leptospirosis, leukemia, Reiter's syndrome, lung injury, lupus,Selected from the group consisting of lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, Mac-Wells syndrome (urticaria deafness amyloidosis), multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis, myocarditis, fungating polyps, myelodysplastic syndrome, myositis, rhinosinusitis, necrotizing enteritis, neonatal-onset multi-organ inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological diseases, non-allergen-induced asthma, obesity, eye allergy, optic neuritis, organ transplantation, osteoarthritis, otitis media, Paget's disease, pain, pancreatitis, Parkinson's disease, pemphigus, pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pertussis, pharyngitis and adenitis (PFAPA syndrome), plant irritant-induced inflammation, pneumonia, pneumonitis, pneumonia infection, Rhus toxicodendron / urushiol oil-induced inflammation, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyositis, psoriasis, psychosocial stress disorder, lung disease, pulmonary hypertension, pulmonary fibrosis, pyoderma gangrenosum, septic arthritis, kidney disease, retinal disease, rheumatic carditis, rheumatic diseases, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cells, 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-associated periodic syndrome (TRAPS), toxoplasmosis, transplantation, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticaria, uveitis, Wegener's 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.,

[0123] In one embodiment, the present invention provides a compound for use in therapy, or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a compound for use in the treatment of disorders mediated by inappropriate PAD4 activity, or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a compound for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis, or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a compound for use in the treatment of rheumatoid arthritis, or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a compound for use in the treatment of systemic lupus erythematosus, or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a compound for use in the treatment of vasculitis, or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a compound for use in the treatment of cutaneous lupus erythematosus, or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a compound for use in the treatment of psoriasis, or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides the use of a compound, or a pharmaceutically acceptable salt thereof, provided in the manufacture of a medicament for use in the treatment of disorders mediated by inappropriate PAD4 activity. In another embodiment, the present invention provides the use of a compound, or a pharmaceutically acceptable salt thereof, provided in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis. In another embodiment, the present invention provides the use of a compound, or a pharmaceutically acceptable salt thereof, provided in the manufacture of a medicament for use in the treatment of rheumatoid arthritis. In another embodiment, the present invention provides the use of a compound, or a pharmaceutically acceptable salt thereof, provided in the manufacture of a medicament for use in the treatment of systemic lupus erythematosus.In another alternative embodiment, the present invention provides the use of the provided compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of vasculitis. In another alternative embodiment, the present invention provides the use of the provided compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cutaneous erythematosus. In another alternative embodiment, the present invention provides the use of the provided compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of psoriasis. In a further embodiment, the present invention provides a pharmaceutical composition for treating or preventing a disorder mediated by inappropriate PAD4 activity, the pharmaceutical composition comprising the provided compound, or a pharmaceutically acceptable salt thereof. In a further embodiment, the present invention provides a pharmaceutical composition for treating or preventing rheumatoid arthritis, vasculitis, systemic erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous erythematosus, or psoriasis, the pharmaceutical composition comprising the provided compound, or a pharmaceutically acceptable salt thereof. In a further embodiment, the present invention provides a pharmaceutical composition for treating or preventing rheumatoid arthritis, the pharmaceutical composition comprising the provided compound, or a pharmaceutically acceptable salt thereof. In a further embodiment, the present invention provides a pharmaceutical composition for treating or preventing systemic erythematosus, the pharmaceutical composition comprising the provided compound, or a pharmaceutically acceptable salt thereof. In a further embodiment, the present invention provides a pharmaceutical composition for treating or preventing vasculitis, the pharmaceutical composition comprising the provided compound, or a pharmaceutically acceptable salt thereof. In a further embodiment, the present invention provides a pharmaceutical composition for treating or preventing cutaneous erythematosus, the pharmaceutical composition comprising the provided compound, or a pharmaceutically acceptable salt thereof. In a further embodiment, the present invention provides a pharmaceutical composition for treating or preventing psoriasis, the pharmaceutical composition comprising the provided compound, or a pharmaceutically acceptable salt thereof.

[0124] All features of each aspect of the present invention, where appropriate, may be modified and applied mutatis mutandis to all other aspects. To better understand the invention described herein, the following examples are used to illustrate the invention. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the invention in any way.

[0125] 6. Exemplification As described in the examples below, in certain embodiments, as specific illustrations, compounds are prepared according to the following general procedures. The general methods illustrate the synthesis of specific compounds of the invention, but it will be understood that the following general methods and other methods known to those skilled in the art can be applied to all compounds and to each of these compounds of the subgroups and species, as described herein.

[0126] Synthesis Scheme In examples where linker B contains a nucleophilic residue such as NH in pyrazole or imidazole, a macrocycle can be formed as shown in general chemical scheme 1. Those skilled in the art can also design a similar synthetic route where the linker between group C and the bicyclic tube can be a variable group.

[0127] Scheme 1

Chemical formula

[0128] An example where linker B and C are coupled using a Suzuki coupling reaction, followed by final macrocyclization through the simultaneous formation of a benzimidazole ring, can be prepared as shown in general chemical scheme 2.

[0129] Scheme 2

Chemical formula

[0130] General scheme 3 describes obtaining a macrocycle by cyclization via ring-closing metathesis, followed by subjecting the newly generated olefin to ring addition, hydroxylation, or hydrogenation to obtain a C-containing compound as defined in the scheme.

[0131] Scheme 3

Chem.

[0132] General chemical scheme 4 describes obtaining a macrocycle by cyclization via ring-closing metathesis, followed by subjecting the newly generated olefin to dihydroxylation to obtain a compound containing adjacent diols as shown in the scheme. Other conversions to the olefin can be carried out by those skilled in the art.

[0133] Scheme 4

Chem.

[0134] General chemical scheme 5 describes a macrocycle cyclized via the formation of an amide bond as shown in the scheme.

[0135] Scheme 5

Chem.

[0136] Description of analytical LCMS method: Method 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile: water + 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile: water + 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 minutes, then hold at 100% B for 0.75 minutes; Flow rate: 1 mL / min; Detection: MS and UV (220 nm)

[0137] Method 2: Column: Waters Acquity C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile: water + 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water + 0.1% trifluoroacetic acid; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 minutes, then hold at 100% B for 0.75 minutes; Flow rate: 1 mL / min; Detection: MS and UV (220 nm)

[0138] Method 3: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 μm particles; Mobile phase A: water + 0.05% TFA; Mobile phase B: ACN + 0.05% TFA; Gradient: 2% B to 98% B over 1 minute, then hold at 98% B for 0.5 minutes; Flow rate: 0.8 mL / min; Detection: MS and UV (220 nm)

[0139] Method 4: Shimadzu UPLC C18, 2.1 x 50 mm, 1.9 μm particles; Mobile phase A: 5:95 ACN: water + 0.05% TFA; Mobile phase B: 95:5 ACN: water + 0.05% TFA; Temperature: 50 °C; Gradient: 0 to 100% B over 1.5 minutes, then hold at 100% B for 0.30 minutes; Flow rate: 0.60 mL / min; Detection: UV (254 nm)

[0140] Method 5: Shimadzu UPLC BEH C18, 2.1 x 50 mm, 1.7 μm particles; Mobile phase A: water + 0.05% TFA; Mobile phase B: ACN + 0.05% TFA; Gradient: 2% B to 98% B over 3 minutes, then hold at 98% B for 0.5 minutes; Flow rate: 1.0 mL / min; Detection: MS and UV (220 nm)

[0141] Method 6: Shimadzu UPLC C18, 2.1 x 50 mm, 1.9 μm particles; Mobile phase A: 5:95 ACN: water + 0.05% TFA; Mobile phase B: 95:5 ACN: water + 0.05% TFA; Temperature: 50 °C; Gradient: 0 to 100% B over 3.5 minutes, then hold at 100% B for 0.30 minutes; Flow rate: 0.60 mL / min; Detection: UV (254 nm)

[0142] All final products were treated with resin to remove trace amounts of metals as follows. The purified material was diluted with DMF, treated with Si-pyridine, and shaken for at least 2 hours. The resulting mixture was filtered and dried by centrifugal evaporation as usual.

[0143] In the present application, the structures generally described below as A and B in (Figure 1) represent a completely chiral structure C or D in which the chiral azabicycloheptane moiety is designated as ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl).

[0144] Figure 1

Chemical formula

[0145] Example 1 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)((Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-2(2,1)-benzo[d]imidazol-1(2,1)-indol-4(4,1)-pyrazolacyclononaphthalen-2 5 -yl)methanone

Chemical formula

[0146] Intermediate 1A: Methyl 4-(((1H-pyrazol-4-yl)methyl)amino)-3-methoxy-5-nitrobenzoate 1-carboxylate

Chemical formula

[0147] A mixture of methyl 4-chloro-3-methoxy-5-nitrobenzoate (867 mg, 3.53 mmol), 1H-pyrazol-4-ylmethylamine dihydrochloride (600 mg, 3.53 mmol) and TEA (2.45 mL, 17.64 mmol) in DMF (5 mL) was stirred at 60 °C for 18 h. The mixture was diluted with EtOAc (15 mL) and washed with saturated aqueous sodium hydrogen carbonate (2 x 15 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO flash chromatography (silica gel / DCM-EtOAc gradient from 100:0 to 0:100). Methyl 4-(((1H-pyrazol-4-yl)methyl)amino)-3-methoxy-5-nitrobenzoate (790 mg, 2.45 mmol, 69.4% yield) was obtained as a red solid. LC / MS (M+H): 307; LC retention time: 0.77 min (analytical HPLC method 3); 1 H NMR (499 MHz, chloroform-d) δ 8.49 (d, J = 1.9 Hz, 1H), 7.59 (s, 2H), 7.54 (d, J = 1.8 Hz, 1H), 4.80 (s, 2H), 3.94 (s, 3H), 3.93 (s, 3H)

[0148] Intermediate 1B: Methyl 1-((1H-pyrazol-4-yl)methyl)-2-(1H-indol-2-yl)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate

