Indole and azaindole inhibitors of pad enzymes

Abstract

The present application provides compounds of Formula (I) useful as PAD4 inhibitors, compositions thereof, and methods of treating PAD4-associated disorders, wherein each of ring A, L, Q, R1, R2, R3, R4, R7, and R8, and other variables, are as defined herein.

Description

[0001] Cross-references

[0002] This application claims U.S. Provisional Application Serial No. 62 / 715,850 (filed August 8, 2018), which is incorporated herein by reference in its entirety.

[0003] [Previous Technology]

[0004] PAD4 is a member of the peptide tyrosine deiminase (PAD) family of enzymes that catalyze the citrullination of arginine to citrulline within the peptide sequence. PAD4 causes deiminization or citrullination of a variety of proteins both in vitro and in vivo, with varying functional consequences in a range of diseases (Jones JE et al., Curr. Opin. Drug Discov. Devel., 12(5), (2009), 616-627). Examples of exemplary diseases include rheumatoid arthritis and diseases whose pathogenesis involves neutrophils, in addition to oncology indications (e.g., vasculitis, systemic lupus erythematosus, ulcerative colitis). PAD4 inhibitors also have broader applicability as tools and therapies for human diseases via epigenetic mechanisms.

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

[0006] PAD4 inhibitors are also suitable for reducing pathological neutrophil activity in various diseases. Studies have shown that the formation of neutrophil extracellular traps (NETs), the intrinsic defense mechanism by which neutrophils can fixate and kill pathogens, is associated with histone citrullination and occurs in PAD4 knockout mice (Neeli I. et al., J. Immunol., 180, (2008), 1895-1902 and LiP. et al., J. Exp. Med., 207(9), (2010), 1853-1862). Therefore, PAD4 inhibitors may be suitable for diseases where NET formation in tissues promotes local damage and disease pathology. Such diseases include (but are not limited to) small vessel vasculitis (Kessenbrock K. et al., Nat. Med., 15(6), (2009), 623-625), systemic lupus erythematosus (Hakkim A. et al., Proc. Natl. Acad. Sci. USA, 107(21), (2010), 9813-9818 and Villanueva E. et al., J. Immunol., 187(1), (2011), 538-52), ulcerative colitis (Savchenko A. et al., Pathol. Int., 61(5), (2011), 290-7), cystic fibrosis, asthma (Dworski R. et al., J. Allergy Clin. Immunol., 127(5), (2011), 1260-6), deep vein thrombosis (Fuchs T. et al., Proc. Natl. Acad. Sci. USA, 107(36), (2010), 15880-5), periostitis of the dental root (Vitkov L. et al., Ultrastructural Pathol., 34(1), (2010), 25-30), sepsis (Clark SR et al., Nat. Med., 13(4), (2007), 463-9), appendicitis (Brinkmann V. et al., Science, 303, (2004), 1532-5), and stroke. Furthermore, there are indications that NETs may contribute to lesions in skin-affecting diseases such as cutaneous lupus erythematosus (Villanueva E. et al., J. Immunol., 187(1), (2011), 538-52) and psoriasis (Lin AM et al., J. Immunol., 187(1), (2011), 490-500), so PAD4 inhibitors may show benefits in treating NET-related skin diseases when administered systemically or through the skin. PAD4 inhibitors can affect additional functions within neutrophils and have broader applicability to neutrophilic disorders.

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

[0008] PAD4 inhibitors are also applicable to the treatment of cancer (Slack JL et al., Cell. Mol. Life Sci., 68(4), (2011), 709-720). Overexpression of PAD4 has been demonstrated in numerous cancers (Chang X et al., BMC Cancer, 9, (2009), 40). The antiproliferative effect of PAD4 inhibitors has been demonstrated by the observation of citrullinated arginine residues in histones at the promoters of p53-target genes such as p21, which are involved in cell cycle arrest and apoptosis (Li P et al., Mol. Cell Biol., 28(15), (2008), 4745-4758).

[0009] The aforementioned role in the deiminization of arginine residues in histones suggests that PAD4 plays a role in the epigenetic regulation of gene expression. PAD4 is a major member of the PAD family observed to reside in the nucleus and cytoplasm. Early evidence that PAD4 can act as a histone deiminase and deiminase is inconsistent and unproven. However, it can indirectly reduce histone arginine methylation (and thus reduce epigenetic regulation associated with this marker) by converting to citrulline and eliminating available arginine residues. PAD4 inhibitors are suitable as epigenetic tools or therapies to influence the expression of altered target genes in additional disease settings. Through such mechanisms, PAD4 inhibitors can also effectively control citrullination levels in stem cells and thus therapeutically influence the pluripotency and differentiation potential of various stem cells, including (but not limited to) embryonic stem cells, neural stem cells, hematopoietic stem cells, and cancer stem cells. Therefore, there remains an unmet need to identify and develop PAD4 inhibitors for the treatment of PAD4-mediated diseases. [Summary of the Invention]

[0010] Compounds of formula (I) have now been found to be suitable as PAD4 inhibitors:

[0011]

[0012] Or a pharmaceutically acceptable salt thereof, wherein each of rings A, Q, L, R1, R2, R3, R4, R7 and R8, together with other variables, is as defined herein.

[0013] In some embodiments, the provided compounds exhibit selectivity for PAD4 relative to PAD2. The present invention also provides pharmaceutically acceptable compositions comprising the provided compounds. The provided compounds are suitable for treating a variety of conditions associated with PAD4. Such conditions 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.

[0014] [Implementation Method]

[0015] 1. General description of certain aspects of the present invention

[0016] In some embodiments, such compounds include those of the formula described herein or pharmaceutically acceptable salts thereof, wherein the variables are as defined herein and described in the embodiments. Such compounds have the structure of formula (I):

[0017]

[0018] Or its pharmaceutically acceptable salt, wherein:

[0019] Q is selected from N and CH;

[0020] Ring A is a 4- to 15-membered heterocyclic group substituted with 1 to 4 R7 groups;

[0021] R1 is selected from CH3 and CD3;

[0022] R2 is selected from H, passing through 0 to 2 C. 3-6 Cycloalkyl-substituted C 1-3 Alkyl, the C 3-6 Cycloalkyl groups via 0 to 4 F, Cl and C atoms 1-3 Alkyl substitution;

[0023] R3 is selected from H, F, Cl, Br, -OR b and through 0 to 5 R e Replacement C 1-3 alkyl;

[0024] L does not exist or is selected from -NRd -、-O-、-C(=O)NR d -and-S(O) p -;

[0025] R4 is selected from 1 to 4 F, OH and C atoms. 3-6 Cycloalkyl-substituted C 1-6 Alkyl groups, -(CH2) substituted with 1 to 7 R5 groups. r -aryl, -(CH2) substituted with 1 to 7 R5 groups r -C 3-12 Cycloalkyl groups, consisting of a carbon atom and 1 to 3 heteroatoms selected from N, NR6, O, and S, and substituted with 1 to 7 R5 atoms (-(CH2)). r - Heterocyclic group;

[0026] R5 is independently selected from H, F, Cl, Br, CN, =O, nitro, and 0 to 5 R groups each time it appears. e Replacement C 1-4 Alkyl, via 0 to 5 R e Replacement C 2-4 alkenyl, via 0 to 5 R e Replacement C 2-4 alkynyl, -(CHR) d ) r OR b -(CHR) d ) r S(O) p R c -(CHR) d ) r S(O) p NR a R a -(CHR) d ) r NR a S(O) p R c -(CHR) d ) r NR a R a -(CHR) d ) r NR a C(=O)R b -(CHR) d ) r NR a C(=O)OR b -(CHR) d ) r NR a C(=O)NR a R a-(CHR) d ) r C(=O)R b -(CHR) d ) r C(=O)OR b -(CHR) d ) r C(=O)NR a R a -(CHR) d ) r OC(=O)R b -(CHR) d ) r OC(=O)OR b -(CHR) d ) r O(CH2) r C(=O)NR a R a , through 0 to 4 R e Replacement C 3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups;

[0027] R6 is selected from H, through 0 to 4 R... e Replacement C 1-3 Alkyl group, -S(O) p R c -(CH2) r C(=O)R b -(CH2) r C(=O)OR b -(CH2) r C(=O)(CH2) r NR a R a -C(=O)(CH2) r NR a C(=O)R b -S(O) p NR a R a , through 0 to 4 R e Substituted -(CH2) r -C 3-6 cycloalkyl, via 0 to 4 R e Substituted -(CH2) r -Aryl and 0 to 4 R e Substituted -(CH2) r - Heterocyclic group;

[0028] R7 is selected from H, F, Cl, CN, C. 1-3 Alkyl, =N-OR b -(CH2) r OR b -(CH2) r NR a R a -NR a C(=NH)C 1-3 Alkyl, -NR a C(=O)OR b Carbocyclic and heterocyclic groups; or, two R7 groups combined to form a carbocyclic or heterocyclic group;

[0029] R8 is independently selected from H, F, Cl, Br, and 0 to 5 R groups each time it appears. e Replacement C 1-4 alkyl;

[0030] R a Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; or R a and R a Together with the nitrogen atom it is attached to, they form a structure with 0 to 5 R atoms. e Substituted heterocycles;

[0031] R b Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0032] R cEach occurrence is independently selected from 0 to 5 R values. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-6 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0033] R d Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl groups and OH groups

[0034] R e Each occurrence is independently selected from 0 to 5 R values. f Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -Aryl, -(CH2) r - Heterocyclic group, Si(C) 1-4 Alkyl groups, F, Cl, Br, CN, NO2, =O, CO2H, -(CH2) r OR f S(O) p R f C(=O)NR f R f S(O) p NR f R f and -(CH2) r NR f R f ;

[0035] R f Each time it appears, it is independently selected from H, F, Cl, Br, CN, OH, or C substituted with OH. 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-6 cycloalkyl and phenyl, or R f and R f Together with the nitrogen atom it is attached to, it forms an optional C-type hydroxyl group. 1-4 Alkyl-substituted heterocycles;

[0036] p is independently selected from 0, 1, and 2 each time it appears;

[0037] r is independently selected from 0, 1, 2, 3, and 4 each time it appears;

[0038] Its limitations are:

[0039] (1) When L does not exist, R4 is not equal to 0. and

[0040] (2) When L is -NR d - At that time, R4 is not and and

[0041] (3) When L is -O-, R4 is not C. 3-6 Cycloalkyl.

[0042] 2. Definition

[0043] Throughout this specification and the appended claims, the given chemical formula or name shall encompass all its stereoisomers, optical isomers, and racemic derivatives (if such isomers exist). Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of this invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, and the like may also exist in the compounds, and all such stable isomers are covered in this invention. Cis and trans (or E- and Z-type) geometric isomers of the compounds of this invention have been described and can be separated as mixtures of isomers or as separated isomers. The compounds of this invention can be separated in optically active or racemic forms. The optically active form can be prepared by resolving the racemic form or by synthesis from optically active starting materials. All methods used to prepare the compounds of this invention and the intermediates prepared therein are considered part of this invention. When preparing enantiomers or diastereomers, they can be separated by conventional methods, such as by chromatography or fractional crystallization. Depending on the process conditions, the final products of this invention are obtained in free (neutralized) or salt form. Both the free form and salts of these final products are within the scope of this invention. If necessary, one form of the compound can be converted to another. Free bases or acids can be converted to salts; salts can be converted to free compounds or another type of salt; mixtures of isomers of this invention can be separated into individual isomers. The compounds of this invention and their salts in free form can exist in various tautomeric forms, wherein hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between atoms in the molecule are thus rearranged. It should be understood that all tautomeric forms that can exist are included within this invention.

[0044] As used herein, the terms "alkyl" or "alkylene" are intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, "C1 to C2" 12 Alkyl or C 1-12 Alkyl (or alkylene) is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 Alkyl; "C4 to C 18 Alkyl or C 4-18 Alkyl (or alkylene) is intended to include C4, C5, C6, C7, C8, C9 ... 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 and C 18 Alkyl. Additionally, for example, "C1 to C6 alkyl" or "C 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms. Alkyl groups may be unsubstituted or substituted, wherein at least one hydrogen atom is replaced by another chemical group. Exemplary 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, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When "CO alkyl" or "CO alkylene" is used, it is intended to indicate a direct bond.

[0045] "Alkenyl" or "alkenyl" is intended to include hydrocarbon chains having a specified number of carbon atoms and one or more, preferably one or two, carbon-carbon double bonds in a straight-chain or branched configuration, the carbon-carbon double bonds being present at any stable point along the chain. For example, "C2 to C6 alkenyl" or "C 2-6 "Alkenyl" (or alkenylylene) is intended to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl groups include (but are not limited to) vinyl, 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.

[0046] "Alynyl" or "ethynyl" is intended to include hydrocarbon chains with one or more, preferably one to three, carbon-carbon triple bonds in a straight-chain or branched configuration, which may be present at any stable point along the chain. For example, "C2 to C6 ethynyl" or "C 2-6 "Alynyl" (or ynylene) is intended to include C2, C3, C4, C5 and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentylyl and hexynyl.

[0047] The term "alkoxy" or "alkyloxy" refers to -O-alkyl. For example, "C1 to C6 alkoxy" or "C 1-6 "Alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Exemplary alkoxy groups include (but are not limited to) methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy. Similarly, "alkathio" or "thioalkoxy" means an alkyl group as defined above having a specified number of carbon atoms connected via a sulfur bridge; for example, methyl-S- and ethyl-S-.

[0048] "Halogen" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Halogenalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms substituted with one or more halogen atoms. Examples of halogenalkyl groups include (but are not limited to) fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of halogenalkyl groups also include "fluoroalkyl," which is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms substituted with one or more fluorine atoms.

[0049] The term "cycloalkyl" refers to cycloalkyl groups, including monocyclic, bicyclic, or polycyclic cyclic systems. For example, "C3 to C6 cycloalkyl" or "C..." 3-6 The term "cycloalkyl" is intended to include C3, C4, C5, and C6 cycloalkyl groups. Exemplary cycloalkyl groups include (but are not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornelalkyl. The definition of "cycloalkyl" includes branched cycloalkyl groups, such as 1-methylcyclopropyl and 2-methylcyclopropyl. The term "cycloalkenyl" refers to a cyclized alkenyl group. C4-6 cycloalkenyl groups are intended to include C4, C5, and C6 cycloalkenyl groups. Exemplary cycloalkenyl groups include (but are not limited to) cyclobutenyl, cyclopentenyl, and cyclohexenyl.

[0050] As used herein, “carbocyclic,” “carbocyclic group,” or “carbocyclic residue” are intended to mean any stable 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered monocyclic or bicyclic or 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 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, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decahydronaphthalene), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, dihydroindene, adamantyl, anthracene, and tetrahydronaphthalene (naphthalene). As shown above, bridging rings are also included in the definition of carbocyclic rings (e.g., [2.2.2]bicyclooctane). Unless otherwise specified, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, dihydroindene, and tetrahydronaphthalene are preferred carbocyclic rings. When the term "carbocyclic ring" is used, it is intended to include "aryl". A bridging ring is formed when one or more, preferably one to three carbon atoms, bond to two non-adjacent carbon atoms. The bridge is preferably one or two carbon atoms. It should be noted that the bridge always transforms a monocyclic ring into a tricyclic ring. When rings are bridged, substituents described for the ring may also be present on the bridge.