Chemical Structure

[0149] A solution of methyl 4-(((1H-pyrazol-4-yl)methyl)amino)-3-methoxy-5-nitrobenzoate (200 mg, 0.65 mmol) and 1H-indole-2-carbaldehyde (95 mg, 0.65 mmol) in EtOH (6 mL) was added with a solution of sodium dithionite (341 mg, 1.95 mmol) in water (3 mL) at room temperature under nitrogen. The mixture was stirred at 80 °C for 18 h. The mixture was diluted with EtOAc (15 mL). The ppt was filtered and washed with water (20 mL) and EtOAc (30 mL). Crude methyl 1-((1H-pyrazol-4-yl)methyl)-2-(1H-indol-2-yl)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate (170 mg, 0.402 mmol, 61.6% yield) was obtained as an off-white solid. LC / MS (M+H): 402; LC retention time: 0.77 min (analytical HPLC method 3); 1 H NMR (499 MHz, DMSO-d6) δ 12.75 (brs, 1H), 11.95 (s, 1H), 7.93 (s, 1H), 7.70 - 7.66 (m, 1H), 7.60 - 7.50 (m, 2H), 7.42 - 7.39 (m, 1H), 7.35 - 7.28 (m, 1H), 7.25 - 7.19 (m, 2H), 7.11 - 7.05 (m, 1H), 5.89 (s, 2H), 4.04 (s, 3H), 3.90 (s, 3H)

[0150] Intermediate 1C: Methyl (Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-2(2,1)-benzo[d]imidazol-1(2,1)-indol-4(4,1)-pyrazolacyclononaphthalen-2 5 -carboxylate

Chemical Structure

[0151] Methyl 1-((1H-pyrazol-4-yl)methyl)-2-(1H-indol-2-yl)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate (25 mg, 0.062 mmol), 1,5-diiodopentane (20.17 mg, 0.062 mmol) and cesium carbonate (40.6 mg, 0.12 mmol) in DMF (0.50 mL) were stirred at 80 °C for 2 h. The mixture was diluted with EtOAc (5 mL) and washed with saturated aqueous sodium hydrogen carbonate (2 x 5 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO flash chromatography (silica gel / hexane-EtOAc gradient 100:0 to 0:100). Methyl (Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-2(2,1)-benzo[d]imidazol-1(2,1)-indol-4(4,1)-pyrazolacyclononaphthalen-2 5 -carboxylate (7.0 mg, 0.014 mmol, 22.74% yield) was obtained as a white solid. LC / MS (M+H): 470; LC retention time: 0.95 min (analytical HPLC method 3); 1 H NMR (400 MHz, methanol-d4) δ 8.05-8.03 (m, 1H), 7.79-7.74 (m, 1H), 7.67-7.65 (m, 1H), 7.59-7.56 (m, 1H), 7.37-7.31 (m, 1H), 7.23-7.17 (m, 3H), 6.50-6.47 (m, 1H), 6.28-6.21 (m, 1H), 5.78-5.72 (m, 1H), 4.73-4.62 (m, 1H), 4.23 (s, 3H), 4.12-4.01 (m, 2H), 3.98 (s, 3H), 3.62-3.49 (m, 1H), 1.76-1.60 (m, 2H), 1.40-1.29 (m, 1H), 0.95-0.76 (m, 2H), -0.69--0.86 (m, 1H)

[0152] Example 1 ((7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)((Z)-2 7 -methoxy-1 1 H,21 H,4 1 H-2(2,1)-benzo[d]imidazola-1(2,1)-indola-4(4,1)-pyrazolacyclononaphan-2 5 -yl)methanone

Chemical formula

[0153] Methyl (Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-2(2,1)-benzo[d]imidazola-1(2,1)-indola-4(4,1)-pyrazolacyclononaphan-2 5 -carboxylate (7.0 mg, 0.015 mmol) and 1.0 M aqueous sodium hydroxide (0.075 mL, 0.075 mmol) in MeOH (1 mL) were stirred at 50 °C for 3 hours. The mixture was cooled to room temperature. 1.0 N aqueous HCl (0.080 mL) was added and the mixture was concentrated to give the crude (Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-2(2,1)-benzo[d]imidazola-1(2,1)-indola-4(4,1)-pyrazolacyclononaphan-2 5 -carboxylic acid. LC / MS (M+H): 456; LC retention time: 0.84 minutes (analytical HPLC method 3)

[0154] (Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-2(2,1)-benzo[d]imidazola-1(2,1)-indola-4(4,1)-pyrazolacyclononaphan-2 5-Carboxylic acid, tert-butyl ((7R)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate (3.16 mg, 0.015 mmol), BOP (6.59 mg, 0.015 mmol) and TEA (6.23 μl, 0.045 mmol) in DMF (1 mL) were stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (5 mL) and washed with saturated aqueous sodium hydrogen carbonate (2 x 5 mL). The ethyl acetate layer was dried over sodium sulfate, concentrated to give crude tert-butyl ((7R)-2-((Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-2(2,1)-benzo[d]imidazola-1(2,1)-indola-4(4,1)-pyrazolacyclononaphane-2 5 -carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate. LC / MS (M+H): 650; LC retention time: 0.91 minutes (analytical HPLC method 3)

[0155] tert-butyl ((7R)-2-((Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-2(2,1)-benzo[d]imidazola-1(2,1)-indola-4(4,1)-pyrazolacyclononaphane-2 5The mixture of ((7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl) ((Z)-2-methoxy-1H,2H,4H-2(2,1)-benz[d]imidazol-1(2,1)-indol-4(4,1)-pyrazolacyclononaphthalen-2-yl)methanecarbamate (8.20 mg, 0.015 mmol, 98% yield) in DCM (0.5 mL) and TFA (0.5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated. The crude material was purified via preparative LC / MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile: water + 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water + 10 mM ammonium acetate; gradient: held at 18% B for 0 minutes, changed to 18 - 58% B over 20 minutes, then held at 100% B for 4 minutes; flow rate: 20 mL / min; column temperature: 25 °C. Fraction collection was initiated by MS and UV signals. The fractions containing the desired product were combined and dried via centrifugal evaporation. 7 -methoxy-1 1 H,2 1 H,4 1 H-2(2,1)-benz[d]imidazol-1(2,1)-indol-4(4,1)-pyrazolacyclononaphthalen-2 5 -yl)methanone (8.20 mg, 0.015 mmol, 98% yield) was obtained. LC / MS (M+H): 550; LC retention time: 1.31 minutes (analytical HPLC method 2); 1 1H NMR (500 MHz, DMSO-d6) δ 7.76 - 7.71 (m, 1H), 7.64 - 7.59 (m, 1H), 7.45 - 7.21 (m, 3H), 7.18 - 7.02 (m, 3H), 6.41 - 6.36 (m, 1H), 6.06 - 5.99 (m, 1H), 5.68 - 5.61 (m, 1H), 4.70 - 4.63 (m, 1H), 4.19 - 4.03 (m, 4H), 4.00 - 3.77 (m, 2H), 3.64 - 3.46 (m, 6H), 3.22 - 2.99 (m, 2H), 2.08 - 1.93 (m, 2H), 1.67 - 1.40 (m, 3H), 1.19 - 1.04 (m, 1H), 0.83 - 0.57 (m, 2H), -0.81 - -0.93 (m, 1H)

[0156] Example 2 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)((Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridine-4(4,1)-pyrazolacyclodecafan-2 5 -yl)methanone

Chemical Structure

[0157] Intermediate 2A: 1-(6-((Tert-butyldimethylsilyl)oxy)hexyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde

Chemical Structure

[0158] A solution of 1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (200 mg, 1.36 mmol) in DMF (2 mL) was added to a suspension of sodium hydride (71.2 mg, 1.779 mmol) in anhydrous DMF (5 mL) under nitrogen, and the mixture was stirred at room temperature for 45 minutes. (6-Bromohexyloxy)-tert-butyldimethylsilane (445 mg, 1.50 mmol) / DMF (1 mL) was added to the mixture, and the reaction was stirred at room temperature for 18 hours. The mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous sodium bicarbonate (2 x 20 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO flash chromatography (silica gel / hexane-EtOAc gradient of 100:0 to 60:40). 1-(6-((tert-Butyldimethylsilyl)oxy)hexyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (417 mg, 1.099 mmol, 80% yield) was obtained as a clear oil. LC / MS (M+H): 361; LC retention time: 1.30 minutes (analytical HPLC method 3); 11H NMR (499 MHz, chloroform-d) δ 9.95 (s, 1H), 8.57 (dd, J = 4.6, 1.6 Hz, 1H), 8.08 (dd, J = 8.0, 1.7 Hz, 1H), 7.23 (s, 1H), 7.17 (dd, J = 8.0, 4.6 Hz, 1H), 4.75 - 4.67 (m, 2H), 3.59 (t, J = 6.6 Hz, 2H), 1.87 - 1.78 (m, 2H), 1.55 - 1.45 (m, 2H), 1.42 - 1.28 (m, 4H), 0.94 - 0.84 (m, 9H), 0.04 - 0.02 (m, 6H)

[0159] Intermediate 2B: Methyl 1-((1H-pyrazol-4-yl)methyl)-2-(1-(6-hydroxyhexyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate

Chemical Structure

[0160] A solution of 1-(6-((tert-butyldimethylsilyl)oxy)hexyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (177 mg, 0.49 mmol) and methyl 4-(((1H-pyrazol-4-yl)methyl)amino)-3-methoxy-5-nitrobenzoate (150 mg, 0.49 mmol) in EtOH (4 mL) was added to a solution of sodium dithionite (256 mg, 1.46 mmol) in water (2 mL), and the mixture was stirred at 80 °C for 18 h. The mixture was diluted with EtOAc (15 mL) and washed with saturated aqueous sodium hydrogen carbonate (2 x 15 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO flash chromatography (gradient of silica gel / hexane-EtOAc 100:0 to 0:100). Methyl 1-((1H-pyrazol-4-yl)methyl)-2-(1-(6-hydroxyhexyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate (159 mg, 0.301 mmol, 61.4% yield) was obtained as a yellowish brown foam. LC / MS (M+H): 503; LC retention time: 0.75 min (analytical HPLC method 3); 1 H NMR (499 MHz, chloroform-d) δ 8.48 - 8.45 (m, 1H), 8.23 - 8.21 (m, 1H), 8.03 - 8.00 (m, 1H), 7.56 - 7.54 (m, 1H), 7.21 - 7.15 (m, 3H), 6.85 (s, 1H), 5.84 - 5.78 (m, 2H), 4.62 - 4.56 (m, 2H), 4.10 (s, 3H), 3.99 (s, 3H), 3.53 - 3.47 (m, 2H), 1.37 - 1.24 (m, 6H), 1.18 - 1.03 (m, 4H)

[0161] Intermediate 2C: Methyl (Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridina-4(4,1)-pyrazolacyclodecane-2 5 -carboxylate [Chemical Structure]