[0051] As used herein, the terms "bicyclic carbocyclic" or "bicyclic carbocyclic group" are intended to mean a stable 9- or 10-membered carbocyclic ring system consisting of two fused rings composed of carbon atoms. Of the two fused rings, one is a benzo[a] ring fused to a second ring; and the second ring is a 5- or 6-membered saturated, partially unsaturated, or unsaturated carbocyclic ring. A bicyclic carbocyclic group may be attached to its side group at any carbon atom that produces a stable structure. If the resulting compound is stable, the bicyclic carbocyclic group described herein may be substituted at any carbon atom. Examples of bicyclic carbocyclic groups include (but are not limited to) naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and dihydroindenyl.

[0052] "Aryl" refers to monocyclic or bicyclic aromatic hydrocarbons, including, for example, phenyl and naphthyl. The aryl moiety is well-known and described, for example, in Lewis, RJ, ed., Hawley's Condensed Chemical Dictionary, 15th edition, John Wiley & Sons, Inc., New York (2007). "C 6-10 "Aryl" refers to phenyl and naphthyl groups.

[0053] As used herein, the terms “heterocyclic,” “heterocyclic group,” or “heterocyclic radical” are intended to mean stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic, or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic heterocycles that are saturated, partially unsaturated, or fully unsaturated and contain a carbon atom and one, two, three, or four heteroatoms independently selected from the groups of N, O, and S; and include any polycyclic radical fused to a benzene ring as defined above. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)). p (where p is 0, 1, or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, if defined). The heterocycle may be attached to its side group at any heteroatom or carbon atom that produces a stable structure. If the resulting compound is stable, the heterocycle described herein may be substituted at either a carbon or nitrogen atom. The nitrogen in the heterocycle may optionally be quaternarily ammonized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle does not exceed 1. When the term "heterocycle" is used, it is intended to include heteroaryl groups.

[0054] Examples of heterocycles include (but are not limited to) acridine, azacyclic butyl, acridine, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophene, benzooxazolyl, benzooxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisooxazolyl, benzoisothiazolyl, benzimidazolinyl, carbazole, 4aH-carbazole, carbolinyl, chromyl, chromenyl, cenyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofurano[2,3-b]tetrahydrofuran, furanyl, furazolidyl, imidazolyl, imidazolinyl, 1H -Indazole, imidazopyridyl, indolenyl, indololinyl, indolazinyl, indolyl, 3H-indolyl, indigocyanoyl, isobenzofuranyl, isocyanyl, isoindazole, isoindololinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isothiazolyl, isoxazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthidyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolylalkyl, oxazolyl, oxazolylpyridyl, oxazolylalkylpyrimidinyl ( oxazolinylperimidinyl), hydroxyindole, pyrimidinyl, phenanthridine, phenanthrinyl, phenazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinoneyl, 4-piperidinoneyl, helichrysinyl, pteridinyl, purine, pyranyl, pyrazinyl, pyrazolylalkyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolylalkyl, pyrrololinyl, 2-pyrrolidoneyl, 2H-pyrrolyl, pyrrolyl, quinyl Zolazolinyl, quinolinyl, 4H-quinazinyl, quinoxolinyl, quininylcycloyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, thiazolyl, thienyl, thiazopyridyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthaneyl. Also includes fused ring and spirocyclic compounds containing, for example, the heterocycles described above.

[0055] Examples of 5- to 10-membered heterocycles include (but are not limited to) pyridyl, furanyl, thiophene, pyrrole, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazoalkyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolalkyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, IH-indazolyl, benzofuranyl, benzyl The compounds include thiofuranyl, benzotetrazolyl, benzotriazolyl, benzoisoxazolyl, benzoxazolyl, hydroxyindolyl, benzoxazolinyl, benzothiazolyl, benzoisothiazolyl, indorubicinyl, isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridyl, quinazolinyl, isothiazolopyridyl, thiazopyridyl, oxazolopyridyl, imidazopyridyl, and pyrazolopyridyl. They also include fused ring and spirocyclic compounds containing, for example, the heterocycles described above.

[0056] Bridging rings are also included in the definition of heterocycles. A bridging ring exists when one or more, preferably one to three atoms (i.e., C, O, N, or S) are bonded to two non-adjacent carbon or nitrogen atoms. Examples of bridging rings include (but are not limited to) one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It should be noted that bridging always transforms a monocyclic ring into a tricyclic ring. When rings are bridged, the substituents described for the ring may also be present on the bridge.

[0057] As used herein, the terms "bicyclic heterocycle" or "bicyclic heterocyclic group" are intended to refer to a stable 9- or 10-membered heterocyclic system containing two fused rings composed of a carbon atom and one, two, three, or four heteroatoms independently selected from the groups N, O, and S. Of the two fused rings, one is a 5- or 6-membered monocyclic aromatic ring comprising a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, or a benzo[a] ring, each fused to the second ring. The second ring is a 5- or 6-membered monocyclic ring, which is saturated, partially unsaturated, or unsaturated and comprises a 5-membered heterocycle, a 6-membered heterocycle, or a carbocyclic ring (with the constraint that if the second ring is a carbocyclic ring, then the first ring is not a benzo[a] ring).

[0058] Bicyclic heterocyclic groups can be attached to their side groups at any heteroatom or carbon atom that produces a stable structure. If the resulting compound is stable, the bicyclic heterocyclic groups described herein can be substituted at a carbon or nitrogen atom. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle does not exceed 1.

[0059] Examples of bicyclic heterocyclic groups include (but are not limited to) quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indololinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 2,3-dihydro-benzofuranyl, cromoglycyl, 1,2,3,4-tetrahydroquinoxolinyl, and 1,2,3,4-tetrahydroquinazolinyl.

[0060] As used herein, the term "aromatic heterocyclic" or "heteroaryl" is intended to mean a stable monocyclic and polycyclic aromatic hydrocarbon comprising at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl includes (but is not limited to) pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thiopheneyl, imidazolyl, thiazolyl, indolyl, pyrroleyl, oxazolyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazoleyl, benzimidazolyl, indololinyl, benzodioxane, and benzodioxane. Heteroaryl may be substituted or unsubstituted. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, if defined). Nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., N→O and S(O)). p (where p is 0, 1, or 2).

[0061] Examples of 5- to 6-membered heteroaryl groups include (but are not limited to) pyridyl, furanyl, thiophenyl, pyrroleyl, pyrazolyl, pyrazinyl, imidazolyl, imidazoalkyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolalkyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl.

[0062] The term "relative ion" is used to refer to negatively charged substances, such as chloride ions, bromide ions, hydroxide ions, acetate ions, and sulfate ions; or positively charged substances, such as sodium (Na₂O₃). + ), potassium (K) + ), ammonium (R) n NH m +, where n = 0-4 and m = 0-4); and similar substances.

[0063] When a dashed ring is used within a ring structure, this indicates that the ring structure can be saturated, partially saturated, or unsaturated.

[0064] As used herein, the term "amine protecting group" means any group known in organic synthesis for protecting amino groups that is stable against ester reducing agents, disubstituted hydrazines, R4-M and R7-M, nucleophiles, hydrazine reducing agents, activators, strong bases, hindered amine bases, and cyclizing agents. Such amine protecting groups that meet these criteria include those listed in Protecting Groups in Organic Synthesis, Wuts, PGM et al. (4th edition, Wiley (2007) and The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981)), the disclosure of which is hereby incorporated by reference. Examples of amine protecting groups include (but are not limited to) the following: (1) acyl groups, such as formyl, trifluoroacetyl, phthaloyl, and p-toluenesulfonyl; (2) aromatic carbamate groups, such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyl, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethoxycarbonyl (Fmoc); (3) aliphatic carbamate groups, such as tert-butoxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and olefins. (3) Propoxycarbonyl; (4) Cycloalkylcarbamate type, such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; (5) Alkyl type, such as triphenylmethyl and benzyl; (6) Trialkylsilane, such as trimethylsilane; (7) Thiol type, such as phenylthiocarbonyl and dithiosuccinyl; and (8) Alkyl type, such as triphenylmethyl, methyl and benzyl; and substituted alkyl type, such as 2,2,2-trichloroethyl, 2-phenylethyl and tert-butyl; and trialkylsilane type, such as trimethylsilane.

[0065] As mentioned herein, the term "substituted" means that at least one hydrogen atom is replaced by a non-hydrogen group, with the constraint that the normal valence is maintained and the substitution produces a stable compound. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0066] In the presence of nitrogen atoms (e.g., amines) on the compounds of the present invention, these nitrogen atoms can be converted into N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to obtain other compounds of the present invention. Therefore, the nitrogen atoms shown and claimed are considered to cover the nitrogen shown and its N-oxide (N→O) derivatives.

[0067] When any variable appears more than once in any component or formula of a compound, its definition for each occurrence is independent of its definition for each other occurrence. Thus, for example, if a group is shown to be substituted with 0 to 3 R groups, then the group may optionally be substituted with up to three R groups, and R is independently selected from the definition of R each time it appears.

[0068] When a bond to a substituent is shown to cross the bonds of two atoms in a connecting ring, the substituent may be bonded to any atom in that ring. If the listed substituent does not indicate that it is bonded to any atom of the remaining part of the compound in the given formula, the substituent may be bonded to any atom of the substituent.

[0069] Combinations of substituents and / or variables are permitted only if such combinations produce stable compounds.

[0070] The phrase “pharmaceutically acceptable” is used in this article to refer to compounds, substances, compositions and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and in proportion to a reasonable benefit / risk ratio.

[0071] As used herein, “pharmaceutically acceptable salt” refers to a derivative of the disclosed compound, wherein the parent compound is modified by preparing its acid salt or base salt. Examples of pharmaceutically acceptable salts include (but are not limited to) inorganic or organic acid salts of bases (such as amines); and alkali metal or organic salts of acids (such as carboxylic acids). Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts formed from the parent compound with, for example, non-toxic inorganic or organic acids. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed from amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucohepanoate, glyceryl phosphate, glucuronate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, p-pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and similar salts.

[0072] Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and similar salts. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using relative ions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, low-carbon alkyl sulfonate, and aryl sulfonate.

[0073] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Generally, these salts can be prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture thereof; generally, non-aqueous media (such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred. A list of suitable salts is provided in Allen, Jr., LV, ed., Remington: The Science and Practice of Pharmacy, 22nd edition, Pharmaceuticalpress, London, UK (2012), the disclosure of which is hereby incorporated by reference.

[0074] Additionally, compounds of Formula I may have a prodrug form. Any compound that can be converted in vivo to yield a bioactive pharmaceutical agent (i.e., a compound of Formula I) is a prodrug within the scope and spirit of this invention. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:

[0075] a) Bundgaard, H. (ed.), Design of Prodrugs, Elsevier (1985), and Widder, K. et al. (eds.), Methods in Enzymology, 112: 309-396, Academic Press (1985);

[0076] b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”, in Krosgaard-Larsen, P. et al. (eds.), A Textbook of Drug Design and Development, pp. 113-191, Harwood Academic Publishers (1991);

[0077] c) Bundgaard, H., Adv.Drug Deliv.Rev., 8: 1-38 (1992);

[0078] d) Bundgaard, H. et al., J. Pharm. Sci., 77: 285 (1988);

[0079] e) Kakeya, N. et al., Chem. Pharm. Bull., 32: 692 (1984); and

[0080] f) Rautio, J., ed., Prodrugs and Targeted Delivery (Methods and Principles in Medicinal Chemistry), Volume 47, Wiley-VCH (2011).

[0081] Compounds containing a carboxyl group can form physiologically hydrolyzable esters, which act as prodrugs that produce the compound of formula I itself through hydrolysis in vivo. Such prodrugs are preferably administered orally because hydrolysis often occurs primarily under the influence of digestive enzymes. In cases where the ester itself is active or where hydrolysis occurs in the bloodstream, non-enteral administration may be used. Examples of physiologically hydrolyzable esters of formula I compounds include C... 1-6 Alkyl, C 1-6 Alkylbenzyl, 4-methoxybenzyl, dihydroindene, phthaloyl, methoxymethyl, C 1-6 Alkyloxy-C 1-6 Alkyl groups (e.g., acetoxymethyl, pivaloyloxymethyl, or propionyloxymethyl), C 1-6 Alkoxycarbonyl-C 1-6 Alkyl groups (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyl-oxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl)-methyl), and other well-known physiologically hydrolyzable esters used in techniques for example, penicillin and cephalosporin. Such esters can be prepared using conventional techniques known in the art.

[0082] The preparation of prodrugs is well known in the art and described, for example, in King, FD, ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (2nd ed., reprinted (2006)); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, CG, ed., The Practice of Medicinal Chemistry, 3rd ed., Academic Press, San Diego, CA (2008).

[0083] This invention is intended to include all isotopes of atoms present in the compounds of this invention. Isotopes include atoms with the same number of atoms but different mass numbers. By way of general examples and not limitation, isotopes of hydrogen include deuterium (symbol D or 2H) and tritium (symbol T or 3H). For example, methyl groups may be represented by CH3 or CD3. Carbon isotopes include 13 C and 14 C. The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using appropriately isotopically labeled reagents instead of the originally used unlabeled reagents.

[0084] The term "solvent" refers to the physical association of the compound of the present invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, the solvate can be separated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in the solvate may be present in an ordered and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvent" encompasses both solution phases and separable solvates. Exemplary solvates include (but are not limited to) hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are generally known in the art.

[0085] As used herein, the terms “measurable affinity” and “measurable inhibition” mean a measurable change in PAD4 activity between a sample containing the compound or a combination thereof of the present invention and PAD4 and an equivalent sample containing PAD4 but without the compound or the combination thereof.

[0086] The abbreviations used in this article are defined as follows: "1×" means once, "2×" means twice, "3×" means three times, "℃" means degrees Celsius, "eq" means equivalent, "g" means gram, "mg" means milligram, "L" means liter, "mL" means milliliter, "μL" means microliter, "N" means equivalent concentration, "M" means mole concentration, "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 hour, "conc." means concentrate, "aq" means "aqueous solution", "sat" or "sat'd" means saturated, "MW" means molecular weight, "mp" means melting point, "MS" or "Mass" means... "Spec" indicates mass spectrometry, "ESI" indicates electrospray ionization mass spectrometry, "HR" indicates high resolution, "HRMS" indicates high resolution mass spectrometry, "LCMS" indicates liquid chromatography-mass spectrometry, "HPLC" indicates high performance liquid chromatography, "RPHPLC" indicates reversed-phase HPLC, "TLC" or "tlc" indicates thin-layer chromatography, "NMR" indicates nuclear magnetic resonance spectroscopy, and "nOe" indicates nuclear overhausen effect spectroscopy. 1 "H" represents the proton, "δ" represents the δ peak, "s" represents a singlet, "d" represents a doublet, "t" represents a triplet, "q" represents a quartet, "m" represents a multiplet, "br" represents a broad peak, "Hz" represents Hertz, and "α", "β", "R", "S", "E", "Z", and "ee" are stereochemical names familiar to those skilled in the art. As used herein, the term "pharmaceutically acceptable salt" means a salt that, within the limits of reasonable medical judgment, is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, or similar effects, and is commensurate with a reasonable benefit / risk ratio.

[0087] AcOH or HOAc acetic acid

[0088] ACN Acetonitrile

[0089] Alk alkyl

[0090] AlMe3 Trimethylaluminum

[0091] BBr3 Boron tribromide

[0092] Bn benzyl

[0093] Boc tert-butoxycarbonyl

[0094] BOP reagent benzotriazine-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate

[0095] Bu Butyl

[0096] i-Bu Isobutyl

[0097] t-Bu tert-butyl

[0098] t-BuOH tert-butanol

[0099] Cbz benzyloxycarbonyl

[0100] CDCl3 (deuterated chloroform)

[0101] CD3OD Deuterated Methanol

[0102] CH2Cl2 Dichloromethane

[0103] CH3CN Acetonitrile

[0104] CHCl3 chloroform

[0105] DCM dichloromethane

[0106] DIEA, DIPEA, or Huenig diisopropylethylamine

[0107] Hunig's base

[0108] DMF (dimethylformamide)

[0109] DMSO (dimethyl sulfoxide)

[0110] Et Ethyl

[0111] Et3N or TEA triethylamine

[0112] Et2O diethyl ether

[0113] EtOAc (ethyl acetate)

[0114] EtOH (ethanol)

[0115] HCl hydrochloric acid

[0116] HPLC (High Performance Liquid Chromatography)

[0117] K2CO3 (potassium carbonate)

[0118] K2HPO4 Potassium hydrogen phosphate

[0119] LCMS (Liquid Chromatography-Mass Spectrometry)

[0120] LiHMDS bis(trimethylsilyl)amine lithium

[0121] LG leaving group

[0122] Me methyl

[0123] MeOH (methanol)

[0124] MgSO4 Magnesium sulfate

[0125] MsOH or MSA mesylate

[0126] NaCl (sodium chloride)

[0127] Na2CO3 (Sodium carbonate)

[0128] NaHCO3 (Sodium bicarbonate)

[0129] NaOH (sodium hydroxide)

[0130] Na2SO4 Sodium sulfate

[0131] NH3 ammonia

[0132] NH4Cl ammonium chloride

[0133] NH4OAc ammonium acetate

[0134] Pd(OAc)₂ Palladium(II) acetate

[0135] Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0136] Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0)

[0137] PG protection base

[0138] Ph phenyl

[0139] Pr propyl

[0140] i-Pr isopropyl

[0141] i-PrOH or IPA isopropanol

[0142] Rt retention time

[0143] SiO2 (silicon dioxide)

[0144] SFC Supercritical Fluid Chromatography

[0145] TBAI Tetrabutylammonium iodide

[0146] TEA Triethylamine

[0147] TFA (trifluoroacetic acid)

[0148] TFAA (trifluoroacetic anhydride)

[0149] THF Tetrahydrofuran

[0150] TiCl4 Titanium tetrachloride

[0151] T3P 1-Propanephosphonic Anhydride

[0152] 3. Description of exemplary compounds

[0153] In a first aspect, the present invention provides a compound of formula (I):

[0154]

[0155] Or its pharmaceutically acceptable salt, wherein:

[0156] Q is selected from N and CH;

[0157] Ring A is a 4- to 15-membered heterocyclic group substituted with 1 to 4 R7 groups;

[0158] R1 is selected from CH3 and CD3;

[0159] R2 is selected from H, and passed through 0 to 5 R... e Replacement C 1-3 Alkyl groups and those with 0 to 5 R groups e Replacement C 3-6 cycloalkyl;

[0160] R3 is selected from H, F, Cl, Br, -OR b and through 0 to 5 R e Replacement C 1-3 alkyl;

[0161] L does not exist or is selected from -NR d -、-O-、-C(=O)NR d -and-S(O) p -;

[0162] R4 is selected from -(CH2) substituted with 1 to 5 R5 groups. r -aryl, -(CH2) substituted with 1 to 5 R5 groups r -C 3-12 Cycloalkyl groups, consisting of a carbon atom and 1 to 3 heteroatoms selected from N, NR6, O, and S, and substituted with 1 to 5 R5 atoms (-(CH2)). r - Heterocyclic group;

[0163] R5 is independently selected from H, F, Cl, Br, CN, nitro, and 0 to 5 R groups each time it appears. e Replacement C 1-4 Alkyl, via 0 to 5 R e Replacement C 2-4 alkenyl, via 0 to 5 R e Replacement C 2-4 alkynyl, -(CHR) d ) r ORb -(CHR) d ) r S(O) p R c -(CHR) d ) r S(O) p NR a R a -(CHR) d ) r NR a S(O) p R c -(CHR) d ) r NR a R a -(CHR) d ) r NR a C(=O)R b -(CHR) d ) r NR a C(=O)OR b -(CHR) d ) r NR a C(=O)NR a R a -(CHR) d ) r C(=O)R b -(CHR) d ) r C(=O)OR b -(CHR) d ) r C(=O)NR a R a -(CHR) d ) r OC(=O)R b , through 0 to 4 R e Replacement C 3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups;

[0164] R6 is selected from H, through 0 to 4 R... e Replacement C 1-3 Alkyl group, -S(O) p R c -C(=O)R b -C(=O)OR b -C(=O)(CH2) rNR a R a -S(O) p NR a R a , through 0 to 4 R e Substituted -(CH2) r -C 3-6 cycloalkyl, via 0 to 4 R e Substituted -(CH2) r -Aryl and 0 to 4 R e Substituted -(CH2) r - Heterocyclic group;

[0165] R7 is selected from H, F, Cl, CN, C. 1-3 Alkyl, =N-OR b -(CH2) r OR b -(CH2) r NR a R a -NR a C(=NH)C 1-3 Alkyl, -NR a C(=O)OR b Carbocyclic and heterocyclic rings; or, two R7 groups bonded together to form a carbocyclic or heterocyclic ring;

[0166] R8 is independently selected from H, F, Cl, Br, and 0 to 5 R groups each time it appears. e Replacement C 1-4 alkyl;

[0167] R a Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; or R a and R a Together with the nitrogen atom it is attached to, they form a structure with 0 to 5 R atoms. e Substituted heterocycles;

[0168] R b Each occurrence is independently selected from H, via 0 to 5 R. eReplacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0169] R c Each occurrence is independently selected from 0 to 5 R values. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-6 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0170] R d Each occurrence is independently selected from H and via 0 to 5 R. e Replacement C 1-6 alkyl,

[0171] R e Each occurrence is independently selected from 0 to 5 R values. f Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -Aryl, Si(C) 1-4 Alkyl groups, F, Cl, Br, CN, NO2, =O, CO2H, -(CH2) r OR f S(O) p R f C(=O)NR f R f S(O) p NR f R f and -(CH2) r NR f R f ;

[0172] R f Each time it appears, it is independently selected from H, F, Cl, Br, CN, OH, or C substituted with OH. 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-6 cycloalkyl and phenyl, or R f and R f Together with the nitrogen atom it is attached to, it forms an optional C-type hydroxyl group. 1-4 Alkyl-substituted heterocycles;

[0173] p is independently selected from 0, 1, and 2 each time it appears;

[0174] r is independently selected from 0, 1, 2, 3, and 4 each time it appears; and

[0175] Its limitations are:

[0176] (1) When L does not exist, R4 is not equal to 0. and

[0177] (2) When L is -NR d - At that time, R4 is not and and

[0178] (3) When L is -O-, R4 is not C. 3-6 Cycloalkyl.

[0179] In a second aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which falls within the scope of the first aspect, wherein:

[0180] Ring A is selected from

[0181] and

[0182] R1 is selected from CH3 and CD3;

[0183] R2 is selected from methyl, ethyl, and compounds with 0 to 3 R's. e Substituted -CH2-cyclopropyl;

[0184] R3 is selected from H, F, Cl, Br and -OC. 1-4 alkyl;

[0185] L does not exist or is selected from -NR d -, -O-, -C(=O)NH-, -S- and -S(O)2-;

[0186] R4 is selected from

[0187]

[0188]

[0189]

[0190] and

[0191] R5 is independently selected from H, F, Cl, Br, CN, via 0 to 5 Rs each time it appears. e Replacement C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -(CHR) d ) r OR b -(CH2) r S(O) p R c -(CH2) r S(O) p NR a R a -(CH2) r NR a S(O) p R c -(CH2) r NR a R a -(CH2) r NR a C(=O)R b -(CH2) r NR a C(=O)OR b -(CH2) r NR a C(=O)NR a R a -(CH2) r C(=O)R b -(CH2) r C(=O)OR b -(CH2) r OC(=O)R b -(CH2) r C(=O)NR a R a -(CH2) r OC(=O)R b , through 0 to 4 R e Replacement C3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups;

[0192] R6 is independently selected from H, through 0 to 4 Rs each time it appears. e Replacement C 1-3 Alkyl group, -S(O) p R c -C(=O)R b -C(=O)(CH2) r NR a R a -C(=O)OR b -S(O) p NR a R a , through 0 to 4 R e Substituted -(CH2) r -Aryl and 0 to 4 R e Substituted -(CH2) r - Heterocyclic group;

[0193] R a Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; or R a and R a Together with the nitrogen atom it is attached to, they form a structure with 0 to 5 R atoms. e Substituted heterocycles;

[0194] R b Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groupse Substituted -(CH2) r - Heterocyclic group;

[0195] R c Each occurrence is independently selected from 0 to 5 R values. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-6 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0196] R d Each occurrence is independently selected from H and via 0 to 5 R. e Replacement C 1-6 alkyl;

[0197] R e Each occurrence is independently selected from 0 to 5 R values. f Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -aryl, F, Cl, Br, CN, NO2, =O, -NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C(=O)OH, -C(=O)OC 1-4 Alkyl group, -(CH2) r OH and -(CH2) r OC 1-4 alkyl;

[0198] R f Each time it appears, it is independently selected from H, F, Cl, Br, CN, OH, or C substituted with OH. 1-5 Alkyl, C 3-6 cycloalkyl and phenyl groups;

[0199] p is independently selected from 0, 1, and 2 each time it appears; and

[0200] r is independently selected from 0, 1, 2, 3, and 4 each time it appears.

[0201] In a third aspect, the present invention provides a compound of formula (II):

[0202]

[0203] Or its pharmaceutically acceptable salt, wherein:

[0204] Ring A is selected from

[0205] and

[0206] R2 is selected from methyl and -CH2-cyclopropyl;

[0207] R3 is selected from H, F and -OC. 1-4 alkyl;

[0208] R4 is selected from

[0209]

[0210] and

[0211] R5 is independently selected from H, F, Cl, Br, CN, via 0 to 4 Rs each time it appears. e Replacement C 1-4 Alkyl, -(CHR) d ) r OR b -S(O) p R c -S(O) p NR a R a -(CH2) r NR a S(O) p R c -(CH2) r NR a R a -(CH2) r NR a C(=O)R b -NR a C(=O)OR b -NR a C(=O)NR a R a -(CH2) r C(=O)R b -(CH2) r C(=O)OR b -(CH2) r C(=O)NR aR a -(CH2) r OC(=O)R b , through 0 to 4 R e Replacement C 3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups;

[0212] R6 is independently selected from H, through 0 to 4 Rs each time it appears. e Replacement C 1-3 Alkyl group, -S(O) p R c -C(=O)R b -(CH2) r -C(=O)NR a R a -C(=O)(CH2) r NR a C(=O)R b -C(=O)OR b -S(O) p NR a R a , through 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups;

[0213] R a Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; or R a and R a Together with the nitrogen atom it is attached to, they form a structure with 0 to 5 R atoms. e Substituted heterocycles;

[0214] R b Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 Re Substituted -(CH2) r -C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0215] R c Each occurrence is independently selected from 0 to 5 R values. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-6 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0216] R d Each occurrence is independently selected from H and via 0 to 5 R. e Replacement C 1-6 alkyl;

[0217] R e Each occurrence is independently selected from 0 to 5 R values. f Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -aryl, F, Cl, Br, CN, NO2, =O, -NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C(=O)OH, -C(=O)OC 1-4 Alkyl group, -(CH2) r OH and -(CH2) r OC 1-4 alkyl;

[0218] R f Each time it appears, it is independently selected from H, F, Cl, Br, CN, OH, or C substituted with OH. 1-5 Alkyl, C 3-6 cycloalkyl and phenyl groups;

[0219] p is independently selected from 0, 1, and 2 each time it appears; and

[0220] r is independently selected from 0, 1, 2, 3, and 4 each time it appears.

[0221] In a fourth aspect, the present invention provides a compound of formula (III):

[0222]

[0223] Or its pharmaceutically acceptable salt, wherein:

[0224] Ring A is

[0225] R2 is -CH2-cyclopropyl;

[0226] R3 is -OC 1-4 alkyl;

[0227] R5 is independently selected from H, F, Cl, Br, CN, via 0 to 4 Rs each time it appears. e Replacement C 1-4 Alkyl, -(CHR) d ) r OR b -S(O) p R c -(CH2) r NR a R a -(CH2) r NHC(=O)R b -NHC(=O)OR b -(CH2) r NHS(O) p R c -(CH2) r C(=O)NR a R a -(CH2) r C(=O)OR b , through 0 to 4 R e Replacement C 3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups;

[0228] R a Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 Re Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; or R a and R a Together with the nitrogen atom it is attached to, they form a structure with 0 to 5 R atoms. e Substituted heterocycles;

[0229] R b Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Substituted -(CH2) r -C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0230] R c Each occurrence is independently selected from 0 to 5 R values. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-6 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0231] R d Each time it appears, it is independently selected from H and C. 1-6 alkyl;

[0232] R e Each occurrence is independently selected from 0 to 5 R values. f Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) r -C 3-6Cycloalkyl, -(CH2) r -aryl, F, Cl, Br, CN, NO2, =O, -NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C(=O)OH, -C(=O)OC 1-4 Alkyl group, -(CH2) r OH, -(CH2) r OC 1-4 Alkyl and SO2C 1-4 alkyl;

[0233] R f Each time it appears, it is independently selected from H, F, Cl, Br, CN, OH, or C substituted with OH. 1-5 Alkyl, C 3-6 cycloalkyl and phenyl groups;

[0234] p is independently selected from 0, 1, and 2 each time it appears; and

[0235] r is independently selected from 0, 1, 2, 3, and 4 each time it appears.

[0236] In a fifth aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which falls within the scope of the fourth aspect, wherein:

[0237] R3 is -OCH3; and

[0238] R5 is selected independently from H, F, Cl, Br, and C each time it appears. 1-4 Alkyl, -OH, -OC 1-3 Alkyl groups and -NHS(O)2C 2-4 Alkenyl group.

[0239] In a sixth aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which falls within the scope of the third aspect, wherein:

[0240] Ring A is

[0241] R2 is -CH2-cyclopropyl;

[0242] R3 is -OC 1-4 alkyl;

[0243] R4 is selected from and

[0244] R5 is independently selected from H, F, Cl, Br, CN, via 0 to 4 Rs each time it appears. e Replacement C 1-4 Alkyl group, -(CH2) r ORb -S(O) p R c -S(O) p NR a R a -(CH2) r NR a S(O) p R c -(CH2) r NR a R a -(CH2) r NR a C(=O)R b -NR a C(=O)OR b -NR a C(=O)NR a R a -(CH2) r C(=O)R b -(CH2) r C(=O)OR b -(CH2) r C(=O)NR a R a -(CH2) r OC(=O)R b , through 0 to 4 R e Replacement C 3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups;

[0245] R a Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; or R a and R a Together with the nitrogen atom it is attached to, they form a structure with 0 to 5 R atoms. e Substituted heterocycles;

[0246] R b Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C2-6 alkenyl, via 0 to 5 R e Substituted -(CH2) r -C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0247] R c Each occurrence is independently represented by 0 to 5 R's. e Replacement C 1-6 Alkyl, via 0 to 5 R e Substituted -(CH2) r -C 3-6 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0248] R e Each occurrence is independently selected from 0 to 5 R values. f Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -aryl, F, Cl, Br, CN, NO2, =O, -NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C(=O)OH, -C(=O)OC 1-4 Alkyl group, -(CH2) r OH and -(CH2) r OC 1-4 alkyl;

[0249] R f Each time it appears, it is independently selected from H, F, Cl, Br, CN, OH, or C substituted with OH. 1-5 Alkyl, C 3-6 cycloalkyl and phenyl groups;

[0250] p is independently selected from 0, 1, and 2 each time it appears; and

[0251] r is independently selected from 0, 1, 2, 3, and 4 each time it appears.