[0162] A solution of methyl 1-((1H-pyrazol-4-yl)methyl)-2-(1-(6-hydroxyhexyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate (110 mg, 0.22 mmol) and tri-n-butylphosphine (48.7 mg, 0.24 mmol) in toluene (5 mL) and THF (3 mL) under nitrogen was added to a solution of diamide (41.5 mg, 0.24 mmol) in THF (1 mL), and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated. The crude product was purified by preparative HPLC (Phenomenex, Luna 5 micron 30x250 mm, flow rate = 30 ml / min, gradient = 20% A to 100% B over 30 minutes, A = H2O / ACN / TFA (90:10:0.1), B = H2O / ACN / TFA (10:90:0.1)). Methyl (Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridina-4(4,1)-pyrazolacyclodecane-2 5 -carboxylate (26 mg, 0.051 mmol, 23.29% yield) was obtained. LC / MS (M+H): 485; LC retention time: 0.80 minutes (analytical HPLC method 3); 1 H NMR (499 MHz, methanol-d4) δ 8.42 - 8.40 (m, 1H), 8.31 - 8.28 (m, 1H), 8.10 (d, J = 1.2 Hz, 1H), 7.69 - 7.66 (m, 1H), 7.43 (s, 1H), 7.33 - 7.29 (m, 1H), 7.25 (s, 1H), 7.00 (s, 1H), 6.48 - 6.43 (m, 1H), 5.85 - 5.80 (m, 1H), 4.76 - 4.64 (m, 2H), 4.20 (s, 3H), 3.99 (s, 3H), 3.98 - 3.88 (m, 2H), 1.84 - 1.59 (m, 2H), 1.42 - 1.27 (m, 2H), 0.93 - 0.81 (m, 2H), 0.45 - 0.33 (m, 1H), -0.33 - -0.43 (m, 1H)

[0163] Example 2 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)((Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridine-4(4,1)-pyrazolacyclodeca-2 5 -yl)methanone

Chemical formula

[0164] Methyl (Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridine-4(4,1)-pyrazolacyclodeca-2 5 -carboxylate (15 mg, 0.031 mmol) and 1.0 M sodium hydroxide (155 μl, 0.16 mmol) in MeOH (2 mL) were stirred at 55 °C for 18 h. 1.0 M aqueous HCl (0.32 mL) was added and the mixture was concentrated. The crude product was purified by preparative HPLC (Phenomenex, Luna 5 micron 30x250 mm, flow rate = 30 ml / min, gradient = 20% A to 100% B over 30 min, A = H2O / ACN / TFA (90:10:0.1), B = H2O / ACN / TFA (10:90:0.1)). (Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridine-4(4,1)-pyrazolacyclodeca-2 5 -carboxylic acid was obtained. LC / MS (M+H): 471; LC retention time: 0.74 min (analytical HPLC method 3)

[0165] (Z)-2 7 -methoxy-1 1 H,2 1 H,4 1H-1,2(2,1)-dipyrrolo[2,3-b]pyridine-4(4,1)-pyrazolacyclodecane-2 5 A mixture of tert-butyl ((7R)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate (6.57 mg, 0.031 mmol), BOP (13.69 mg, 0.031 mmol) and TEA (21.57 μl, 0.16 mmol) in DMF (1 mL) was stirred at room temperature for 1 h. The mixture was diluted with EtOAc (5 mL) and washed with saturated aqueous sodium bicarbonate (2 x 5 mL). The ethyl acetate layer was dried over sodium sulfate, concentrated to give crude tert-butyl ((7R)-2-((Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridine-4(4,1)-pyrazolacyclodecane-2 5 -carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate. LC / MS (M+H): 665; LC retention time: 0.86 min (analytical HPLC method 3)

[0166] tert-butyl ((7R)-2-((Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridine-4(4,1)-pyrazolacyclodecane-2 5The mixture of ((7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl) ((Z)-2-((7-oxo-2-azabicyclo[2.2.1]heptan-7-yl)carbamate) in DCM (1 mL) and TFA (1 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated. The crude product was purified by preparative HPLC (XBridge C18, 200 mm x 19 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile: water + 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water + 10 mM ammonium acetate; gradient: held at 11% B for 0 minutes, changed to 11 - 51% B over 20 minutes, then held at 100% B for 0 minutes; flow rate: 20 mL / min; column temperature: 25 °C). ((7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl) ((Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridin-4(4,1)-pyrazolacyclodeca-2 5 -yl)methanone (4.70 mg, 7.92 micromol, 25.6% yield) was obtained. LC / MS (M+H): 565; LC retention time: 1.11 minutes (analytical HPLC method 2); 1 H NMR (500 MHz, DMSO-d6) δ 8.39 - 8.33 (m, 1H), 8.18 - 8.11 (m, 1H), 7.54 - 7.35 (m, 2H), 7.23 - 7.03 (m, 3H), 6.91 (s, 1H), 6.26 - 6.13 (m, 1H), 5.83 - 5.71 (m, 1H), 4.70 - 4.61 (m, 2H), 4.13 - 4.03 (m, 3H), 3.95 - 3.77 (m, 2H), 3.75 - 3.30 (m, 1H), 3.26 - 2.66 (m, 2H), 2.30 - 2.16 (m, 1H), 2.08 - 1.68 (m, 4H), 1.56 - 1.12 (m, 6H), 1.07 - 0.67 (m, 3H), 0.37 - 0.22 (m, 1H), -0.39 - -0.59 (m, 1H)

[0167] Example 3 ((3R,5R)-3-amino-5-fluoropiperidin-1-yl) ((Z)-2 7 -methoxy-1 1 H,2 1 H,41 H-6-oxa-2(2,1)-benzo[d]imidazol-1(2,1)-indol-4(4,1)-pyrazolo-5(1,2)-benzena[5,6]cyclononaphthalen-2 5 -yl)methanone [Chemical Structure]

[0168] Intermediate 3A: 1-(3-(2-Bromophenoxy)propyl)-1H-indole-2-carbaldehyde [Chemical Structure]

[0169] A solution of indole-2-carboxaldehyde (1.0 g, 6.89 mmol) in DMF (10 mL) was added to a suspension of sodium hydride (0.303 g, 7.58 mmol) in anhydrous DMF (10 mL), and the mixture was stirred under nitrogen at room temperature for 60 minutes. Next, 1-bromo-2-(3-bromopropoxy)benzene (2.23 g, 7.58 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (45 mL) and washed with saturated aqueous sodium bicarbonate (2 x 45 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO flash chromatography (silica gel / hexane-EtOAc gradient from 100:0 to 0:100). 1-(3-(2-Bromophenoxy)propyl)-1H-indole-2-carbaldehyde (1.98 g, 5.25 mmol, 76% yield) was obtained as a brown gum. LC / MS (M+H): 359; LC retention time: 1.15 minutes (analytical HPLC method 3)

[0170] Intermediate 3B: Methyl 1-((1H-pyrazol-4-yl)methyl)-2-(1-(3-(2-bromophenoxy)propyl)-1H-indol-2-yl)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate [Chemical Structure]

[0171] A solution of sodium dithionite (495 mg, 2.84 mmol) in water (3 mL) was added to a solution of 1-(3-(2-bromophenoxy)propyl)-1H-indole-2-carbaldehyde (339 mg, 0.95 mmol) and methyl 4-(((1H-pyrazol-4-yl)methyl)amino)-3-methoxy-5-nitrobenzoate (290 mg, 0.95 mmol) in EtOH (6 mL), and the mixture was stirred at 80 °C for 18 h. The mixture was diluted with EtOAc (25 mL) and washed with saturated aqueous sodium hydrogen carbonate (2 x 25 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO flash chromatography (silica gel / gradient of hexane - 5% MeOH / EtOAc 100:0 to 0:100). Methyl 1-((1H-pyrazol-4-yl)methyl)-2-(1-(3-(2-bromophenoxy)propyl)-1H-indol-2-yl)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate (321 mg, 0.522 mmol, 55.2% yield) was obtained as a yellowish-brown foam. LC / MS (M+H): 615; LC retention time: 0.96 min (analytical HPLC method 3)

[0172] Intermediate 3C: (Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-6-oxa-2(2,1)-benzodimidazol-1(2,1)-indol-4(4,1)-pyrazol-5(1,2)-benzenacyclononaphthalen-2 5 -carboxylic acid

Chemical Structure

[0173] Methyl 1-((1H-pyrazol-4-yl)methyl)-2-(1-(3-(2-bromophenoxy)propyl)-1H-indol-2-yl)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate (80 mg, 0.13 mmol), copper(I) iodide (24.79 mg, 0.13 mmol), potassium phosphate (83 mg, 0.39 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (18.52 mg, 0.13 mmol) in degassed dioxane (12 mL) were stirred at 110 °C for 18 h in a sealed vial under nitrogen. The mixture was diluted with EtOAc (5 mL), the Ppt was filtered and the filtrate was concentrated. The crude product was subjected to ISCO flash chromatography (silica gel / hexane-EtOAc gradient 100:0 to 0:100). Methyl (Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-6-oxa-2(2,1)-benzo[d]imidazol-1(2,1)-indol-4(4,1)-pyrazol-5(1,2)-benzena[cyclononaphthalene-2 5 -carboxylate (32 mg, 0.057 mmol, 43.8% yield) was obtained. LC / MS (M+H): 534; LC retention time: 1.03 min (analytical HPLC method 3); 1 H NMR (499 MHz, chloroform-d) δ 8.29 (s, 1H), 7.77 - 7.72 (m, 1H), 7.66 - 7.59 (m, 2H), 7.52 - 7.47 (m, 2H), 7.41 - 7.36 (m, 1H), 7.2 7 -7.21 (m, 2H), 7.16 (s, 1H), 7.11 - 7.06 (m, 1H), 7.01 - 6.97 (m, 1H), 6.89 (s, 1H), 6.38 - 6.33 (m, 1H), 5.96 - 5.90 (m, 1H), 4.80 - 4.70 (m, 1H), 4.62 - 4.51 (m, 1H), 4.16 (s, 3H), 4.02 - 3.91 (m, 5H), 2.03 - 1.93 (m, 1H), 1.80 - 1.69 (m, 1H)