[0252] In a seventh aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which falls within the scope of the sixth aspect, wherein:

[0253] R3 is -OCH3; and

[0254] R5 is selected independently from H, F, Cl, Br, and C each time it appears. 1-4 Alkyl, -OH, -OC 1-3 Alkyl groups and -NHS(O)2C 2-4 Alkenyl group.

[0255] In an eighth aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which falls within the scope of the third aspect, wherein:

[0256] Ring A is

[0257] R2 is -CH2-cyclopropyl;

[0258] R3 is -OC 1-4 alkyl;

[0259] R4 is selected from

[0260] and

[0261] R5 is independently selected from H, F, Cl, Br, CN, and C each time it appears. 1-4 Alkyl, -OR b -S(O) p R c -(CH2) r NR a R a -(CH2) r NR a C(=O)R b -NR a C(=O)OR b -(CH2) r NR a S(O) p R c -C(=O)NR a R a -C(=O)OR b , through 0 to 4 R e Replacement C 3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups;

[0262] R6 is independently selected from H, through 0 to 4 Rs each time it appears. e Replacement C 1-3Alkyl group, -S(O) p R c -C(=O)R b -(CH2) r -C(=O)NR a R a -C(=O)(CH2) r NR a C(=O)R b -C(=O)OR b -S(O) p NR a R a , through 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups;

[0263] R a Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; or R a and R a Together with the nitrogen atom it is attached to, they form a structure with 0 to 5 R atoms. e Substituted heterocycles;

[0264] R b Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Substituted -(CH2) r -C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0265] R c Each occurrence is independently selected from 0 to 5 R values. eReplacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-6 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0266] R e Each occurrence is independently selected from 0 to 5 R values. f Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -aryl, F, Cl, Br, CN, NO2, =O, -NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C(=O)OH, -C(=O)OC 1-4 Alkyl group, -(CH2) r OH and -(CH2) r OC 1-4 alkyl;

[0267] R f Each time it appears, it is independently selected from H, F, Cl, Br, CN, OH, or C substituted with OH. 1-5 Alkyl, C 3-6 cycloalkyl and phenyl groups;

[0268] p is independently selected from 0, 1, and 2 each time it appears; and

[0269] r is independently selected from 0, 1, 2, 3, and 4 each time it appears.

[0270] In a ninth aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which falls within the scope of the eighth aspect, wherein:

[0271] R4 is selected from

[0272] and

[0273] R5 is selected independently from H, F, Cl, Br, and C each time it appears. 1-4 Alkyl groups and OH.

[0274] In a tenth aspect, the present invention provides a compound of formula (IV):

[0275]

[0276] Or its pharmaceutically acceptable salt, which falls within the scope of the ninth aspect, wherein:

[0277] Ring A is

[0278] R2 is selected from methyl and -CH2-cyclopropyl;

[0279] R3 is selected from H, F and -OC. 1-4 alkyl;

[0280] R4 is selected from and

[0281] R5 is independently selected from H, F, Cl, Br, CN, and C each time it appears. 1-4 Alkyl group, -(CH2) r OR b -NR a R a -NR a C(=O)R b -NR a C(=O)OR b -C(=O)OR b NR a S(O) p R c -C(=O)NR a R a -NR a C(=O)NR a R a , through 0 to 4 R e Replacement C 3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups;

[0282] R6 is selected independently from H and C each time it appears. 1-3 alkyl;

[0283] R a Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0284] R b Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0285] R c Each occurrence is independently selected from 0 to 5 R values. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-6 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0286] R d Each time it appears, it is independently selected from H and C. 1-3 alkyl;

[0287] R e Each occurrence is independently selected from 0 to 5 R values. f Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -Aryl, F, Cl, Br, CN, NO2, =O, N(C) 1-4 Alkyl)2, -C(=O)OH, -C(=O)OC 1-4Alkyl group, -(CH2) r OH and -(CH2) r OC 1-4 alkyl;

[0288] R f Each time it appears, it is independently selected from H, F, Cl, Br, CN, OH, or C substituted with OH. 1-5 Alkyl, C 3-6 cycloalkyl and phenyl groups;

[0289] p is independently selected from 0, 1, and 2 each time it appears; and

[0290] r is independently selected from 0, 1, 2, 3, and 4 each time it appears.

[0291] In the eleventh aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which falls within the scope of the tenth aspect, wherein:

[0292] R2 is CH2-cyclopropyl;

[0293] R3 is -OCH3;

[0294] R4 is

[0295] R5 is selected independently from H, F, Cl, Br, and C each time it appears. 1-4 Alkyl groups and -(CH2) 0-1 OH; and

[0296] R d For H.

[0297] In a twelfth aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which falls within the scope of the second aspect, wherein:

[0298] L is -C(=O)NH-;

[0299] R2 is -CH2-cyclopropyl;

[0300] R3 is -OC 1-4 alkyl;

[0301] R4 is selected from

[0302] and

[0303] R5 is selected independently from H, F, Cl, Br, and C each time it appears. 1-4 Alkyl groups, -OH groups, and -CN groups; and

[0304] R6 is selected independently from H and C each time it appears. 1-3alkyl.

[0305] In the thirteenth aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which falls within the scope of the second aspect, wherein:

[0306] L is -O-;

[0307] R2 is -CH2-cyclopropyl;

[0308] R3 is -OC 1-4 alkyl;

[0309] R4 is selected from and and

[0310] R5 is selected independently from H, F, Cl, Br, and C each time it appears. 1-4 Alkyl groups, -OH groups, and -CN groups.

[0311] In a fourteenth aspect, the present invention provides a compound of formula (I):

[0312]

[0313] Or its pharmaceutically acceptable salt, wherein:

[0314] Q is selected from N and CH;

[0315] Ring A is a 4- to 15-membered heterocyclic group substituted with 1 to 4 R7 groups;

[0316] R1 is selected from CH3, CD3, and contains carbon atoms and 1 to 3 atoms selected from N, NC. 1-4 -CH2-5-membered heterocyclic groups of alkyl, O, and S atoms;

[0317] R2 is selected from H, and passed through 0 to 5 R... e Replacement C 1-3 Alkyl groups and those with 0 to 5 R groups e Substituted -(CH2) r -C 3-6 cycloalkyl;

[0318] R3 is selected from H, F, Cl, Br, -OR b and through 0 to 5 R e Replacement C 1-3 alkyl;

[0319] L does not exist or is selected from -NR d -、-O-、-C(=O)NR d -and-S(O) p -;

[0320] R4 is selected from -(CH2) substituted with 1 to 7 R5 groups.r -Aryl, -(CH2) r -C 3-12 cycloalkyl (via 1 to 2 OR) b C(=O)OR b -C(=O)NR a R a -NR a C(=O)R b (Substitution), comprising a carbon atom and 1 to 3 heteroatoms selected from N, NR6, O and S, and substituted with 1 to 7 R5 atoms -(CH2). r - Heterocyclic group;

[0321] R5 is independently selected from H, F, Cl, Br, CN, =O, nitro, and 0 to 5 R groups each time it appears. e Replacement C 1-4 Alkyl, via 0 to 5 R e Replacement C 2-4 alkenyl, via 0 to 5 R e Replacement C 2-4 alkynyl, -(CHR) d ) r OR b -(CHR) d ) r S(O) p R c -(CHR) d ) r S(O) p NR a R a -(CHR) d ) r NR a S(O) p R c -(CHR) d ) r NR a R a -(CHR) d ) r NR a C(=O)R b -(CHR) d ) r NR a C(=O)OR b -(CHR) d ) r NR a C(=O)NR a R a -(CHR) d ) r C(=O)Rb -(CHR) d ) r C(=O)OR b -(CHR) d ) r C(=O)NR a R a -(CHR) d ) r OC(=O)R b -(CHR) d ) r OC(=O)OR b -(CHR) d ) r O(CH2) r C(=O)NR a R a , through 0 to 4 R e Replacement C 3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups;

[0322] R6 is selected from H, through 0 to 4 R... e Replacement C 1-3 Alkyl group, -S(O) p R c -(CH2) r C(=O)R b -(CH2) r C(=O)OR b -(CH2) r C(=O)(CH2) r NR a R a -C(=O)(CH2) r NR a C(=O)R b -S(O) p NR a R a , through 0 to 4 R e Substituted -(CH2) r -C 3-6 cycloalkyl, via 0 to 4 R e Substituted -(CH2) r -Aryl and 0 to 4 R e Substituted -(CH2) r - Heterocyclic group;

[0323] R7 is selected from H, F, Cl, CN, C. 1-3 Alkyl, =N-ORb -(CH2) r OR b -(CH2) r NR a R a -NR a C(=NH)C 1-3 Alkyl, -NR a C(=O)OR b Carbocyclic and heterocyclic groups; or, two R7 groups combined together to form a carbocyclic or heterocyclic group;

[0324] R8 is independently selected from H, F, Cl, Br, and 0 to 5 R groups each time it appears. e Replacement C 1-4 alkyl;

[0325] R a Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; or R a and R a Together with the nitrogen atom it is attached to, they form a structure with 0 to 5 R atoms. e Substituted heterocycles;

[0326] R b Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0327] R c Each occurrence is independently selected from 0 to 5 R values. e Replacement C 1-6Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-6 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0328] R d Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl groups and OH groups

[0329] R e Each occurrence is independently selected from 0 to 5 R values. f Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -Aryl, -(CH2) r - Heterocyclic group, Si(C) 1-4 Alkyl groups, F, Cl, Br, CN, NO2, =O, CO2H, -(CH2) r OR f S(O) p R f C(=O)NR f R f S(O) p NR f R f and -(CH2) r NR f R f ;

[0330] R f Each time it appears, it is independently selected from H, F, Cl, Br, CN, OH, or C substituted with OH. 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-6 cycloalkyl and phenyl, or R f and R f Together with the nitrogen atom it is attached to, it forms an optional C-type hydroxyl group. 1-4 Alkyl-substituted heterocycles;

[0331] p is independently selected from 0, 1, and 2 each time it appears;

[0332] r is independently selected from 0, 1, 2, 3, and 4 each time it appears;

[0333] Its limitations are:

[0334] (1) When L does not exist, R4 is not equal to 0. and

[0335] (2) When L is -NR d - At that time, R4 is not and and

[0336] (3) When L is -O-, R4 is not C. 3-6 Cycloalkyl.

[0337] In the fifteenth aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which falls within the scope of the fourteenth aspect, wherein:

[0338] For selection and

[0339] R1 is selected from CH3 and CD3;

[0340] R2 is selected from methyl, ethyl, and compounds with 0 to 3 R's. e Substituted -CH2-cyclopropyl;

[0341] R3 is selected from H, F, Cl, Br and -OC. 1-4 alkyl;

[0342] L does not exist or is selected from -NR d -, -O-, -C(=O)NH-, -S- and -S(O)2-;

[0343] R4 is selected from 1 to 4 F, Cl, OH and C atoms. 3-6 Cycloalkyl-substituted C 1-5 alkyl,

[0344]

[0345]

[0346]

[0347]

[0348] R5 is independently selected from H, F, Cl, Br, CN, =O, and 0 to 5 Rs each time it appears. e Replacement C1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -(CHR) d ) r OR b -(CH2) r S(O) p R c -(CH2) r S(O) p NR a R a -(CH2) r NR a S(O) p R c -(CH2) r NR a R a -(CH2) r NR a C(=O)R b -(CH2) r NR a C(=O)OR b -(CH2) r NR a C(=O)NR a R a -(CH2) r C(=O)R b -(CH2) r C(=O)OR b -(CHR) d ) r C(=O)NR a R a -(CH2) r OC(=O)R b -(CH2) r OC(=O)OR b -(CH2) r O(CH2) r C(=O)NR a R a , through 0 to 4 R e Replacement C 3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups;

[0349] R6 is independently selected from H, through 0 to 4 Rs each time it appears. e Replacement C 1-3 Alkyl group, -S(O) p Rc -C(=O)R b -(CH2) r C(=O)OR b -(CH2) r C(=O)(CH2) r NR a R a -C(=O)(CH2) r NR a C(=O)R b -S(O) p NR a R a , through 0 to 4 R e Substituted -(CH2) r -Aryl and 0 to 4 R e Substituted -(CH2) r - Heterocyclic group;

[0350] R a Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; or R a and R a Together with the nitrogen atom it is attached to, they form a structure with 0 to 5 R atoms. e Substituted heterocycles;

[0351] R b Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0352] R cEach occurrence is independently selected from 0 to 5 R values. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-6 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0353] R d Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl groups and OH groups;

[0354] R e Each occurrence is independently selected from 0 to 5 R values. f Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -Aryl, -(CH2) r -Heterocyclic groups, F, Cl, Br, CN, NO2, =O, -NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C(=O)OH, -C(=O)OC 1-4 Alkyl group, -(CH2) r OH and -(CH2) r OC 1-4 alkyl;

[0355] R f Each time it appears, it is independently selected from H, F, Cl, Br, CN, OH, or C substituted with OH. 1-5 Alkyl, C 3-6 cycloalkyl and phenyl groups;

[0356] p is independently selected from 0, 1, and 2 each time it appears; and

[0357] r is independently selected from 0, 1, 2, 3, and 4 each time it appears.

[0358] In a sixteenth aspect, the present invention provides a compound of formula (II):

[0359]

[0360] Or its pharmaceutically acceptable salt, which falls within the scope of aspect fifteen, wherein:

[0361] Selected from

[0362] and

[0363] R2 is selected from CH3, CH2CH3 and -CH2-cyclopropyl groups substituted with 0 to 2 F, Cl and CH3 groups;

[0364] R3 is selected from H, F and -OC. 1-4 alkyl;

[0365] R4 is selected from

[0366]

[0367]

[0368] and

[0369] R5 is independently selected from H, F, Cl, Br, CN, =O, and 0 to 4 Rs each time it appears. e Replacement C 1-4 Alkyl, -(CHR) d ) r OR b -(CH2) r S(O) p R c -S(O) p NR a R a -(CH2) r NR a S(O) p R c -(CH2) r NR a R a -(CH2) r NR a C(=O)R b -NR a C(=O)OR b -NR a C(=O)NR a R a -(CH2) r C(=O)R b -(CH2) r C(=O)ORb -(CHR) d ) r C(=O)NR a R a -(CH2) r OC(=O)R b -(CH2) r OC(=O)OR b -(CH2) r O(CH2) r C(=O)NR a R a , through 0 to 4 R e Replacement C 3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups;

[0370] R6 is independently selected from H, through 0 to 4 Rs each time it appears. e Replacement C 1-3 Alkyl group, -S(O) p R c -C(=O)R b -(CH2) r C(=O)OR b -(CH2) r C(=O)NR a R a -C(=O)(CH2) r NR a C(=O)R b -S(O) p NR a R a , through 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups;

[0371] R a Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; or R aand R a Together with the nitrogen atom it is attached to, they form a structure with 0 to 5 R atoms. e Substituted heterocycles;

[0372] R b Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Substituted -(CH2) r -C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0373] R c Each occurrence is independently selected from 0 to 5 R values. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-6 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0374] R d Each occurrence is independently selected from H and via 0 to 5 R. e Replacement C 1-6 alkyl;

[0375] R e Each occurrence is independently selected from 0 to 5 R values. f Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -Aryl, -(CH2) r -Heterocyclic groups, F, Cl, Br, CN, NO2, =O, -NH2, -NHC 1-4 Alkyl, -N(C) 1-4Alkyl)2, -C(=O)OH, -C(=O)OC 1-4 Alkyl group, -(CH2) r OH and -(CH2) r OC 1-4 alkyl;

[0376] R f Each time it appears, it is independently selected from H, F, Cl, Br, CN, OH, or C substituted with OH. 1-5 Alkyl, C 3-6 cycloalkyl and phenyl groups;

[0377] p is independently selected from 0, 1, and 2 each time it appears; and

[0378] r is independently selected from 0, 1, 2, 3, and 4 each time it appears.

[0379] In the seventeenth aspect, the present invention provides a compound of formula (III):

[0380]

[0381] Or its pharmaceutically acceptable salt, which falls within the scope of the sixteenth aspect, wherein:

[0382] For selection and

[0383] R2 is -CH2-cyclopropyl;

[0384] R3 is -OC 1-4 alkyl;

[0385] R5 is independently selected from H, F, Cl, Br, CN, via 0 to 4 Rs each time it appears. e Replacement C 1-4 Alkyl, -(CHR) d ) r OR b -(CH2) r S(O) p R c -S(O) p NR a R a -(CH2) r NHS(O) p R c -(CH2) r NR a R a -(CH2) r NHC(=O)R b -NHC(=O)ORb -(CHR) d ) r C(=O)NR a R a -(CH2) r C(=O)OR b -OC(=O)OR b -O(CH2)0-1C(=O)NR a R a , through 0 to 4 R e Replacement C 3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups;

[0386] R a Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; or R a and R a Together with the nitrogen atom it is attached to, they form a structure with 0 to 5 R atoms. e Substituted heterocycles;

[0387] R b Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Substituted -(CH2) r -C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0388] R c Each occurrence is independently selected from 0 to 5 R values. e Replacement C1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-6 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0389] R d Each time it appears, it is independently selected from H and C. 1-4 Alkyl groups and OH groups;

[0390] R e Each occurrence is independently selected from 0 to 5 R values. f Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -Aryl, -(CH2) r -Heterocyclic groups, F, Cl, Br, CN, NO2, =O, -NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C(=O)OH, -C(=O)OC 1-4 Alkyl group, -(CH2) r OH, -(CH2) r OC 1-4 Alkyl and SO2C 1-4 alkyl;

[0391] R f Each time it appears, it is independently selected from H, F, Cl, Br, CN, OH, or C substituted with OH. 1-5 Alkyl, C 3-6 cycloalkyl and phenyl groups;

[0392] p is independently selected from 0, 1, and 2 each time it appears; and

[0393] r is independently selected from 0, 1, 2, 3, and 4 each time it appears.

[0394] In the eighteenth aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which falls within the scope of the seventeenth aspect, wherein:

[0395] R3 is -OCH3;

[0396] R5 is independently selected from H, F, Cl, Br, CN, and C each time it appears. 1-4 Alkyl group, -(CH2) 0-1 OR b -S(O)2NH2, -NHS(O)2C 1-3 Alkyl group, -NHS(O)2C 2-4 alkenyl, -NHC(=O)R b -C(=O)NH2 and selected from and heterocyclic groups;

[0397] R b Each occurrence is independently selected from H and via 0 to 5 R. e Replacement C 1-6 alkyl;

[0398] R e Each time it appears, it is independently selected from C. 1-6 Alkyl, F, Cl, Br, CN, NO2, =O, -NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C(=O)OH, -C(=O)OC 1-4 Alkyl group, -(CH2) r OH, -(CH2) r OC 1-4 Alkyl and SO2C 1-4 alkyl.

[0399] In the nineteenth aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which falls within the scope of the sixteenth aspect, wherein:

[0400] For selection and

[0401] R2 is -CH2-cyclopropyl;

[0402] R3 is -OC 1-4 alkyl;

[0403] R4 is selected from and

[0404] R5 is independently selected from H, F, Cl, Br, CN, via 0 to 4 Rs each time it appears. e Replacement C 1-4 Alkyl group, -(CH2) r OR b -S(O) p R c -S(O) pNR a R a -(CH2) r NR a S(O) p R c -(CH2) r NR a R a -(CH2) r NR a C(=O)R b -NR a C(=O)OR b -NR a C(=O)NR a R a -(CH2) r C(=O)R b -(CH2) r C(=O)OR b -(CH2) r C(=O)NR a R a -(CH2) r OC(=O)R b , through 0 to 4 R e Replacement C 3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups;

[0405] R a Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; or R a and R a Together with the nitrogen atom it is attached to, they form a structure with 0 to 5 R atoms. e Substituted heterocycles;

[0406] R b Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 Re Replacement C 2-6 alkenyl, via 0 to 5 R e Substituted -(CH2) r -C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0407] R c Each occurrence is independently selected from 0 to 5 R values. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-6 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0408] R e Each occurrence is independently selected from 0 to 5 R values. f Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -aryl, F, Cl, Br, CN, NO2, =O, -NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C(=O)OH, -C(=O)OC 1-4 Alkyl group, -(CH2) r OH and -(CH2) r OC 1-4 alkyl;

[0409] R f Each time it appears, it is independently selected from H, F, Cl, Br, CN, OH, or C substituted with OH. 1-5 Alkyl, C 3-6 cycloalkyl and phenyl groups;

[0410] p is independently selected from 0, 1, and 2 each time it appears; and

[0411] r is independently selected from 0, 1, 2, 3, and 4 each time it appears.

[0412] In the twentieth aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which falls within the scope of the nineteenth aspect, wherein:

[0413] R3 is -OCH3;

[0414] R5 is selected independently from H, F, Cl, Br, and C each time it appears. 1-4 Alkyl, -OH, -OC 1-3 Alkyl group, -NHS(O)2C 2-4 alkenyl, NHC(=O)OC 1-4 Alkyl group, C(=O)NH2, C(=O)NHC 1-4 Alkyl groups and heterocyclic groups selected from the following:

[0415] and

[0416] R e Each time it appears, it is independently selected from C. 1-6 Alkyl, F, Cl, Br, CN, NO2, =O, -NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C(=O)OH, -C(=O)OC 1-4 Alkyl group, -(CH2) r OH, -(CH2) r OC 1-4 Alkyl and SO2C 1-4 alkyl.

[0417] In the twenty-first aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which falls within the scope of the sixteenth aspect, wherein:

[0418] For selection and

[0419] R2 is -CH2-cyclopropyl;

[0420] R3 is -OC 1-4 alkyl;

[0421] R4 is selected from

[0422]

[0423] and

[0424] R5 is independently selected from H, F, Cl, Br, CN, and C each time it appears. 1-4 Alkyl, -OR b -S(O) p R c -(CH2) r NR a S(O) p R c -(CH2) r NR a R a -(CH2) r NR a C(=O)R b -NR a C(=O)OR b -C(=O)OR b C(=O)NR a R a , through 0 to 4 R e Replacement C 3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups;

[0425] R6 is independently selected from H, through 0 to 4 Rs each time it appears. e Replacement C 1-3 Alkyl group, -S(O) p R c -C(=O)R b -C(=O)OR b -(CH2) r -C(=O)NR a R a -C(=O)(CH2) r NR a C(=O)R b -S(O) p NR a R a , through 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups;

[0426] R a Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groupse Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; or R a and R a Together with the nitrogen atom it is attached to, they form a structure with 0 to 5 R atoms. e Substituted heterocycles;

[0427] R b Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Substituted -(CH2) r -C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0428] R c Each occurrence is independently selected from 0 to 5 R values. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-6 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group;

[0429] R e Each occurrence is independently selected from 0 to 5 R values. f Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -aryl, F, Cl, Br, CN, NO2, =O, -NH2, -NHC 1-4 Alkyl, -N(C) 1-4Alkyl)2, -C(=O)OH, -C(=O)OC 1-4 Alkyl group, -(CH2) r OH and -(CH2) r OC 1-4 alkyl;

[0430] R f Each time it appears, it is independently selected from H, F, Cl, Br, CN, OH, or C substituted with OH. 1-5 Alkyl, C 3-6 cycloalkyl and phenyl groups;

[0431] p is independently selected from 0, 1, and 2 each time it appears; and

[0432] r is independently selected from 0, 1, 2, 3, and 4 each time it appears.

[0433] In the twenty-second aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, which falls within the scope of the twenty-first aspect, wherein:

[0434] R4 is selected from

[0435] and and

[0436] R5 is selected independently from H, F, Cl, Br, and C each time it appears. 1-4 Alkyl groups, OH groups, and -C(=O)OH groups.

[0437] In its twenty-third aspect, the present invention provides a compound of formula (V):

[0438]

[0439] Or its pharmaceutically acceptable salt, wherein:

[0440] For selection and

[0441] R2 is -CH2-cyclopropyl;

[0442] R3 is -OCH3; and

[0443] R4 is selected from

[0444] and

[0445] In its twenty-fourth aspect, the present invention provides a compound of formula (VI):

[0446]

[0447] Or its pharmaceutically acceptable salt, wherein:

[0448] For selection and

[0449] R2 is -CH2-cyclopropyl;

[0450] R4 is selected from and and

[0451] R5 is selected from H, OH, CH2OH and -C(CH3)2OH.

[0452] In the twenty-fifth aspect, the present invention provides a compound of formula (VII):

[0453]

[0454] Or its pharmaceutically acceptable salt, wherein:

[0455] For selection and

[0456] R2 is -CH2-cyclopropyl;

[0457] R4 is selected from and

[0458] R5 is selected independently from F, Cl, and C each time it appears. 1-4 Alkyl group, -(CH2) r OR b -S(O)2NR a R a -NR a S(O)2R c and -C(=O)NR a R a ;

[0459] R6 is selected independently from H and C each time it appears. 1-3 alkyl;

[0460] R a Each occurrence is independently selected from H and via 0 to 5 R. e Replacement C 1-4 alkyl;

[0461] R b Each occurrence is independently selected from H and via 0 to 5 R. e Replacement C1-4 alkyl;

[0462] R c Each occurrence is independently represented by 0 to 5 R's. e Replacement C 1-4 alkyl;

[0463] R e Each time it appears, it is independently selected from F, Cl, Br, -OH, and -OC. 1-4 Alkyl groups; and

[0464] r is independently selected from 0, 1, and 2 each time it appears.

[0465] In one embodiment, using the RFMS PAD4 functional test disclosed herein, the compound provided by the present invention has an IC50 value ≤ 4.000 μM, preferably ≤ 1.000 μM, preferably ≤ 0.500 μM, preferably ≤ 0.100 μM, more preferably ≤ 0.050 μM, more preferably ≤ 0.03 μM, more preferably ≤ 0.02 μM, and even more preferably ≤ 0.01 μM.

[0466] As defined above and described herein, R1 is selected from CH3 and CD3. In some embodiments, R1 is CH3. In some embodiments, R1 is CD3.

[0467] As defined above and described in this article, R2 is hydrogen, with 0 to 5 R atoms. e Replacement C 1-3 Alkyl groups or those with 0 to 5 R groups e Replacement C 3-6 Cycloalkyl. In some embodiments, R2 is hydrogen. In some embodiments, R2 is C-hydroxyl. 3-6 Cycloalkyl-substituted C 1-2 Alkyl group. In some embodiments, R2 is C2. 3-6Cycloalkyl. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is cyclopropyl. In some embodiments, R2 is cyclobutyl. In some embodiments, R2 is cyclopentyl. In some embodiments, R2 is cyclohexyl. In some embodiments, R2 is cyclopropylmethyl. In some embodiments, R2 is cyclobutylmethyl. In some embodiments, R2 is cyclopentylmethyl. In some embodiments, R2 is cyclohexylmethyl. In some embodiments, R2 is cyclopropylethyl. In some embodiments, R2 is cyclobutylethyl. In some embodiments, R2 is cyclopentylethyl. In some embodiments, R2 is cyclohexylethyl. In some embodiments, R2 is -CH2-cyclopropyl or -CH2-cyclobutyl. In some embodiments, R2 is optionally -CH2-cyclobutyl substituted with methyl and -OH. In some embodiments, R2 is a functional group selected from those depicted in the following examples.

[0468] As defined above and described herein, Q is N or CH. In some embodiments, Q is N. In some embodiments, Q is CH. In some embodiments, Q is selected from those functional groups depicted in the following embodiments.

[0469] As defined above and described in this article, R3 is selected from H, F, Cl, Br, -OR b and through 0 to 5 R e Replacement C 1-3 Alkyl group. In some embodiments, R3 is H. In some embodiments, R3 is F, Cl, or Br. In some embodiments, R... 3 For F. In some implementations, R 3 C 1-3 Alkyl group. In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl. In some embodiments, R3 is propyl. In some embodiments, R3 is OR. b In some embodiments, R3 is -OCH3. In some embodiments, R3 is -OCH2CH3. In some embodiments, R3 is -OCH2CH2CH3. In some embodiments, R3 is -OCH(F)2. In some embodiments, R3 is a functional group selected from those described in the following examples.

[0470] As defined above and described in this article, L does not exist and is -NR. d -、-O-、-C(=O)NR d -or -S(O) p -; In some implementations, L is absent. In some implementations, L is -NR. d -, R dFor H or C 1-3 Alkyl group. In some embodiments, L is -O-. In some embodiments, L is -C(=O)NH-. In some embodiments, L is -S(O)2-. In some embodiments, L is -S-. In some embodiments, L is selected from those functional groups depicted in the following examples.

[0471] As defined above and described in this article, each R4 is

[0472]

[0473]

[0474] In some implementations, R4 is In some implementations, R4 is In some implementations, R4 is In some implementations, R4 is

[0475] In some implementations, R4 is

[0476] In some implementations, R4 is In some implementations, R4 is In some implementations, R4 is

[0477] In some implementations, R4 is

[0478] In some implementations, R4 is

[0479]

[0480] In some implementations, R4 is and

[0481] In some implementations, R4 is and

[0482] In some implementations, R4 is and

[0483] In some implementations, R4 is and

[0484] In some embodiments, R4 is formed by 1 to 4 F, Cl, Br, OH and C atoms. 3-6Cycloalkyl-substituted C 1-5 alkyl.

[0485] In some implementations, R4 is selected from... and

[0486] As defined above and described in this article, R5 is H, F, Cl, Br, CN, with 0 to 5 R... e Replacement C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne, nitro, -S(O) p R c -S(O) p NR a R a -NR a S(O) p R c -(CH2) r OR b -(CH2) r NR a R a -NR a C(=O)R b NR a C(=O)OR b -NR a C(=O)NR a R a -C(=O)R b -C(=O)OR b C(=O)NR a R a -OC(=O)R b , through 0 to 4 R e Replacement C 3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups.

[0487] In some implementations, R5 is H, F, Cl, CN, C. 1-4 Alkyl, C 1-4 Alkyl groups (substituted with OH, NH2, and COOH), SC 1-4 Alkyl, S(O)2C 1-4 Alkyl, S(O)2NH-cyclopropyl, -(CH2) 0-1 NHS(O)2C 1-4 Alkyl, N(R) d S(O)2C 2-4 Alkenyl, -(CH2)0-1 OH, OC 1-4 Alkyl group, -(CH2) 0-1 NH2、-(CH2) 0-1 NHC(=O)C 1-4 Alkyl, -NR d C(=O)C 2-4 alkenyl, -NHC(=O)C 2-4 Alkyne group, -(CH2) 0-1 C(=O)OH、-C(=O)OC 1-4 Alkyl group, -NHC(=O)OC 1-4 Alkyl group, -NHC(=O)O(CH2)2OC 1-4 Alkyl, -NHC(=O)OCH2-cyclopropyl, -NHC(=O)NH2, C(=O)NHC 1-4 Alkyl group, CONH(CH2) 1-2 C(=O)OH, -(CH2) 0-1 C(=O)NH2、-(CH2) 0-1 C(=O)NHC 1-4 Alkyl, C(=O)NH-pyridine, -C(=O)NH(CH2)2N(C 1-4 Alkyl group 2, -C(=O)NH(CH2)2OH, -C(=O)NH(CH2)2S(O)2C 1-4 Alkyl groups and -OC(=O)C 1-4 alkyl.