[0174] Methyl (Z)-2 7 -methoxy-11 H,2 1 H,4 1 H-6-oxa-2(2,1)-benzo[d]imidazol-1(2,1)-indol-4(4,1)-pyrazolo-5(1,2)-benzena[1,9]naphthalen-2 5 -carboxylate (32 mg, 0.057 mmol, 43.8% yield) and 2.0 N aqueous lithium hydroxide (0.33 mL, 0.65 mmol) in MeOH (2 mL) were stirred at 50 °C for 2 h. 1.0 N HCl aqueous solution (0.66 mL) was added and the mixture was concentrated. The crude (Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-6-oxa-2(2,1)-benzo[d]imidazol-1(2,1)-indol-4(4,1)-pyrazolo-5(1,2)-benzena[1,9]naphthalen-2 5 -carboxylic acid (123 mg, 0.11 mmol, 91% yield) was obtained. LC / MS (M+H): 520; LC retention time: 0.92 min (analytical HPLC method 3)

[0175] Example 3 ((3R,5R)-3-Amino-5-fluoropiperidin-1-yl)((Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-6-oxa-2(2,1)-benzo[d]imidazol-1(2,1)-indol-4(4,1)-pyrazolo-5(1,2)-benzena[1,9]naphthalen-2 5 -yl)methanone

Chemical Structure

[0176] (Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-6-oxa-2(2,1)-benzo[d]imidazol-1(2,1)-indol-4(4,1)-pyrazolo-5(1,2)-benzena[1,9]naphthalen-2 5-Carboxylic acid (60 mg, 0.12 mmol), tert-butyl ((3R,5R)-5-fluoropiperidin-3-yl)carbamate (25.2 mg, 0.12 mmol), BOP (51.1 mg, 0.12 mmol) and TEA (80 μl, 0.58 mmol) in DMF (1 mL) were stirred at room temperature for 2 h. The mixture was diluted with EtOAc (5 mL) and washed with saturated aqueous sodium hydrogen carbonate (2 x 5 mL). The ethyl acetate layer was dried over sodium sulfate, concentrated, and the crude tert-butyl ((3R,5R)-5-fluoro-1-((Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-6-oxa-2(2,1)-benzo[d]imidazola-1(2,1)-indola-4(4,1)-pyrazola-5(1,2)-benzena[cyclononaphan]-2 5 -carbonyl)piperidin-3-yl)carbamate was obtained. LC / MS (M+H): 720; LC retention time: 0.96 min (analytical HPLC method 3)

[0177] tert-butyl ((3R,5R)-5-fluoro-1-((Z)-2 7 -methoxy-1 1 H,2 1 H,4 1 H-6-oxa-2(2,1)-benzo[d]imidazola-1(2,1)-indola-4(4,1)-pyrazola-5(1,2)-benzena[cyclononaphan]-2 5 -carbonyl)piperidin-3-yl)carbamate in DCM (1 mL) and TFA (0.5 mL) was stirred at room temperature for 30 min. The mixture was concentrated. The mixture was concentrated. The crude product was purified by preparative HPLC (Phenomenex, Luna 5 micron 30 x 250 mm, flow rate = 30 ml / min, gradient = 20% A to 100% B in 30 min, A = H2O / ACN / TFA (90:10:0.1), B = H2O / ACN / TFA (10:90:0.1)). ((3R,5R)-3-Amino-5-fluoropiperidin-1-yl)((Z)-2 7 -methoxy-1 1 H,2 1 H,41 H-6-oxa-2(2,1)-benzo[d]imidazol-1(2,1)-indol-4(4,1)-pyrazolo-5(1,2)-benzena[1,9]annulen-2-yl)methanone (11.38 mg, 0.018 mmol, yield 15.58%) was obtained as a white powder. LC / MS (M+H): 620; LC retention time: 0.81 min (analytical HPLC method 3); 5 -yl)methanone (11.38 mg, 0.018 mmol, yield 15.58%) was obtained as a white powder. LC / MS (M+H): 620; LC retention time: 0.81 min (analytical HPLC method 3); 1 H NMR (499 MHz, chloroform-d) δ 7.73 - 7.68 (m, 1H), 7.53 - 7.47 (m, 3H), 7.44 - 7.40 (m, 1H), 7.32 - 7.29 (m, 1H), 7.25 - 7.14 (m, 2H), 7.09 - 6.94 (m, 4H), 6.85 - 6.80 (m, 1H), 6.28 - 6.22 (m, 1H), 5.87 - 5.81 (m, 1H), 5.23 - 5.15 (m, 1H), 4.44 - 4.33 (m, 1H), 4.07 (s, 3H), 3.93 - 3.82 (m, 1H), 3.57 - 3.51 (m, 1H), 3.42 - 3.33 (m, 1H), 3.27 - 3.09 (m, 1H), 2.79 - 2.48 (m, 1H), 2.43 - 2.32 (m, 1H), 1.87 - 1.77 (m, 2H), 1.71 - 1.08 (m, 6H)

[0178] Examples 4 to 20 in Table 1 were produced as described by the general procedures shown for Examples 1 - 3. Table 1

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

[0179] Example 21 ((3R,5R)-3-Amino-5-fluoropiperidin-1-yl)(2 7 -Methoxy-1 1 H,2 1 H-2(2,1)-Benzimidazo[1,2-a]indol-4(1,3),5(1,2)-dibenzenacyclononaphan-2 5 -yl)methanone

Chemical Structure

[0180]

Chemical Structure

[0181] [Chemical Structure] Step 2: 1-(4-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)-1H-indole-2-carbaldehyde: In a 40 mL scintillation vial, a mixture of 1-(4-(2-bromophenyl)butyl)-1H-indole-2-carbaldehyde (235 mg, 0.660 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (201 mg, 0.792 mmol), potassium acetate (129 mg, 1.319 mmol), and PdCl2(dppf)-dichloromethane adduct (48.3 mg, 0.066 mmol) in dioxane (4 mL) was degassed by bubbling nitrogen through it for 10 minutes. The vial was sealed and the reaction mixture was stirred at 85 °C for 18 hours, at which point the reaction was judged to be complete by LCMS. The mixture was diluted with ethyl acetate (5 mL), filtered, and the filtrate was concentrated under vacuum. The residue was subjected to chromatography via MPLC on a 40 g silica gel column (eluting at 40 mL / min with a gradient of 0% - 50% ethyl acetate / hexane over 16 column volumes). The fractions containing the desired product were pooled and concentrated under vacuum to give the title compound (220 mg, 0.545 mmol, 83% yield). 11H NMR (400 MHz, chloroform-d) δ 9.89 (s, 1H), 7.83 - 7.71 (m, 2H), 7.43 - 7.40 (m, 2H), 7.37 - 7.32 (m, 1H), 7.27 (s, 1H), 7.22 - 7.13 (m, 3H), 4.61 (t, J = 7.4 Hz, 2H), 2.99 - 2.86 (m, 2H), 1.89 (quin, J = 7.5 Hz, 2H), 1.70 - 1.59 (m, 2H), 1.31 (s, 12H); LCMS retention time = 1.28 minutes, MS ESI m / z = 404.4 (M + H) (Method 3)

[0182] [Chemical Structure] Step 3: Methyl 4 - ((3 - bromobenzyl)amino)-3 - methoxy - 5 - nitrobenzoate: A stirred solution of methyl 4 - chloro - 3 - methoxy - 5 - nitrobenzoate (1.79 g, 7.29 mmol) and Hunig's base (2.55 mL, 14.58 mmol) in DMF (15 mL) was treated with (3 - bromophenyl)methanamine (2.71 g, 14.58 mmol). The reaction was stirred at room temperature for 60 h. LCMS indicated that the reaction had not yet gone to completion. The mixture was treated with (3 - bromophenyl)methanamine (2.71 g, 14.58 mmol) and the reaction was stirred at 50 °C for 24 h, at which point the reaction was judged to be complete by LCMS. The mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate (200 mL). The turbid solution was washed once with water, twice with 10% lithium chloride, and once with brine, then dried over sodium sulfate and concentrated under vacuum. The residue was subjected to chromatography via MPLC on a 220 g silica gel column (eluting at 100 mL / min with a gradient of 20% - 40% ethyl acetate / hexane over 12 column volumes). Fractions containing the desired product were pooled and concentrated under vacuum to afford the title compound (2.23 g, 5.64 mmol, 77% yield). 11H NMR (499 MHz, chloroform-d) δ 8.56 - 8.47 (m, 2H), 7.52 (d, J = 1.7 Hz, 1H), 7.47 (s, 1H), 7.45 - 7.40 (m, 1H), 7.26 - 7.22 (m, 2H), 4.85 (d, J = 6.2 Hz, 2H), 3.92 (s, 3H), 3.83 (s, 3H); LCMS retention time = 1.04 minutes, MS ESI m / z = 395.2 (M + H) (Method 3)

[0183]

Chem.

[0184] [Chemical formula] Step 5: Methyl 2 7 -methoxy-1 1 H,2 1 H-2(2,1)-benzo[d]imidazol-1(2,1)-indol-4(1,3),5(1,2)-dibenzena-syn-cyclononaphthalen-2 5 -carboxylate: In a 2-drum vial, a stirred suspension of methyl 4-(((2’-(4-(2-formyl-1H-indol-1-yl)butyl)-[1,1’-biphenyl]-3-yl)methyl)amino)-3-methoxy-5-nitrobenzoate (122 mg, 0.206 mmol) in 2:1 EtOH / water (20 mL) was treated with sodium dithionite (264 mg, 2.062 mmol). The reaction was stirred at 80 °C for 2 hours. By LCMS, a 5:1 starting material / product was detected. After stirring for an additional 2 hours at 80 °C, LCMS detected the same ratio. The mixture was cooled to room temperature and treated with sodium dithionite (134 mg, 1.048 mmol). The vial was sealed and the reaction was stirred at 80 °C for 2 hours, at which point the reaction was judged to be complete by LCMS. Some ethanol was evaporated and the remaining mixture was poured into ethyl acetate (25 mL). The turbid solution was washed 3 times with water and once with brine, then dried over sodium sulfate and concentrated in vacuo. The residue was subjected to chromatography via MPLC on a 12 g silica gel column (eluting at 30 mL / min with 20% ethyl acetate / hexane). The fractions containing the desired product were pooled and concentrated in vacuo to give the title compound (55 mg, 0.102 mmol, 49.2% yield) as an off-white solid. 11H NMR (499 MHz, chloroform-d) δ 8.18 (d, J = 1.3 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 1.2 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.28 - 7.23 (m, 2H), 7.19 - 7.09 (m, 4H), 7.08 - 7.02 (m, 4H), 6.63 (s, 1H), 6.29 (d, J = 15.1 Hz, 1H), 6.06 (d, J = 15.1 Hz, 1H), 5.29 (dt, J = 14.5, 4.7 Hz, 1H), 4.31 (ddd, J = 14.2, 10.1, 3.8 Hz, 1H), 4.17 (s, 3H), 3.98 (s, 3H), 2.26 (ddd, J = 13.3, 11.1, 6.3 Hz, 1H), 2.01 (ddd, J = 13.5, 10.3, 3.5 Hz, 1H), 1.36 - 1.17 (m, 2H), 0.84 - 0.71 (m, 1H); LCMS retention time = 1.20 minutes, MS ESI m / z = 542.4 (M + H) (Method 3)

[0185]

Chem.