[0488] In some implementations, R5 is

[0489] In some implementations, R5 is and

[0490] In some implementations, R5 is F. In some implementations, R5 is C. 1-4 Alkyl group. In some embodiments, R5 is -OH or -OC. 1-3 Alkyl group. In some embodiments, R5 is -NHS(O)2C. 2-4 Alkenyl. In some embodiments, R5 is selected from those functional groups depicted in the following examples.

[0491] As defined above and described in this article, R6 is H, passing through 0 to 4 R... e Replacement C 1-3 Alkyl group, -S(O) p R c -C(=O)R b -(CH2)r -C(=O)NR a R a -C(=O)(CH2) r NR a C(=O)R b -C(=O)OR b -S(O) p NR a R a , through 0 to 4 R e Substituted aryl groups or those with 0 to 4 R groups e Substituted heterocyclic groups.

[0492] In some embodiments, R6 is H. In some embodiments, R6 is methyl or isopropyl. In some embodiments, R6 is -(CH2)2C(=O)NH2. In some embodiments, R6 is -(CH2)2OH. In some embodiments, R6 is C(=O)C 1-4 Alkyl group. In some embodiments, R6 is selected from those functional groups depicted in the following examples.

[0493] As defined above and described in this article, R7 represents H, F, Cl, and C. 1-3 Alkyl, -NR a R a or -NR a C(=O)OR b In some implementations, R7 is NH2. In some implementations, R7 is F.

[0494] As defined above and described in this article, R8 is H, F, Cl, Br, or derived from 0 to 5 R groups. e Replacement C 1-4 Alkyl group. In some embodiments, R8 is H. In some embodiments, R8 is a C1-3 alkyl group.

[0495] As defined above, ring A is

[0496] In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is

[0497] In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is

[0498] In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementation schemes, ring A is... In some implementations, ring A is In some implementations, ring A is

[0499] In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is

[0500] In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is

[0501] In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is

[0502] In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, R4 is selected from those functional groups depicted in the following embodiments.

[0503] As defined above and described herein, r ranges from 0 to 4. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4.

[0504] In some implementations, ring A is R1 is CH3, R2 is cyclopropylmethyl, Q is N or CH, R3 is H, F or -OCH3, and R4 is... And R5 is H, F, Cl, CN, C 1-4 Alkyl groups, C substituted with OH, NH2, and COOH 1-4 Alkyl, SC 1-4Alkyl, S(O)2C 1-4 Alkyl, S(O)2NH-cyclopropyl, -(CH2) 0-1 NHS(O)2C 1-4 Alkyl, N(R) d S(O)2C 2-4 Alkenyl, -(CH2) 0-1 OH, OC 1-4 Alkyl group, -(CH2) 0-1 NH2、-(CH2) 0- 1NHC(=O)C 1-4 Alkyl, -NR d C(=O)C 2-4 alkenyl, -NHC(=O)C 2-4 Alkyne group, -(CH2) 0-1 C(=O)OH、-C(=O)OC 1-4 Alkyl group, -NHC(=O)OC 1-4 Alkyl group, -NHC(=O)O(CH2)2OC 1-4 Alkyl, -NHC(=O)OCH2-cyclopropyl, -NHC(=O)NH2, C(=O)NHC 1-4 Alkyl group, CONH(CH2) 1-2 C(=O)OH, -(CH2) 0-1 C(=O)NH2、-(CH2) 0-1 C(=O)NHC 1-4 Alkyl, C(=O)NH-pyridine, -C(=O)NH(CH2)2N(C 1-4 Alkyl group 2, -C(=O)NH(CH2)2OH, -C(=O)NH(CH2)2S(O)2C 1-4 Alkyl groups and -OC(=O)C 1-4 alkyl,

[0505] In some implementations, ring A is R1 is CH3, R2 is cyclopropylmethyl, Q is N or CH, R3 is H, F or -OCH3, and R5 is... And R5 is H, F, Cl, CN, C 1-4 Alkyl groups, C substituted with OH, NH2, and COOH 1-4 Alkyl, SC 1-4 Alkyl, S(O)2C 1-4 Alkyl, S(O)2NH-cyclopropyl, -(CH2) 0-1 NHS(O)2C 1-4 Alkyl, N(R) d S(O)2C 2-4 Alkenyl, -(CH2)0-1 OH, OC 1-4 Alkyl group, -(CH2) 0-1 NH2、-(CH2) 0-1 NHC(=O)C 1-4 Alkyl, -NR d C(=O)C 2-4 alkenyl, -NHC(=O)C 2-4 Alkyne group, -(CH2) 0-1 C(=O)OH、-C(=O)OC 1-4 Alkyl group, -NHC(=O)OC 1-4 Alkyl group, -NHC(=O)O(CH2)2OC 1-4 Alkyl, -NHC(=O)OCH2-cyclopropyl, -NHC(=O)NH2, C(=O)NHC 1-4 Alkyl group, CONH(CH2) 1-2 C(=O)OH, -(CH2) 0-1 C(=O)NH2、-(CH2) 0-1 C(=O)NHC 1-4 Alkyl, C(=O)NH-pyridine, -C(=O)NH(CH2)2N(C 1-4 Alkyl group 2, -C(=O)NH(CH2)2OH, -C(=O)NH(CH2)2S(O)2C 1-4 Alkyl groups and -OC(=O)C 1-4 alkyl,

[0506] In some implementations, ring A is R1 is CH3, R2 is cyclopropylmethyl, Q is N or CH, R3 is H, F or -OCH3, and R4 is...

[0507] In some implementations, ring A is R1 is CH3, R2 is cyclopropylmethyl, Q is N or CH, R3 is H, F or -OCH3, and R4 is...

[0508] In some implementations, ring A is R1 is CH3, R2 is cyclopropylmethyl, Q is N or CH, R3 is H, F or -OCH3, and R4 is...

[0509] In some implementations, ring A is R1 is CH3, R2 is cyclopropylmethyl, Q is N or CH, R3 is H, F or -OCH3, and R4 is...

[0510] In some implementations, ring A is R1 is CH3, R2 is cyclopropylmethyl, Q is N or CH, R3 is H, F or -OCH3, and R4 is... and

[0511] In some implementations, ring A is R1 is CH3, R2 is cyclopropylmethyl, Q is N or CH, R3 is H, F or -OCH3, and R4 is... and

[0512] In some implementations, ring A is R1 is CH3, R2 is cyclopropylmethyl, Q is N or CH, R3 is H, F or -OCH3, and R4 is... and And R5 is H, F, C 1-4 Alkyl, -OH, -OC 1-3 Alkyl groups and -NHS(O)2C 2-4 Alkenyl group.

[0513] In some embodiments, the compound of formula (I) is selected from the examples described below. In some embodiments, the invention provides any compound or a pharmaceutically acceptable salt or composition thereof for therapeutic purposes described above and herein. In some embodiments, the invention provides any compound described above and herein in isolated form. In some embodiments, the invention provides a compound as described in any of claims 1 to 16.

[0514] 4. Purpose, preparation and distribution

[0515] Pharmaceutically acceptable compositions

[0516] According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator. The amount of the compound in the composition of the present invention is such that it can effectively and measurably inhibit PAD4 in a biological sample or patient. In some embodiments, the amount of the compound in the composition of the present invention is such that it can effectively and measurably inhibit PAD4 in a biological sample or patient. In some embodiments, the composition of the present invention is formulated for administration to a patient requiring such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0517] As used herein, the terms "individual" and "patient" are used interchangeably and refer to an animal, preferably a mammal. In some embodiments, the individual or patient is a human. In other embodiments, the individual (or patient) is a veterinary individual (or patient). In some embodiments, the veterinary individual (or patient) is a dog, cat, or equine individual.

[0518] The term "pharmaceutically acceptable carrier, adjuvant, or catalyst" refers to a non-toxic carrier, adjuvant, or catalyst that does not impair the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable carriers, adjuvants, or catalysts that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates, glycine, sorbic acid, potassium sorbate), mixtures of metaglycerides 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, sodium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates), waxes, polyethylene-polypropylene oxide-block copolymers, polyethylene glycol, and lanolin.

[0519] The compositions of this invention can be administered orally, non-enterically, via inhalation spray, topically, rectally, nasally, buccally, vaginally, or by means of an implantable reservoir. As used herein, the term "non-enteric" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrasheath, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions of this invention can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable formulation can also be a sterile injectable solution or suspension in a non-toxic, non-enteric acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among acceptable mediators and solvents, water, Ringer's solution, and isotonic sodium chloride solution may be used. Furthermore, sterile, non-volatile oils are routinely used as solvents or suspension media.

[0520] For this purpose, any mild, non-volatile oil, including synthetic monoglycerides or diglycerides, may be used. Fatty acids (such as oleic acid and its glycerol derivatives) are suitable for the preparation of injectable formulations, as are pharmaceutically acceptable natural oils (such as olive oil or castor oil, especially their polyoxyethylene forms). These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other commonly used surfactants (such as Tween, Span, and other emulsifiers) or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

[0521] The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form, including (but not limited to) capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. Sweeteners, flavoring agents, or coloring agents may also be added as needed.

[0522] Alternatively, the pharmaceutically acceptable composition of the present invention can be used for administration in the form of rectal suppositories. These suppositories can be prepared by mixing the pharmaceutical preparation with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. The materials include cocoa butter, beeswax, and polyethylene glycol.

[0523] The pharmaceutically acceptable compositions of the present invention can also be administered topically, especially when the therapeutic target includes areas or organs easily accessible by topical application (including diseases of the eyes, skin, or lower intestine). Suitable topical formulations for each of these areas or organs are readily prepared.

[0524] Topical application for the lower intestine can be achieved via rectal suppository formulation (see above) or in a suitable enema formulation. A local percutaneous patch may also be used.

[0525] For topical application, the pharmaceutically acceptable compositions provided may be formulated in a suitable ointment form containing an 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 paraffin, white paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the pharmaceutically acceptable compositions provided may be formulated in a suitable lotion or cream form containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include (but are not limited to) mineral oil, sorbitan monostearate, polysorbate 60, cetyl wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0526] For ophthalmic use, the pharmaceutically acceptable composition provided may be formulated as a micronized suspension, with or without a preservative (such as benzyl chlorobenzyl ammonium), in isotonic pH-adjusted sterile physiological saline, or preferably as a solution in isotonic pH-adjusted sterile physiological saline. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated as an ointment (such as paraffin).

[0527] The pharmaceutically acceptable compositions of the present invention can also be administered via nasal aerosol or inhaler. Such compositions are prepared according to techniques well known in the pharmaceutical formulation field and can be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, bioavailability-enhancing absorption promoters, fluorocarbons, and / or other conventional solvents or dispersants.

[0528] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may or may not be administered with 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.

[0529] The pharmaceutically acceptable compositions of the present invention may be administered to humans and other animals, depending on the severity of the infection being treated, via oral, rectal, non-intestinal, intracisional, vaginal, intraperitoneal, topical (e.g., by powder, ointment, or drops), buccal, as an oral or nasal spray, or similar methods. In some embodiments, the compounds of the present invention may be administered orally or non-intestinally once or more times daily at dose levels of about 0.01 mg / kg to about 50 mg / kg, and preferably about 1 mg / kg to about 25 mg / kg, of individual body weight to achieve the desired therapeutic effect.

[0530] Liquid dosage forms for oral administration include (but are not limited to) pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain: inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0531] Injectable formulations can be formulated using suitable dispersants, wetting agents, and suspending agents according to known techniques, such as sterile injectable aqueous or oily suspensions. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, non-enteric-acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Among acceptable mediators and solvents, water, Ringer's solution, USP, and isotonic sodium chloride solution can be used. Furthermore, sterile non-volatile oils are routinely used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectable formulations.

[0532] Injectable formulations can be sterilized, for example, by filtration through a bacterial trapping filter or by incorporation of a sterilizing agent, and are in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0533] To prolong the effects of the compounds of this invention, it is generally necessary to slow the absorption of compounds administered subcutaneously or intramuscularly. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. The absorption rate of the compound depends on its solubility, which in turn may depend on crystal size and crystal form. Alternatively, delayed absorption of compounds administered non-enterostomically can be achieved by dissolving or suspending the compound in an oil-based medium. Injectable accumulation formulations are prepared by forming microcapsule matrices of the compound in a biodegradable polymer, such as polylactic acid-polyglycolic acid. The release rate of the compound can be controlled depending on the ratio of compound to polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoester) and poly(anhydride). Injectable accumulation formulations can also be prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

[0534] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers (such as cocoa butter, polyethylene glycol, or suppository waxes) that are solid at ambient temperature but liquid at body temperature and thus melt in the rectal or vaginal cavity and release the active compound.

[0535] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate; and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; d) disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution blockers, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) humectants, such as cetyl alcohol and glycerol monostearate; h) adsorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffers.

[0536] Similar solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose or tartrate and high molecular weight polyethylene glycol and its analogues. Solid dosage forms of tablets, sugar-coated pills, capsules, pellets, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings known in pharmaceutical compounding techniques. They may optionally contain emulsifiers and may also have compositions that release the active ingredient only or preferentially in a portion of the intestine or optionally in a delayed manner. Examples of encapsulation compositions that can be used include polymeric substances and waxes. Similar solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose or tartrate and high molecular weight polyethylene glycol and its analogues.

[0537] The active compound may also be present in microencapsulation with one or more excipients as noted above. Solid dosage forms of tablets, sugar-coated pills, capsules, pellets, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlled coatings, and other coatings well known in pharmaceutical compounding techniques. In these solid dosage forms, the active compound may be mixed with at least one inert diluent (such as sucrose, lactose, or starch). As is common practice, such dosage forms may also contain substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage form may also contain a buffer. It may optionally contain an emulsifier and may also have a composition that releases the active ingredient only or preferentially in a portion of the intestine or optionally in a delayed manner. Examples of encapsulation compositions that can be used include polymers and waxes.

[0538] Dosage forms for topical or transdermal administration of the compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of this invention. Additionally, this invention covers the use of transdermal patches, which offer the added advantage of controlled delivery of the compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers may also be used to increase the transdermal amount of the compound. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0539] The amount of the compounds of the present invention that can be combined with a carrier to produce a single-dosage composition will vary depending on the host being treated and the specific administration pattern. Preferably, the provided compositions are formulated to allow administration to patients receiving these compositions at doses between 0.01 mg / kg body weight / day and 100 mg / kg body weight / day as inhibitors.

[0540] The compounds of this invention can be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies may be administered in a fixed combination or alternately or independently of each other, or in combination with a fixed combination and one or more other therapeutic compounds. Exemplary examples of such other therapeutic agents include corticosteroids, rolipram, calciphosphatein, cytokine-suppressive anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide and other immunosuppressants; nuclear translocation inhibitors, such as deoxyspergualin (DSG); nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, celecoxib and rofecoxib; steroids, such as prednisone or dexamethasone; and antiviral agents, such as abacavir. Antiproliferative agents, such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf); cytotoxic drugs, such as azathioprine and cyclophosphamide; TNF-α inhibitors, such as tenidap, anti-TNF antibodies or soluble TNF receptors, and rapamycin (sirolimus or rapamune) or derivatives thereof. The compounds of the present invention may be administered in addition to or in combination with chemotherapy, radiation therapy, immunotherapy, phototherapy, surgical intervention, or combinations thereof for the treatment of cancer. As described above, long-term therapy is also possible, as is the adjuvant therapy in the case of other treatment strategies. Other possible treatments include therapies to maintain the patient's condition after tumor regression, or even chemopreventive therapy (e.g., for patients at risk).

[0541] Other agents may be administered separately from the composition containing the compound of the present invention as part of a multiple-dose regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compound of the present invention in a single composition. If administered as part of a multiple-dose regimen, the two active agents may be provided simultaneously, sequentially, or at intervals (typically within five hours of each other).

[0542] As used herein, the terms "combination" and related terms refer to the simultaneous or sequential administration of a therapeutic agent according to the invention. For example, the compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in individual unit dosage forms or together in a single unit dosage form. Therefore, the present invention provides a single unit dosage form comprising the compound of the invention, other therapeutic agents, and pharmaceutically acceptable carriers, adjuvants, or mediators.

[0543] The amount of the compounds of the present invention and other therapeutic agents (in those compositions comprising other therapeutic agents as described above) that can be combined with a carrier substance to produce a single dosage form will vary depending on the host being treated and the specific administration pattern. Preferably, the compositions of the present invention should be formulated such that the dosage of the compounds of the present invention is between 0.01 and 100 mg / kg body weight / day.

[0544] In compositions that include additional therapeutic agents, the other therapeutic agents and the compounds of the present invention can act synergistically. Therefore, the amount of the other therapeutic agent in such compositions will be less than that required in monotherapy using only that therapeutic agent.

[0545] The amount of other therapeutic agents present in the compositions of the present invention will not exceed the amount typically given in compositions containing that therapeutic agent as the sole active agent. Preferably, the amount of other therapeutic agents in the compositions disclosed in this invention will be in the range of about 50% to 100% of the amount typically present in compositions containing that agent as the sole active agent.

[0546] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health status, sex, diet, administration time, excretion rate, drug combination, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of the compound of the present invention in the composition will also depend on the specific compound in the composition.

[0547] 5. Use of the compound and pharmaceutically acceptable composition

[0548] The compounds and compositions described herein are generally suitable for inhibiting PAD4.

[0549] The activity of the compounds used as PAD4 inhibitors in this invention can be analyzed in vitro, in vivo, or in cell lines. In vitro analysis includes assays to determine PAD4 inhibition. Detailed conditions for analyzing the compounds used as PAD4 inhibitors in this invention are described in the following examples. In some embodiments, the provided compounds selectively inhibit PAD4 compared to PAD2.

[0550] As used herein, the term "treatment / treat / treating" refers to reversing or alleviating a disease or condition or one or more symptoms thereof as described herein, delaying its onset, or inhibiting its progression. In some implementations, treatment may be given after one or more symptoms have appeared. In other implementations, treatment may be given in the absence of symptoms. For example, treatment may be given to a susceptible individual before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also continue after symptoms have subsided, for example, to prevent or delay their recurrence.

[0551] The provided compounds are PAD4 inhibitors and are therefore suitable for treating one or more conditions associated with PAD4 activity. Accordingly, in some embodiments, the present invention provides a method for treating PAD4-mediated conditions, comprising the step of administering the compound of the present invention or a pharmaceutically acceptable composition thereof to a patient in need.

[0552] In one embodiment, PAD4-mediated conditions are diseases, symptoms, or conditions mediated by inappropriate PAD4 activity. In some embodiments, PAD4-mediated conditions are selected from the group consisting of: rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, and psoriasis. In another embodiment, the condition mediated by inappropriate PAD4 activity is rheumatoid arthritis. In another embodiment, the condition mediated by inappropriate PAD4 activity is systemic lupus erythematosus. In another embodiment, the condition mediated by inappropriate PAD4 activity is vasculitis. In another embodiment, the condition mediated by inappropriate PAD4 activity is cutaneous lupus erythematosus. In another embodiment, the condition mediated by inappropriate PAD4 activity is psoriasis.

[0553] In one embodiment, a method for treating rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis is provided, the method comprising administering to a human individual in need a therapeutically effective amount of the provided compound or a pharmaceutically acceptable salt thereof.

[0554] In one embodiment, a method for treating rheumatoid arthritis is provided, the method comprising administering to a human individual in need a therapeutically effective amount of the provided compound or a pharmaceutically acceptable salt thereof. In one embodiment, a method for treating systemic lupus erythematosus is provided, the method comprising administering to a human individual in need a therapeutically effective amount of the provided compound or a pharmaceutically acceptable salt thereof. In one embodiment, a method for treating vasculitis is provided, the method comprising administering to a human individual in need a therapeutically effective amount of the provided compound or a pharmaceutically acceptable salt thereof. In one embodiment, a method for treating cutaneous lupus erythematosus is provided, the method comprising administering to a human individual in need a therapeutically effective amount of the provided compound or a pharmaceutically acceptable salt thereof. In one embodiment, a method for treating psoriasis is provided, the method comprising administering to a human individual in need a therapeutically effective amount of the provided compound or a pharmaceutically acceptable salt thereof.

[0555] In some implementations, PAD4-mediated conditions are selected from the following groups: acid-induced lung injury, acne (PAPA), acute lymphoblastic leukemia, acute respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenal insufficiency, aging, AIDS, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis and weight loss, angina pectoris, angioedema, anhidroticecodermal dysplasia-ID, and ankylosing spondylitis. Spondylitis, anterior segment inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, Behcet's syndrome, Bell's Palsey, beryllium poisoning, Blau syndrome, bone pain, bronchiolitis, burning pain, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorder, cataract, cerebral aneurysm. Aneurysm, chemically induced inflammation, chorioretinitis, chronic heart failure, chronic lung disease in premature infants, chronic lymphocytic leukemia, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue disease, corneal ulcer, Crohn's disease, and cryopyrin-associated periodic syndrome.Syndrome, cryptococcosis, cystic fibrosis, interleukin-1 receptor antagonist (IRA) deficiency, dermatitis, dermatitis endotoxemia, dermatomyositis, diffuse intrinsic pontine glioma, endometriosis, endotoxemia, epicondylitis, erythroblastopenia, familial amyloidotic polyneuropathy, familial cold urticaria, familial Mediterranean fever, embryonic growth restriction, glaucoma, glomerular disease, glomerulonephritis. nephritis, gout, gouty arthritis, graft-versus-host disease, enteropathy, head injury, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Scholein purpura, hepatitis, hereditary periodic fever syndrome, herpes zoster and herpes simplex, HIV-1, Hodgkin's disease, Huntington's disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulinemia D with recurrent fever (HIDS), hypoplastic anemia and other anemias, hypoplastic anemia, idiopathic thrombocytopenic purpura, incontinentia. pigmenti), infectious mononucleosisMononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, iritis, irritant-induced inflammation, local ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, nephropathy, kidney injury caused by parasitic infection, kidney transplant rejection prevention, leptospirosis, leukemia, Loeffler's syndrome, lung injury, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria deafness amyloidosis), multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis, myocarditis, mycosis Fungoide, mycosis fungoides, myelodysplastic syndrome, myositis, sinusitis, necrotizing enterocolitis, neonatal onset multisystem inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological diseases, non-allergen-induced asthma, obesity, ocular allergies, optic neuritis, organ transplantation, osteoarthritis, otitis media, Paget's disease, pain, pancreatitis, Parkinson's disease, pemphigus, pericarditis, periodic fever, periostitis, peritoneometriosis, pertussis, pharyngitis and adenitis (PFAPA syndrome), plant-induced inflammation, pneumonia, pneumocystis pneumonia, pneumocystis infection. Infection), inflammation induced by poison ivy / urushiol oil, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyositis, psoriasis, psoriasis, psoriasis, psoriasis, psychosocial stress disorders, pulmonary diseases.Diseases including pulmonary hypertension, pulmonary fibrosis, pyoderma gangrenosum, pyogenic sterile arthritis, nephropathy, retinal diseases, rheumatic carditis, rheumatic diseases, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cells, sickle cell anemia, silica-induced diseases, Sjogren's syndrome, skin diseases, sleep apnea, solid tumors, spinal cord injury, Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, and temporal arteritis. 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, urticarial uveitis, Wegener's granulomatosis, interstitial lung disease, psoriatic arthritis, juvenile idiopathic arthritis, Hughley's syndrome ( Antineutrophil syndrome (ANCA)-associated vasculitis, antiphospholipid antibody syndrome, sepsis, deep vein thrombosis, fibrosis, Alzheimer's disease, scleroderma, and CREST syndrome.

[0556] In one embodiment, the present invention provides a provided compound or a pharmaceutically acceptable salt thereof for use in a therapy. In another embodiment, the present invention provides a provided compound or a pharmaceutically acceptable salt thereof for treating a condition mediated by inappropriate PAD4 activity. In another embodiment, the present invention provides a provided compound or a pharmaceutically acceptable salt thereof for treating rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis. In another embodiment, the present invention provides a provided compound or a pharmaceutically acceptable salt thereof for treating rheumatoid arthritis. In another embodiment, the present invention provides a provided compound or a pharmaceutically acceptable salt thereof for treating systemic lupus erythematosus. In another embodiment, the present invention provides a provided compound or a pharmaceutically acceptable salt thereof for treating vasculitis. In another embodiment, the present invention provides a provided compound or a pharmaceutically acceptable salt thereof for treating cutaneous lupus erythematosus. In another embodiment, the present invention provides a provided compound or a pharmaceutically acceptable salt thereof for treating psoriasis. In another embodiment, the present invention provides the use of the provided compound or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating a condition mediated by inappropriate PAD4 activity. In another embodiment, the present invention provides the use of the provided compound or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis. In another embodiment, the present invention provides the use of the provided compound or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating rheumatoid arthritis. In another embodiment, the present invention provides the use of the provided compound or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating systemic lupus erythematosus. In another embodiment, the present invention provides the use of the provided compound or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating vasculitis. In another embodiment, the present invention provides the use of the provided compound or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating cutaneous lupus erythematosus. In another embodiment, the present invention provides the use of the provided compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating psoriasis. In another embodiment, the present invention provides a pharmaceutical composition for treating or preventing conditions mediated by inappropriate PAD4 activity, comprising the provided compound or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a pharmaceutical composition for treating or preventing rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis, comprising the provided compound or a pharmaceutically acceptable salt thereof.In another embodiment, the present invention provides a pharmaceutical composition for treating or preventing rheumatoid arthritis, comprising the provided compound or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a pharmaceutical composition for treating or preventing systemic lupus erythematosus, comprising the provided compound or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a pharmaceutical composition for treating or preventing vasculitis, comprising the provided compound or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a pharmaceutical composition for treating or preventing cutaneous lupus erythematosus, comprising the provided compound or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a pharmaceutical composition for treating or preventing psoriasis, comprising the provided compound or a pharmaceutically acceptable salt thereof.

[0557] All features of each aspect of the invention, with necessary modifications to the details, apply to all other aspects.

[0558] To provide a more complete understanding of the invention described herein, the following embodiments are illustrated. It should be understood that these embodiments are for illustrative purposes only and should not be construed as limiting the invention in any way.

[0559] Examples

[0560] As depicted in the following examples, in some exemplary embodiments, the compounds are prepared according to the following general procedure. It should be understood that although the general approach describes the synthesis of certain compounds of the present invention, the following general approach and other methods known to those skilled in the art can be applied to all compounds as described herein and to subclasses and types of each of these compounds.

[0561] Some of the compounds of this invention were prepared according to the process described below.

[0562] Process 1

[0563]

[0564] For compounds involving heteroatom coupling, see Procedure 2.

[0565] Process 2

[0566]

[0567] For the synthesis of sulfones, see process 3.

[0568] Process 3

[0569]

[0570] For the synthesis of formamide, see process 4.

[0571] Process 4

[0572]

[0573] For the synthesis of compounds involving photoredox chemistry methods, see process 5.

[0574] Process 5

[0575]

[0576] Description of analytical LCMS methods:

[0577] Method 1: Column: Waters XBridge C18, 2.1 mm × 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 min, followed by 0.5 min at 100% B; Flow rate: 1 mL / min; Detection: MS and UV (220 nm).

[0578] Method 2: Column: Waters XBridge C18, 2.1 mm × 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 min, followed by 0.5 min at 100% B; Flow rate: 1 mL / min; Detection: MS and UV (220 nm).

[0579] Method 3: Waters Acquity UPLC BEH C18, 2.1 × 50 mm, 1.7 μm particles; Mobile phase A: water + 0.05% TFA; Mobile phase B: ACN + 0.05% TFA; Gradient: 2-98% B for 1 min, followed by 0.5 min at 98% B; Flow rate: 0.8 mL / min; Detection: UV at 254 nm.

[0580] The structures drawn in this application are generally as follows: A represents a fully chiral structure B, wherein the chiral azibicycloheptane moiety is called ((1R,4R,7R)-7-amino-2-azibicyclo[2.2.1]hept-2-yl).

[0581]

[0582] Intermediate 1

[0583] 2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carboxylic acid

[0584]

[0585] Intermediate 1

[0586] 4 g (9.41 mmol) of methyl 2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazolium-5-carboxylate [for information on this starting material, see: WO 2017 / 0100594] was dissolved in THF (45 mL), MeOH (15 mL), and 2 M LiOH aqueous solution (9.41 mL). The solution was stirred at 70 °C for 90 min. To add to it, the reaction was repeated as follows: Methyl 2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazolium-5-carboxylic acid (2.9 g, 6.83 mmol) was dissolved in THF (24 mL), MeOH (8 mL), and 2M LiOH aqueous solution (6.83 mL). Over-saponification was found according to LCMS. This crude material was combined with the crude material from the earlier reaction. The mixture was slowly treated with 2N HCl until the pH reached approximately 6. At this stage, a precipitate formed as a brown solid in the form of 2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazolium-5-carboxylic acid (6.9 g). 1 H NMR (400MHz, DMSO-d6) δ 12.83 (br s, 1H), 8.20 (d, J = 8.3Hz, 1H), 7.96 (s, 1H), 7.41 (s, 1H), 7.28 (d, J = 8.2Hz, 1H), 7.17 (s, 1H), 4.44 (br d, J = 6.9Hz, 2H), 4.15 (s, 3H), 4.02 (s, 3H), 1.18–1.04 (m, 1H), 0.36–0.27 (m, 2H), 0.13 (q, J = 4.7Hz, 2H), LCMS (M+H)+ = 411.3, retention time = 1.01 min (Method 3).