[0186]

Chem.

[0187] Table 2 The following compounds can be prepared by the procedure described in Example 21, using 1H - pyrrolo[2,3 - b]pyridine - 2 - carbaldehyde instead of 1H - indole - 2 - carbaldehyde in Step 1 and / or 1 - bromo - 2-(3 - bromopropoxy)benzene instead of 1 - bromo - 2-(4 - bromobutyl)benzene, and using an appropriate benzylamine derivative instead of (3 - bromophenyl)methanamine in Step 3, or using tert - butyl ((1R,4R,7R)-2 - azabicyclo[2.2.1]heptan - 7 - yl)carbamate instead of tert - butyl ((3R,5R)-5 - fluoropiperidin - 3 - yl)carbamate in Step 7 of Example 21.

[0188]

Table 10

Table 11

Table 12

Table 13

Table 14

[0189] Examples 37 and 38 2 5 -((1R,4R,7R)-7-Amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-2 7 -Methoxy-1 1 H,2 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridine-4(3,1)-pyrrolidine-5(1,2)-benzenacyclononaphane-4 5 -one·TFA (Isomer 1 and Isomer 2)

Chemical formula

[0190]

Chemical formula

[0191]

Chemical formula

[0192]

Chem.

[0193] [Chemical] Step 4: Methyl 2 7 -Methoxy-4 5 -Oxo-1 1 H,2 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridine-4(3,1)-pyrrolidina-5(1,2)-benzenacyclononaphane-2 5 -Carboxylate: A stirred mixture of methyl 2-(1-(4-(2-bromophenyl)butyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-((5-oxopyrrolidin-3-yl)methyl)-1H-benzo[d]imidazole-5-carboxylate (117 mg, 0.186 mmol), Xantphos (32.2 mg, 0.056 mmol), Pd2(dba)3 (16.99 mg, 0.019 mmol), and cesium carbonate (91 mg, 0.278 mmol) in dioxane (5 mL) was subjected to degassing by passing nitrogen through it for 10 minutes. The vial was sealed and the reaction was stirred at 110 °C for 18 hours, at which point the reaction was judged to be complete by LCMS. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was subjected to chromatography via MPLC on 24 g of silica gel (eluting at 40 mL / min with a gradient of 1% - 7% methanol / dichloromethane over 15 column volumes). The fractions containing the desired product were pooled and concentrated under vacuum to give the title compound (80 mg, 0.146 mmol, 78% yield). LCMS retention time = 0.89 minutes, MS ESI m / z = 550.3 (M+H) (Method 3)

[0194] [Chemical] Step 5: 2 7 -Methoxy-4 5 -Oxo-1 1 H,2 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridine-4(3,1)-pyrrolidina-5(1,2)-benzenacyclononaphane-2 5 -Carboxylic acid: The labeled compound was prepared from methyl 2 7 -methoxy-4 5 -oxo-1 1 H,2 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridine-4(3,1)-pyrrolidina-5(1,2)-benzenacyclononaphthalene-2 5 -carboxylate. LCMS retention time = 0.78 minutes, MS ESI m / z = 536.3 (M+H) (Method 3)

[0195] [Chemical formula] Step 6: tert-Butyl ((1R,4R,7R)-2-(2 7 -methoxy-4 5 -oxo-1 1 H,2 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridine-4(3,1)-pyrrolidina-5(1,2)-benzenacyclononaphthalene-2 5 -carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate, (isomers 1 and 2): 2 7 -methoxy-4 5 -oxo-1 1 H,2 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridine-4(3,1)-pyrrolidina-5(1,2)-benzenacyclononaphthalene-2 5A stirred solution of carboxylic acid (78 mg, 0.146 mmol), tert-butyl ((7R)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate (34.1 mg, 0.161 mmol), and triethylamine (0.061 mL, 0.438 mmol) was treated with BOP (71.0 mg, 0.161 mmol). The reaction was brought to room temperature and stirred for 4 hours, at which point the reaction was judged to be complete by LCMS. The reaction mixture was subjected to chromatography via MPLC on a 24 g silica gel column (eluting at 40 mL / min with a gradient of 1% - 20% [7M ammonia in methanol] / dichloromethane over 15 column volumes). The fractions containing the desired product were pooled and concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed twice with 10% lithium chloride and once with brine, then dried over sodium sulfate and concentrated in vacuo. The residue was subjected to chromatography via MPLC on an ISCO GOLD 40 g silica gel column (eluting at 40 mL / min with a gradient of 2% - 10% 7M ammonia in methanol / dichloromethane over 15 column volumes). The fractions containing the desired product were pooled and concentrated in vacuo to give the title compound (77 mg, 0.105 mmol, 72.3% yield) as a mixture of diastereomers. LCMS retention time = 0.87 minutes, MS ESI m / z = 730.5 (M+H) (Method 3). The isomers were separated by SFC using the conditions shown below to give 37 mg of isomer 1 (first eluate). LCMS retention time = 0.87 minutes, MS ESI m / z = 730.5 (M+H) (Method 3); and 35 mg of isomer 2 (next eluate). LCMS retention time = 0.87 minutes, MS ESI m / z = 730.5 (M+H) (Method 3)

[0196] Preparative chromatography conditions: Apparatus: Berger SFC Column: AD 25x3 cm ID, 5 mm Temperature: 40 °C Flow rate: 85 mL / min Mobile phase: 60 / 40 CO2 / IPA Detector wavelength: 215 nm Injection volume: 1000 μL Sample preparation: Dissolve 70 mg of the sample in 2 mL of IPA / 1 mL of MeOH

[0197]

Chemical formula

[0198] Step 7-2: Example 38: tert-Butyl ((7R)-2-(2 7 -Methoxy-4 5 -Oxo-1 1 H,2 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridine-4(3,1)-pyrrolidina-5(1,2)-benzenacyclononaphane-2 5A stirred solution of ((1S,3S,4R)-3-((R)-1-(3-(trifluoromethyl)phenyl)ethylcarbamoyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate (isomer 2) (37 mg, 0.051 mmol) in dichloromethane (1 mL) was treated with TFA (1 mL). The reaction was stirred at room temperature for 1 h at which point the reaction was judged complete by LCMS. The mixture was concentrated 3x from dichloromethane to remove residual TFA and the remaining material was purified via preparative LC / MS using the following conditions: column: XBridge C18, 200 mm x 19 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile:water + 0.05% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water + 0.05% trifluoroacetic acid; gradient: hold at 11% B for 0 min, go from 11 - 51% B over 20 min then hold at 100% B for 0 min; flow rate: 20 mL / min; column temperature: 25 °C. Collection of fractions was initiated by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation. The purified material was then diluted with a 1:1 mixture of ethylene dichloride and methanol (EDM), treated with Si-pyridine and shaken for at least 2 h. The resulting mixture was filtered and dried via centrifugal evaporation to give the title compound (26.0 mg, 0.035 mmol, 69% yield). 1 H NMR (500 MHz, DMSO-d6) (rotamer) δ 8.46 (brs,0.2H), 8.32 (brd, J = 3.7 Hz,0.8H), 8.14 (brd, J = 7.9 Hz,0.2H), 8.07 (brd, J = 7.9 Hz,0.8H), 7.65 - 7.55 (m,0.4H), 7.51 - 7.41 (m,0.6H), 7.31 - 7.26 (m,1H), 7.20 - 6.99 (m,7H), 5.31 - 4.86 (m,4H), 4.61 - 4.52 (m,0.4H), 4.34 - 4.18 (m,0.6H), 4.06 (brs,3H), 3.63 - 3.56 (m,1H), 3.47 - 3.13 (m,3H), 2.86 - 2.59 (m,2H), 2.49 - 2.22 (m,2H), 2.09 - 1.61 (m,8H), 1.55 - 1.13 (m,3H), 0.67 - 0.36 (m,1H); MS ESI m / z 630.2 (M+H); analytical HPLC retention time: 1.44 min (method 1)

[0199] Example 39 ((1R,4R,7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)((cis)-6,7-dihydroxy-2 7 -methoxy-1 1 H,2 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridine-4(1,3),5(1,2)-dibenzenacyclononaphan-2 5 -yl)methanone (isomer 1)

Chemical formula

[0200]

Chemical formula

[0201]

Chemical formula

[0202]

Chemical formula

[0203] [Chemical formula] Step 4: Methyl 2-(1-(but-3-en-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-((5-(2-vinylphenyl)pyridin-3-yl)methyl)-1H-benzo[d]imidazole-5-carboxylate: In a 2-drum vial, a stirred mixture of methyl 1-((5-bromopyridin-3-yl)methyl)-2-(1-(but-3-en-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate (189 mg, 0.346 mmol), (2-vinylphenyl)boronic acid (77 mg, 0.519 mmol), and 2 M tripotassium phosphate (0.692 mL, 1.384 mmol) in dioxane (4 mL) was subjected to degassing by passing nitrogen through it for 10 minutes. XPhos-Pd G2 (26.6 mg, 0.035 mmol) was added and degassing was continued for an additional 10 minutes. At this point, the volume of the solution had decreased to approximately half. The vial was sealed and the reaction mixture was stirred at 50 °C for 6 hours and then at room temperature for 14 hours, at which point the reaction was judged to be complete by LCMS. The mixture was diluted with ethyl acetate (20 mL) and filtered, and the filtrate was washed 3 times with water and once with brine. The aqueous phases were combined, extracted once with ethyl acetate, the organic phases were combined, dried over sodium sulfate, and concentrated under vacuum. The residue was subjected to chromatography via MPLC on a 40 g silica gel column (eluting at 40 mL / min with a gradient of 20% - 100% ethyl acetate / hexane over 10 column volumes) to elute the desired product. The fractions containing the desired product were pooled and concentrated under vacuum to give the title compound (170 mg, 0.298 mmol, 86% yield). LCMS retention time = 0.97 minutes, MS ESI m / z = 570.3 (M+H) (method 3)

[0204]

Chemical formula

[0205]

Chem.

[0206]

Chemical Structure

[0207]

Chemical Structure

[0208] Preparative chromatography conditions: Apparatus: SFC 150 Column: YMC SB 25x3 cm ID, 5 μm Temperature: 40 °C Flow rate: 100 mL / min Mobile phase: 65 / 35 CO2 / EtOH Detector wavelength: 220 nm Injection volume: 1 mL Sample preparation: 44 mg of the sample was dissolved in MeOH

[0209] The fraction containing the initially eluted peak was pooled and concentrated under vacuum to give the compound (4 mg, 0.053 mmol, 14.5% yield). LCMS retention time = 1.54 minutes, MS ESI m / z = 756.3 (M+H) (Method 6). The material was dissolved in dichloromethane (1 mL) and the solution was treated with TFA (0.25 mL). The reaction mixture was stirred at room temperature for 1 hour, at which point the reaction was judged to be complete by LCMS. The mixture was concentrated 3x from dichloromethane and 3x from methanol to remove the remaining TFA. The residue was dissolved in 1:1 dichloromethane / methanol and the mixture was treated with 3 mg of PVP resin. The mixture was shaken for 2 hours, then filtered and concentrated. The residue was dissolved in 2:1 acetonitrile / water and the solution was lyophilized to give the title compound (4 mg, 4.94 micromol, 93% yield). 1 H NMR (499 MHz, methanol-d4) δ 8.52 - 8.35 (m, 2H), 8.23 (dd, J = 7.9, 1.3 Hz, 1H), 7.62 - 7.51 (m, 2H), 7.44 (s, 1H), 7.38 (td, J = 7.6, 1.0 Hz, 1H), 7.30 - 7.24 (m, 2H), 7.23 - 7.19 (m, 1H), 7.06 (d, J = 7.3 Hz, 1H), 7.01 (s, 1H), 6.42 (brd, J = 15.6 Hz, 1H), 6.30 - 6.15 (m, 1H), 5.17 - 4.96 (m, 2H), 4.81 - 4.69 (m, 1H), 4.43 - 4.23 (m, 3H), 4.00 (brd, J = 3.1 Hz, 1H), 3.89 - 3.61 (m, 2H), 3.40 (brd, J = 11.6 Hz, 1H), 2.90 - 2.62 (m, 2H), 2.20 (brd, J = 13.6 Hz, 1H), 2.08 - 1.96 (m, 2H), 1.94 - 1.61 (m, 2H), 1.01 - 0.81 (m, 2H); MS ESI m / z 656.3 (M+H); analytical HPLC retention time: 0.61 minutes, (Method 3)

[0210] Example 40 21-((1R,4R,7R)-7-Amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-19-methoxy-7,8,16,17-tetrahydro-6H-benzo[b]benzo[4,5]imidazo[1,2-h]pyrido[3’,2’:4,5]pyrrolo[2,1-j][1]oxa[4,8,11]triazacyclotetradecin-15(14H)-one

Chem.

[0211]

Chem.

[0212]

Chem.

[0213]

Chem.

[0214]

Chemical Structure

[0215] [Chemistry] Step 5: 3-(2-(1-(3-(2-Aminophenoxy)propyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-5-(methoxycarbonyl)-1H-benzo[d]imidazol-1-yl)propanoic acid·3HCl A stirred solution of methyl 2-(1-(3-(2-aminophenoxy)propyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(3-(tert-butoxy)-3-oxopropyl)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate (98 mg, 0.163 mmol) in dichloromethane (3 mL) was treated with 4M HCl in dioxane (2 mL). The reaction was stirred at room temperature for 18 h at which point the reaction was judged complete by LCMS. The mixture was concentrated 3x from dichloromethane to afford the title compound which was used immediately in the next step. LCMS retention time = 0.71 min, MS ESI m / z = 544.2 (M+H) (Method 3)

[0216] [Chemistry] Step 6: Methyl 19-methoxy-15-oxo-7,8,14,15,16,17-hexahydro-6H-benzo[b]benzo[4,5]imidazo[1,2-h]pyrido[3’,2’:4,5]pyrrolo[2,1-j][1]oxa[4,8,11]triazacyclotetradecine-21-carboxylate 3-(2-(1-(3-(2-Aminophenoxy)propyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-5-(methoxycarbonyl)-1H-benzo[d]imidazol-1-yl)propanoic acid·3HCl (106 mg, 0.163 mmol) and triethylamine (0.227 mL, 1.630 mmol) in DMF (2 mL) were treated with HATU (74.4 mg, 0.196 mmol), and the reaction mixture was stirred at room temperature for 3 h, at which point the reaction was judged complete by LCMS. The mixture was poured into ethyl acetate (30 mL), and the solution was washed three times with 10% lithium chloride and once with brine, then dried over sodium sulfate and concentrated in vacuo. The residue was subjected to chromatography via MPLC on an ISCO GOLD 24 g silica gel column (eluting at 40 mL / min with a gradient of 20% - 100% ethyl acetate / hexane over 15 column volumes). The fractions containing the desired product were pooled and concentrated in vacuo to afford the title compound (50 mg, 0.095 mmol, 58.4% yield). LCMS retention time = 0.80 min, MS ESI m / z = 526.2 (M + H) (Method 3)

[0217]

Chemical Structure

[0218]

Chem.

[0219]

Chem.

[0220] [Chemical formula]

[0221] Step 2: 1-(Hex-5-en-1-yl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde: To a 20 mL vial, 1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (200 mg, 1.368 mmol), K2CO3 (567 mg, 4.11 mmol) / DMF (4562 μL) were added. The solution was stirred at room temperature for 30 minutes. The mixture was stirred and treated with hex-5-en-1-yl 4-methylbenzenesulfonate (383 mg, 1.505 mmol), and the solution was heated to 80 °C until completion by LCMS. The reaction was diluted with ethyl acetate, washed 3 times with LiCl (10%), once with water and once with brine, dried over sodium sulfate and evaporated to dryness. The mixture was subjected to MPLC and purified using a gradient of 15% - 25% ethyl acetate / hexane. The fractions containing the desired product were collected and concentrated under vacuum to give the title compound (150 mg, yield 48%). 11H NMR (499 MHz, DMSO-d6) δ 10.13 - 9.78 (m, 1H), 8.74 - 8.42 (m, 1H), 8.42 - 8.07 (m, 1H), 7.62 - 7.37 (m, 1H), 7.37 - 7.08 (m, 1H), 5.86 - 5.57 (m, 1H), 5.12 - 4.78 (m, 2H), 4.78 - 4.39 (m, 2H), 2.17 - 1.87 (m, 2H), 1.87 - 1.52 (m, 2H), 1.52 - 1.21 (m, 2H); LCMS Tr = 0.97 minutes, MS ESI m / z = 229.2 (M + H) (Method 3)

[0222]

Chem.

[0223]

Chem.

[0224]

Chemical formula

[0225]

Chemical Structure

[0226]

Chem.

[0227]

Chemical Structure

[0228]

Chem.

[0229]

Chem.

[0230]

Chemical formula

[0231]

Chemical formula

[0232]

Chemical formula

[0233]

Chemical formula

[0234]

Chemical Structure

[0235]

Chem.

[0236] [Chemical Structure] Example 44 ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptan-2-yl)((5 1 S,5 2 R)-5 3 ,5 3 -difluoro-2 7 -methoxy-1 1 H,2 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridina-4(1,3)-benzena-5(1,2)-cyclopropanacyclononaphan-2 5 -yl)methanone

[0237]

Chemical formula

[0238]

Chemical formula

[0239]

Chemical formula

[0240] Using the intermediate from Step 5 of Example 41, the following compounds listed in Table 3 were produced according to the procedure described in Example 39.

[0241] Table 3

Table 15

Table 16

[0242]

Chem.

[0243] Using the intermediate from Step 5 of Example 41 and using (3R,5R)-5-fluoropiperidin-3-amine instead of (1R,4R,7R)-2-azabicyclo[2.2.1]heptan-7-amine, the above-described compound was produced according to the procedure described in Example 41. LCMS Tr = 1.75 minutes, MS ESI m / z = 579.3 (M+H) (Method 2)

[0244] Example 52 ((3R,5R)-3-Amino-5-fluoropiperidin-1-yl)(16-(2-hydroxypropan-2-yl)-2 7 -methoxy-1 1 H,2 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridine-4(3,5)-pyridine-5(1,2)-benzenacyclononane-2 5 -yl)methanone

Chem.

[0245]

Chem.

[0246]

Chem.

[0247]

Chemical Structure

[0248] [Chemical formula] Step 4: 6-(2-Hydroxypropan-2-yl)-N-methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide: In a dry flask, a stirred solution of tert-butyl 6-acetyl-2-(methoxy(methyl)carbamoyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (600 mg, 1.727 mmol) in anhydrous THF (10 mL) was cooled to -78 °C and treated by dropwise addition of methylmagnesium chloride (3 M in ether) (0.691 mL, 2.073 mmol). The reaction was stirred at -78 °C for 2 h and then quenched with half-saturated ammonium chloride. The mixture was brought to room temperature. The cloudy mixture was extracted three times with ethyl acetate, then the organic phases were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to chromatography via MPLC on an ISCO GOLD 40 g silica gel column (eluting at 40 mL / min with a gradient of 15% - 35% ethyl acetate / hexane over 15 column volumes). The fractions containing the desired product were pooled and concentrated in vacuo to give tert-butyl 6-(2-hydroxypropan-2-yl)-2-(methoxy(methyl)carbamoyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (287 mg, 0.790 mmol, 45.7% yield) as a slightly amber solid. LCMS retention time = 0.74 min, MS ESI m / z = 364.2 (M+H) (Method 3). A stirred solution of tert-butyl 6-(2-hydroxypropan-2-yl)-2-(methoxy(methyl)carbamoyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (387 mg, 1.065 mmol) in dichloromethane (5 mL) was treated with TFA (2 mL). The reaction was stirred at room temperature for 1 h at which point the reaction was judged complete by LCMS. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated sodium carbonate. After stirring for 10 min, the layers were separated and the organic phase was washed twice with saturated sodium carbonate. The aqueous phases were combined, extracted twice with ethyl acetate, then the organic phases were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo to give the title compound (259 mg, 0.984 mmol, 92% yield). LCMS retention time = 0.62 min, MS ESI m / z = 264.2 (M+H) (Method 3)

[0249] [Chemical formula] Step 5: 1-(4-(2-Bromophenyl)butyl)-6-(2-hydroxypropan-2-yl)-N-methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide: In a 40 mL scintillation vial, a stirred mixture of 6-(2-hydroxypropan-2-yl)-N-methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (259 mg, 0.984 mmol) and potassium carbonate (408 mg, 2.95 mmol) in anhydrous DMF (3 mL) was treated with 4-(2-bromophenyl)butyl 4-methylbenzenesulfonate (377 mg, 0.984 mmol). The vial was sealed and the reaction mixture was stirred at 70 °C for 48 h, at which point the reaction was judged to be complete by LCMS. The mixture was diluted with ethyl acetate (25 mL) and the turbid solution was washed once with water, twice with 10% lithium chloride solution, and once with brine, then dried over sodium sulfate and concentrated in vacuo. The residue was adsorbed onto celite and subjected to chromatography via MPLC on a 40 g silica gel column (eluting at 40 mL / min with a gradient of 0% - 100% ethyl acetate / hexane over 15 column volumes). The fractions containing the desired product were pooled and concentrated in vacuo to give the title compound (400 mg, 0.843 mmol, 86% yield). LCMS retention time = 1.04 min, MS ESI m / z = 474.1 (M+H) (Method 3)

[0250] [Chemical formula] Step 6: 1-(4-(2-Bromophenyl)butyl)-6-(2-hydroxypropan-2-yl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde: A stirred solution of 1-(4-(2-bromophenyl)butyl)-6-(2-hydroxypropan-2-yl)-N-methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (390 mg, 0.822 mmol) in anhydrous THF (5 mL) was cooled to -78 °C and treated with DIBAL-H (1 M in dichloromethane) (1.644 mL, 1.644 mmol). The reaction was allowed to warm to 0 °C and stirred for 1 h at which point the reaction was judged complete by LCMS. The reaction was quenched with ice cold water and stirred for 5 min to give a viscous gel-like mixture. The mixture was diluted with ethyl acetate (100 mL) and 30 mL of saturated Rochelle salt solution and stirred vigorously for 18 h. The now clear two-phase solution was separated and the organic phase was washed twice with water. The aqueous phases were combined, extracted once with ethyl acetate, then the organic phases were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was adsorbed onto celite and subjected to chromatography via MPLC on an ISCO GOLD 40 g silica gel column eluting at 40 mL / min with a gradient of 0% - 100% acetone / hexanes over 25 column volumes. The fractions containing the desired product were pooled and concentrated in vacuo to give the title compound (192 mg, 0.462 mmol, 56.2% yield). LCMS retention time = 1.09 min, MS ESI m / z = 415.0 (M+H) (Method 3)

[0251] [Chemical Formula] Step 7: Example 52 DG21: The title compound can be prepared from 1-(4-(2-bromophenyl)butyl)-6-(2-hydroxypropan-2-yl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde using Example 21. 11H NMR (500 MHz, chloroform-d) δ 8.83 (dd, J = 7.5, 1.9 Hz, 1H), 8.38 (t, J = 2.1 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.28 - 7.23 (m, 1H), 7.22 - 7.17 (m, 2H), 7.15 (d, J = 7.5 Hz, 1H), 7.08 (ddd, J = 7.5, 3.4, 1.2 Hz, 1H), 7.07 - 7.03 (m, 1H), 7.03 - 7.00 (m, 1H), 6.99 (s, 1H), 6.25 (d, J = 15.0 Hz, 1H), 6.08 (d, J = 15.0 Hz, 1H), 5.29 (brd, J = 6.0 Hz, 1H), 5.16 - 4.65 (m, 4H), 4.18 (s, 3H), 3.37 (brs, 1H), 3.28 - 3.10 (m, 1H), 2.88 - 2.51 (m, 1H), 2.47 - 2.33 (m, 2H), 1.93 - 1.83 (m, 1H), 1.80 - 1.68 (m, 1H), 1.61 (s, 6H), 1.59 - 1.45 (m, 3H), 1.20 - 1.05 (m, 1H), 0.81 - 0.62 (m, 1H); LCMS retention time = 0.73 minutes, MS ESI m / z = 688.3 (M + H) (Method 3)

[0252] Example 53 ((1R,4R,7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(16-(2-hydroxypropan-2-yl)-2 7 -methoxy-1 1 H,2 1 H-1,2(2,1)-dipyrrolo[2,3-b]pyridine-4(3,5)-pyridine-5(1,2)-benzenacyclononaphthalen-2 5 -yl)methanone

Chemical Structure

[0253] The title compound can be prepared from 1-(4-(2-bromophenyl)butyl)-6-(2-hydroxypropan-2-yl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde using Example 21. 11H NMR (500 MHz, chloroform-d) δ 8.85 - 8.79 (m, 1H), 8.40 - 8.32 (m, 1H), 7.99 (dd, J = 8.1, 1.8 Hz, 1H), 7.57 - 7.50 (m, 1H), 7.27 - 7.22 (m, 1H), 7.21 - 7.17 (m, 2H), 7.16 - 7.06 (m, 3H), 7.06 - 7.01 (m, 1H), 6.99 (s, 1H), 6.32 - 6.20 (m, 1H), 6.13 - 6.00 (m, 1H), 5.29 (d, J = 6.3 Hz, 1H), 5.13 - 4.96 (m, 2H), 4.19 (d, J = 3.2 Hz, 3H), 4.11 - 3.96 (m, 1H), 3.82 - 3.65 (m, 1H), 3.53 - 3.36 (m, 1H), 3.32 - 3.17 (m, 1H), 2.45 - 2.23 (m, 2H), 2.19 - 1.82 (m, 4H), 1.79 - 1.68 (m, 1H), 1.68 - 1.62 (m, 1H), 1.59 (brs, 2H), 1.56 - 1.44 (m, 2H), 1.13 (brs, 3H), 0.81 - 0.59 (m, 1H) LCMS retention time = 0.69 minutes, MS ESI m / z = 682.4 (M + H) (Method 3)

[0254] 7. Biological Assay The compounds of the present invention were assayed as inhibitors of PAD4 using the assay protocol described below.

[0255] RFMS Human PAD4 Function Assay: The compounds were solubilized in 100% DMSO and the concentration of the compounds was made 10 mM. The stock solution of the compounds was stored at room temperature. A series of dilutions were prepared in DMSO and mixed 8 times with a mixing volume of 20 μL. The final highest concentration of the compounds in the assay was 50 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, 50 μM calcium, and 5 μM TPEN Final concentration: 5 nM hPAD4 enzyme, 250 μM BAEE, and 0.5% DMSO Total incubation time: Subjected to pre-incubation of the compound and enzyme for 30 minutes at 37°C, enzyme / substrate reaction for 90 minutes at 37°C, and reaction with phenylglyoxal for 30 minutes Stop solution: 5% TCA in 40 μl ACN It was.

[0256] A solution of the compound (0.13 μL) was added to PAD4 (13 μL) in 10 nM assay buffer. After 30 minutes, 500 μM BAEE (13 μl) was added to 25 mM hepes, pH 7.5, 5 mM NaCl, 1 mM DTT, 0.2 mg / ml BSA, 0.01% CHAPS, 50 μM calcium, 5 μM TPEN, and the reaction was incubated at 37°C for 90 minutes. 6.1 N TCA (15 μl) was added to quench the enzyme reaction, with a final concentration of 100% being 20%, then 35 μl of 8.5 mM phenylglyoxal (final concentration 4 mM) was added, and the reaction was incubated at 37°C for 30 minutes.

[0257] After 30 minutes, the plate was spun down to remove all precipitates. The enzyme reaction was quenched with an equal volume of methanol containing the internal standard (modified citrulline). The samples were loaded onto a Rapid Fire RF300 system (Agilent), where they were first immersed for 1000 milliseconds and then directly loaded onto a C18 separation cartridge using a mixture of acetonitrile containing 0.01% formic acid for 3000 milliseconds for desalting. The flow rate of the mobile phase was 1.5 ml / min. When the sample eluted from the cartridge, the sample was transferred to the mass spectrometer at a flow rate of 1.25 ml / min for 4000 milliseconds using a mobile phase of acetonitrile containing 0.01% formic acid. Peptidylcitrulline and internal standard ions were analyzed using a Sciex API5500 triple quadrupole mass spectrometer (Applied Biosystems) equipped with ESI.

[0258] The MRM transitions of the product and the internal standard were monitored at m / z 424.5 - 350.4 and m / z 293 - 247, respectively. The retention time for each transition was set to 200 milliseconds, and the ESI voltage was used at 5500 with a source temperature of 400 °C. The ion peaks extracted for each transition were integrated using Rapid Fire Integrator software. The peak area of the analyte was normalized using the internal standard.

[0259] For the compounds of the given examples, Table 4 below shows the IC of human PAD4 (hPAD4) in the Rapid-Fire Mass Spectrometry (RFMS) assay. 50 is shown. Table 4. PAD4 Activity [Table 17] [Table 18]

Claims

1. Formula (II): 【Chemical 1】 [Wherein: Q is selected from the group consisting of N and CH; 【Chemical Formula 3】 is 【Chemical 4】 selected from the group consisting of; A １ is C １－４ alkyl (substituted with 0 to 2 Rs １ ); one or more methylene units of the C １－４ alkylene may be replaced with NH, N(C １－４ alkyl), and C(=O); A ２ is selected from the group consisting of C ６ aryl, and 4- to 6-membered heterocyclyl containing a carbon atom and 1 to 4 heteroatoms selected from N, O, and S(O) ｐ , each being substituted with 0 to 2 R ２ ; A ３ is selected from the group consisting of C ３－６ cycloalkyl, C ６ aryl, and a 4- to 6-membered heterocyclyl containing a carbon atom and 1 to 4 heteroatoms selected from N, O and S(O) ｐ each being substituted with 0 to 2 R ２ ; provided that both A2 and A3 are not (A2)0 and (A3)0; A ４ is selected from the group consisting of C ３－７ alkylene and C ３－７ alkenylene, each being substituted with 0 to 5 R １ ; one to three methylene units of the C ３－７ alkylene, except those directly bonded to the nitrogen atom of the indole or pyrrolopyridine moiety, may be replaced by O, S(O) ｐ , NH, N(C １－４ alkyl), and C(=O); R １ is selected from the group consisting of F, Cl, and -OR ｂ ; R ２ is selected from the group consisting of F, Cl, CN, =O, and C(=O)NR ａ R ａ ; R ３ is selected from the group consisting of F, Cl, Br, and -OC １－４ alkyl; R ４ is selected from the group consisting of F, Cl, C １－５ alkyl, C １－５ haloalkyl and C １－５ hydroxyalkyl; R ａ is each independently selected from the group consisting of H and C １－５ alkyl; R ｂ is independently selected from the group consisting of H and C １－５ alkyl; and p is an integer selected from 0, 1, and 2, respectively] A compound represented by, or a pharmaceutically acceptable salt thereof.

2. Formula (III): 【Chemical Formula 4】 [Wherein: 【Chemical Formula 6】 is 【Chemical Formula 7】 selected from the group consisting of; A ２ is selected from the group consisting of C ６ aryl, and 4- to 6-membered heterocyclyl containing a carbon atom and 1 to 4 heteroatoms selected from N, O and S(O) ｐ , each being substituted with 0 to 2 R ２ ; A ３ is selected from the group consisting of C ３－６ cycloalkyl, C ６ aryl, and a 4- to 6-membered heterocyclyl containing a carbon atom and 1 to 4 heteroatoms selected from N, O, and S(O) ｐ , each being substituted with 0 to 2 R ２ ; A ４ is selected from the group consisting of C ３－７ alkylene and C ３－７ alkenylene, each being substituted with 0 to 5 R １ ; one or more methylene units of the C ３－７ alkylene, except those directly bonded to the nitrogen atom of the indole or pyrrolopyridine moiety, may be replaced by O, S(O) ｐ , NH, and N(C １－４ alkyl); R １ is selected from the group consisting of F, Cl, and -OR ｂ ; R ２ is selected from the group consisting of F, Cl, CN, =O, and C(=O)NR ａ R ａ ; R ３ is selected from the group consisting of F, Cl, Br, and -OC １－４ alkyl; R ４ is selected from the group consisting of F, C １－４ alkyl, C １－４ haloalkyl and C １－４ hydroxyalkyl; R ａ is each independently selected from the group consisting of H and C １－５ alkyl; and R ｂ is independently selected from the group consisting of H and C １－５ alkyl], respectively A compound according to claim 1, or a pharmaceutically acceptable salt thereof, represented by.

3. Formula (IV): 【Chemical Formula 7】 [Wherein: 【Chemical Formula 9】 is 【Chemical Formula 10】 selected from the group consisting of; A ２ is selected from the group consisting of C ６ aryl, and 5- or 6-membered heterocyclyl containing a carbon atom and 1 to 4 heteroatoms selected from N, O and S(O) ｐ each being substituted with 0 to 2 R ２ ; A ４ is selected from the group consisting of C ３－７ alkylene and C ３－７ alkenylene, each being substituted with 0 to 5 R １ ; one or more methylene units of the C ３－７ alkylene may be replaced by O, NH, and N(C １－４ alkyl); R １ is selected from the group consisting of F and -OR ｂ ; R ２ is selected from the group consisting of F, CN, =O, and C(=O)NR ａ R ａ and; and R ４ is selected from the group consisting of C １－３ alkyl, C １－３ haloalkyl and C １－３ hydroxyalkyl]] A compound according to claim 2, or a pharmaceutically acceptable salt thereof, represented by.

4. Formula (V): 【Chemical 10】 [Wherein: A ４ is selected from the group consisting of C ３－７ alkylene and C ３－７ alkenylene, each being substituted with 0 to 5 R １ ; one or more methylene units of the C ３－７ alkylene may be replaced by O and NH, except those directly bonded to the nitrogen atom of the indole or pyrrolopyridine moiety; R １ is selected from the group consisting of F and -OH; R ２ is selected from the group consisting of F, CN, and C(=O)NH ２ ; and R ４ is selected from the group consisting of C １－４ haloalkyl and C １－４ hydroxyalkyl]] A compound according to claim 3, or a pharmaceutically acceptable salt thereof, represented by.

5. A ４ is C ３－７ alkylene, -OC3-6 alkylene, and C ３－７ The compound according to claim 4, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkenylene.

6. Formula (VI): 【Chemical 11】 [Wherein: A ４ is selected from the group consisting of C ３－７ alkylene, -OC3-6 alkylene, and C ３－７ alkenylene, each being substituted with 0 to 5 R １ ; R １ is - OR ｂ and C １－３ is selected from the group consisting of alkyl; R ２ is selected from the group consisting of F and CN; R ３ is - OC １－４ alkyl; R ４ is C １－３ haloalkyl and C １－３ selected from the group consisting of hydroxyalkyl; and R ｂ are each independently selected from the group consisting of H and C １－３ alkyl] A compound according to claim 3, or a pharmaceutically acceptable salt thereof, represented by.

7. 【Fig. 12】 is 【Chemical Formula 14】 ; A ４ is C ３－５ an alkylene; R ３ is -OCH ３ The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein R is -OCH

8. Formula (VII): 【Chemical Formula 14】 [Wherein: A ２ is 【Chemical 16】 selected from the group consisting of; A ４ is selected from the group consisting of C ３－６ alkylene, -OC ３－６ alkylene, and C ３－６ alkenylene, each being substituted with 0 to 5 R １ ; and R ２ is selected from the group consisting of F and =O] A compound according to claim 3, or a pharmaceutically acceptable salt thereof, represented by.

9. Formula (VIII): 【Chemical Formula 16】 [Wherein: 【Chemical 18】 is 【Chemical Formula 19】 selected from the group consisting of; A ３ is selected from the group consisting of C ３－６ cycloalkyl, and 4- to 6-membered heterocyclyl containing a carbon atom and 1 to 4 heteroatoms selected from N, O and S(O) ｐ each of which is substituted with 0 to 2 R ２ ; A ４ is selected from the group consisting of C ３－７ alkylene and C ３－７ alkenylene, each being substituted with 0 to 5 R １ ; one or two methylene units of the C ３－７ alkylene may be replaced by O, S(O) ｐ , NH, and N(C １－４ alkyl); R １ is selected from the group consisting of F and -OR ｂ ; R ２ is selected from the group consisting of F, Cl, and CN; R ３ is selected from the group consisting of F, Cl, and -OC １－４ alkyl; R ４ is selected from the group consisting of C １－４ alkyl, C １－４ haloalkyl and C １－４ hydroxyalkyl; R ａ is each independently selected from the group consisting of H and C １－４ alkyl; and R ｂ each independently selected from the group consisting of H and C １－４ alkyl]] A compound according to claim 2, or a pharmaceutically acceptable salt thereof, represented by.

10. A ３ is cyclopropyl (substituted with 0 to 2 R ２ and 【Chemical Formula 19】 selected from the group consisting of; A ４ is C ３－７ alkylene, -OC3-6 alkylene, and C ３－７ alkenylene, each of which is selected from the group consisting of 0 to 5 R １ substituted; R ２ is selected from the group consisting of F and Cl; and R ３ is -OCH ３ is, A compound according to claim 9, or a pharmaceutically acceptable salt thereof.

11. Formula (IX): 【Chemical 20】 [Wherein: 【Chemical 22】 is 【Chemical 23】 selected from the group consisting of; A ２ is selected from the group consisting of C ６ aryl, and a 4- to 6-membered heterocyclyl containing a carbon atom and 1 to 2 heteroatoms selected from N, each being substituted with 0 to 2 R ２ ; A ４ is selected from the group consisting of C ３－７ alkylene and C ３－７ alkenylene, each being substituted with 0 to 3 R １ ; one to three methylene units of the C ３－７ alkylene may be replaced by O and C(=O), except those directly bonded to the nitrogen atom of the indole or pyrrolopyridine moiety; R １ is selected from the group consisting of F, Cl, and -OH; R ２ is selected from the group consisting of F, Cl, and CN; and R ３ is selected from the group consisting of F, Cl, and -OC １－４ alkyl] A compound according to claim 1, or a pharmaceutically acceptable salt thereof, represented by.

12. Formula (X): 【Chemical 23】 [Wherein: 【Chemical Formula 25】 is 【Chemical 26】 selected from the group consisting of; A ４ is selected from the group consisting of C ３－７ alkylene (substituted with 0 to 3 R １ ), -OC3-6 alkylene, and C ３－７ alkenylene; R １ is selected from the group consisting of F and -OH; and R ３ is - OC １－４ alkyl] A compound according to claim 11, or a pharmaceutically acceptable salt thereof, represented by.

13. A ２ is 【Chemical 26】 ; A ４ is C ４－７ selected from the group consisting of alkylene and C ４－７ alkenylene; and R ３ is - OCH ３ is, A compound according to claim 11, or a pharmaceutically acceptable salt thereof.

14. Formula (XI): 【Chemical 27】 [Wherein: ​ is 【Chemical Formula 30】 selected from the group consisting of; A １ is C １－３ an alkylene, wherein one or two methylene units of the C １－３ alkylene are replaced by NH, N(C １－４ alkyl), and C(=O); A ４ is selected from the group consisting of C ３－７ alkylene, -OC3-6 alkylene, and C ３－７ alkenylene; and R ３ is selected from the group consisting of F, Cl, and -OC １－４ alkyl] A compound according to claim 1, or a pharmaceutically acceptable salt thereof, represented by.

15. Formula (XII): 【Chemical 30】 [Wherein: 【Chemical 32】 is 【Chemical 33】 selected from the group consisting of; A １ is C １－２ an alkylene; A ４ is C ３－７ alkylene, and the first two methylene units of the C ３－７ alkylene are replaced by S(=O) ２ -NH or S(=O) ２ -N(C １－３ alkyl); and R ３ is - OC １－４ alkyl] A compound according to claim 1, or a pharmaceutically acceptable salt thereof, represented by.

16. A pharmaceutically acceptable composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or excipient.

17. The composition according to claim 16, combined with a further therapeutic agent.

18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for inhibiting PAD4.

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for treating a PAD4-mediated disease, disorder or symptom selected from the group consisting of acute lymphoblastic leukemia, ankylosing spondylitis, cancer, chronic lymphocytic leukemia, colitis, lupus, rheumatoid arthritis, multiple sclerosis, and ulcerative colitis.

20. The pharmaceutical composition according to claim 19, wherein the PAD4-mediated disease, disorder or symptom is selected from rheumatoid arthritis, ulcerative colitis, and cancer.

21. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use in treatment.

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