[0587] Intermediate 2

[0588] ((1R,4R,7R)-2-(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-2-azabicyclo[2.2.1]hept-7-yl)tert-butyl carbamate

[0589]

[0590] Intermediate 2

[0591] DMF (35 mL) was added to a mixture of 5-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazolium-5-carboxylic acid (5.8 g, 14.12 mmol), ((7R)-2-azabicyclo[2.2.1]hept-7-yl)carbamate tert-butyl (3.30 g, 15.53 mmol), and Huenig's base (7.40 mL, 42.4 mmol). The mixture became a solid, and therefore, additional DMF (100 mL) was added (forming a slurry). Next, it was treated fractionally with HATU (6.44 g, 16.94 mmol) to ensure that the HATU dissolved before adding the next fraction. The reactants eventually became a yellow solution. After stirring at room temperature for 2 h, the reaction was found to be complete. The reaction mixture was diluted with EtOAc and washed with 10% LiCl aqueous solution (2×), followed by washing with brine. Extraction with EtOAc was performed, and the combined aqueous layers were dried (MgSO4), filtered, and concentrated to give a deep yellow-brown oil. This brown oil was purified by rapid chromatography (EtOAc / hexane), and the eluates were combined and concentrated to give ((1R,4R,7R)-2-(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-2-azabicyclo[2.2.1]hept-7-yl) tert-butyl carbamate (11 g): 1H NMR (400MHz, DMSO-d6) δ8.19 (d, J=8.2Hz, 1H), 7.51-7.36 (m, 1H), 7.27 (d, J=8.2Hz, 1H), 7.13 (s, 1H), 7.01-6.95 (m, 1H), 4.44 (br d, J=7.1Hz, 2H), 4.12 (s, 3H), 4.00 (s, 3H), 3.74-3.45 (m, 2H), 3.32 (s, 1H), 3.11-3.03 (m, 1H), 2.48-2.37 (m, 1H), 2.00-1.89 (m, 1H), 1.80 (br s, 2H), 1.52-1.44 (m, 1H), 1.44-1.28 (m, 9H), 1.15-1.05 (m, J = 4.6 Hz, 1H), 0.30 (br d, J = 7.7 Hz, 2H), 0.13 (br d, J = 4.8 Hz, 2H), LCMS(M+H)+ = 605.3, retention time = 1.05 min (Method 3).

[0592] Intermediate 3

[0593] ((1R,4R,7R)-2-(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-2-azabicyclo[2.2.1]hept-7-yl)tert-butyl carbamate

[0594]

[0595] Intermediate 3

[0596] A portion of the above-mentioned ((1R,4R,7R)-2-(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-2-azabicyclo[2.2.1]hept-7-yl) tert-butyl carbamate (9 g) was dissolved in DCM (100 mL) and treated with TFA (25 mL). After 2 h, additional TFA (15 mL) was added. After 1 h, the reactants were concentrated and then dissolved in EtOAc. The mixture was made alkaline by very slowly adding solid NaHCO3. After the foaming subsided, the mixture was stirred for another 30 min. The organic layer was separated and washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated to obtain a yellow, foamy solid of ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone (7 g): 1 H NMR (400MHz, DMSO-d6) δ8.20 (d, J=8.2Hz, 1H), 7.55-7.39 (m, 1H), 7.28 (d, J=8.2Hz, 1H), 7.15 (s, 1H), 7.02-6.95 (m, 1H), 4.44 (br d, J = 6.9 Hz, 2H), 4.13 (s, 3H), 4.07-4.04 (m, 1H), 4.00 (s, 3H), 3.79-3.40 (m, 2H), 3.19-3.10 (m, 1H), 2.48-2.43 (m, 1H), 1.97-1.81 (m, 3H), 1.62-1.53 ​​(m, 1H), 1.14-1.02 (m, 1H), 0.35-0.28 (m, 2H), 0.12 (br s, 2H); LCMS(M+H)+ = 505.3, retention time = 0.86 min (Method 3).

[0597] Example 1

[0598] 6-(2-(5-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,4-dihydroquinoline-2(1H)-one

[0599]

[0600] Example 1

[0601] Add ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone (25 mg, 0.053 mmol) and 6-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborhexacyclopentan-2-yl)-3,4-dihydroquinoline-2(1H)-one (17.25 mg, 0.063 mmol), 3M tripotassium phosphate aqueous solution (0.053 mL, 0.158 mmol), and THF (1 mL) containing a 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (4.30 mg, 5.26 μmol). The vial was capped and the reaction mixture was anaerobic by pump / backfill nitrogen circulation (5×). The reaction mixture was stirred at 70 °C for 7 h. The mixture was concentrated and dried under vacuum. The product was dissolved in DMF and purified by preparative LC / MS under the following conditions: Column: XBridge C18, 200 mm × 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: 0 min at 15% B, 20 min at 15–55% B, followed by 4 min at 100% B; Flow rate: 20 mL / min; Column temperature: 25 °C. The eluent was collected by MS and UV signal triggering. The eluents containing the desired product were combined and evaporated to dryness by centrifugation. The purified product was then diluted with DMF, treated with Si-pyridine, and shaken for at least 2 h. The resulting mixture was filtered and dried by centrifugation and evaporation to give 6-(2-(5-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,4-dihydroquinoline-2(1H)-one (12 mg): 1H NMR (500MHz, DMSO-d6) δ10.08 (s, 1H), 8.15 (d, J=8.2Hz, 1H), 8.02-7.97 (m, 2H), 7.89-7.78 (m, 1H), 7.76-7.69 (m, 2H), 7.45 (br d, J=8.6Hz, 1H), 7.10 (s, 1H), 7.01 (d, J=8.2Hz, 1H), 4.64 (br d, J=7.0Hz, 2H), 3.99 (s, 3H), 3.74 (br s, 1H), 3.63-3.48 (m, 1H), 3.35-3.27 (m, 1H), 3.17-3.04 (m, 1H), 3.01 (br t, J = 7.5 Hz, 2H), 2.56-2.52 (m, 3H), 2.23 (br s, 1H), 2.06-1.91 (m, 2H), 1.72 (br t, J = 9.3 Hz, 1H), 1.49-1.39 (m, 1H), 1.23 (br d, J = 8.4 Hz, 1H), 0.32 (br d, J = 7.8 Hz, 2H), 0.23 (br s, 2H); LC / MS(M+H) = 585.9; retention time = 1.43 min (Method 1).

[0602] Example 2

[0603] ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-((6-fluoropyridin-3-yl)oxy)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) ketone

[0604]

[0605] To a 1-drench vial, add 0.037 g (0.040 mmol) of tert-butyl carbamate ((1R,4R,7R)-2-(2-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-2-azabicyclo[2.2.1]hept-7-yl)carbamate, 5.42 mg (0.048 mmol) of 2-fluoro-5-hydroxypyridine, 0.020 g (0.060 mmol) of cesium carbonate, and 1 mL of dioxane containing Rockphos Pd G3 (3.35 mg, 3.99 μmol). Cap the vial and anaerobic the reaction mixture using a pump / backfill nitrogen circulation (5×). Stir the reaction mixture overnight at 90 °C. After cooling, the mixture was diluted with EtOAc, dried (MgSO4), filtered, and concentrated. The resulting residue was dissolved in dichloromethane (1 mL) and treated with TFA (0.5 mL, 6.49 mmol). The mixture was stirred at room temperature for 90 min, and then concentrated. The residue was dissolved in DMF, filtered, and purified by preparative LC / MS under the following conditions: column: XBridge C18, 19 × 200 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: 26–66% B for 20 min, followed by 100% B for 4 min; flow rate: 20 mL / min. The eluates containing the desired product were combined and evaporated to dryness by centrifugation. The purified substance was then diluted with DMF, treated with Si-pyridine, and shaken for at least 2 h. The resulting mixture was filtered and concentrated by centrifugation and evaporation to obtain ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-((6-fluoropyridin-3-yl)oxy)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) ketone (4.1 mg): 1H NMR (500MHz, DMSO-d6) δ8.03 (br s, 1H), 7.72 (br d, J=8.5Hz, 1H), 7.68 (br t, J=6.0Hz, 1H), 7.44 (br s, 1H), 7.34 (s, 1H), 7.21 (br dd, J=8.7, 2.9Hz, 1H), 7.06 (s, 1H), 6.95-6.90 (m, 2H), 4.37 (br d, J=6.4Hz, 2H), 4.10 (s, 3H), 3.98 (s, 3H), 3.75 (br 3.66-3.48 (m, 1H), 3.17 (s, 1H), 3.08-2.99 (m, 1H), 2.21 (brs, 1H), 2.04-1.91 (m, 2H), 1.74 (br t, J = 9.5 Hz, 1H), 1.48-1.40 (m, 1H), 1.23 (s, 2H), 1.04-0.94 (m, 1H), 0.26 (br d, J = 7.9 Hz, 2H), -0.02 (br s, 2H); LC / MS (M+H) = 581.3; retention time = 1.75 min (Method 1).

[0606] Example 3

[0607] ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(pyridin-4-ylthio)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone

[0608]

[0609] Example 3

[0610] A mixture of (1R,4R,7R)-2-(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-2-azabicyclo[2.2.1]hept-7-yl)carbamate (47 mg, 0.078 mmol), Pd2(dba)3 (14.22 mg, 0.016 mmol), and (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene (8.61 mg, 0.016 mmol) in DME (1.5 mL) was treated with potassium tert-butoxide (10.46 mg, 0.093 mmol). The reaction mixture was sealed in vials and anaerobically induced by a pump / backfill nitrogen circulation (5×). The reaction mixture was stirred at room temperature for 10 min. The vial cap was opened under nitrogen purging and treated with 4-mercaptopyridine (10.36 mg, 0.093 mmol). The vial was capped and anaerobically induced by a pump / backfill N2 circulation (3×). The reaction mixture was stirred overnight at 110 °C. The desired product and some starting materials were observed according to LCMS. To obtain more product, the reaction was repeated and the details are as follows: a mixture of (1R,4R,7R)-2-(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-2-azabicyclo[2.2.1]hept-7-yl)carbamate (110 mg, 0.182 mmol), (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene (20.16 mg, 0.036 mmol), and Pd2(dba)3 (33.3 mg, 0.036 mmol) in dioxane (2 mL) was treated with potassium tert-butoxide (24.48 mg, 0.218 mmol) under nitrogen purging. The reaction mixture was sealed in vials and anaerobically induced by a pump / backfill nitrogen cycle (5×). The reaction mixture was stirred at room temperature for 10 min. The vial cap was opened under nitrogen purging and treated with 4-mercaptopyridine (24.25 mg, 0.218 mmol). The vial was capped and anaerobically induced by a pump / backfill N2 cycle (3×). The reaction mixture was stirred at 110 °C for 20 h. After cooling, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl. It was diluted with EtOAc and then washed with water, followed by washing with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried (MgSO4). The crude products from both experiments were combined and purified by rapid chromatography (using a 12 g ISCO filter cartridge with EtOAc-hexane). The eluent was combined and concentrated (crude product weight = 0.1 g).The resulting residue was dissolved in DCM (1 mL) and treated with TFA (0.5 mL, 6.49 mmol). After 1 h, the solution was concentrated and the residue was dissolved in DMF, filtered, and purified by preparative LC / MS under the following conditions: column: XBridge C18, 200 mm × 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: 0 min at 24% B, 20 min at 24–64% B, followed by 4 min at 100% B; flow rate: 20 mL / min; column temperature: 25 °C. Elution was collected by MS and UV signal triggering. The eluates containing the desired product were combined and dried by centrifugation. The purified substance was then diluted with DMF, treated with Si-pyridine, and shaken for at least 2 h. The resulting mixture was filtered and dried by centrifugation and evaporation to obtain ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(pyridin-4-ylthio)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone (10.1 mg). 1 H NMR (500MHz, DMSO-d6) δ8.49 (br s, 2H), 8.21 (br d, J=7.9Hz, 1H), 7.41-7.35 (m, 4H), 7.15 (s, 1H), 6.98-6.93 (m, 1H), 4.37 (br d, J=6.1Hz, 2H), 4.14 (s, 3H), 4.00 (br s, 3H), 3.71 (br s, 2H), 3.57-3.47 (m, 1H), 3.10 (br d, J=11.0Hz, 1H), 2.91 (s, 1H), 2.75 (s, 1H), 1.92 (br s, 4H), 1.48(br t, J = 8.4 Hz, 1H), 1.08-1.00 (m, 1H), 0.27 (br d, J = 7.6 Hz, 2H), 0.00 (br s, 2H); LC / MS(M+H) = 580.4; retention time = 1.58 min (Method 1).

[0611] Example 4

[0612] ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(pyridin-4-ylsulfonyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) ketone

[0613]

[0614] Example 4

[0615] A mixture of (1R,4R,7R)-2-(2-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-2-azabicyclo[2.2.1]hept-7-yl)carbamate (120 mg, 0.185 mmol), (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene (20.52 mg, 0.037 mmol), and Pd2(dba)3 (33.9 mg, 0.037 mmol) in dioxane (2 mL) was treated with potassium tert-butoxide (24.91 mg, 0.222 mmol) under nitrogen rinsing. The reaction mixture was sealed in vials and anaerobically circulated through a pump / backfill nitrogen system (5×). The reaction mixture was stirred at room temperature for 10 min. The vial cap was opened under nitrogen purging and treated with 4-mercaptopyridine (30.8 mg, 0.278 mmol). The vial was capped and anaerobically circulated through a pump / backfill N2 system (3×). The reaction mixture was stirred overnight at 110 °C. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl. It was diluted with EtOAc and then washed with water, followed by washing with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by rapid chromatography (EtOAc / hexane) to give tert-butyl ((1R,4R,7R)-2-(2-(1-(cyclopropylmethyl)-6-(pyridin-4-ylthio)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-2-azabicyclo[2.2.1]hept-7-yl)carbamate (38 mg, 0.056 mmol, 30.3% yield) as a pale brown oil, dissolved in acetone (1.5 mL) and treated with water (1.500 mL), followed by treatment with potassium persulfate (103 mg, 0.168 mmol). This was stirred overnight. The reaction mixture was diluted with EtOAc and subsequently washed with 1.5 M K₂HPO₄ aqueous solution, followed by washing with brine. The aqueous layers were extracted with EtOAc and combined. The combined organic layers (MgSO4) were dried, filtered, and concentrated. The resulting residue was dissolved in CH2Cl2 (1 mL) and treated with TFA (0.5 mL, 6.49 mmol). After stirring for 1 h, deprotection was observed to be complete. The mixture was concentrated and briefly dried under vacuum.The residue was dissolved in DMF and purified by preparative LC / MS under the following conditions: Column: XBridge C18, 200 mm × 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water + 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water + 0.1% trifluoroacetic acid; Gradient: 0 min at 12% B, 20 min at 12–52% B, followed by 4 min at 100% B; Flow rate: 20 mL / min; Column temperature: 25 °C. The eluent was collected by MS and UV signal triggering. The eluents containing the desired product were combined and evaporated to dryness by centrifugation. The purified material was then diluted with DMF, treated with Si-pyridine, and shaken for at least 2 h. The resulting mixture was filtered and dried by centrifugation and evaporation to give ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(pyridin-4-ylsulfonyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone (12.6 mg, 0.020 mmol, 10.8% yield): 1 HNMR (500MHz, DMSO-d6) δ8.80 (br d, J=5.5Hz, 2H), 8.38 (br s, 1H), 7.90 (br d, J=5.2Hz, 2H), 7.87 (br d, J=8.5Hz, 1H), 7.62 (br d, J=8.5Hz, 1H), 7.35 (s, 1H), 7.49-7.34 (m, 1H), 7.15 (s, 1H), 6.96-6.88 (m, 1H), 4.48 (br d, J=7.0Hz, 2H), 4.02 (s, 3H), 3.93 (br 3.74-3.50 (m, 1H), 3.44-3.39 (m, 1H), 3.15-3.07 (m, 1H), 2.61 (br s, 1H), 1.96-1.77 (m, 3H), 1.65-1.52 (m, 1H), 1.01-0.94 (m, J = 5.8 Hz, 1H), 0.26 (br d, J = 7.6 Hz, 2H), 0.00 (brs, 2H); LC / MS (M+H) = 611.37; retention time = 1.45 min (Method 1).

[0616] Example 5

[0617] ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-((4-hydroxyphenyl)amino)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone

[0618]

[0619] Example 5

[0620] Add to a vial dioxane (1 mL) and tBuOH (0.25 mL) containing ((1R,4R,7R)-2-(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-2-azabicyclo[2.2.1]hept-7-yl)carbamate (25 mg, 0.041 mmol), 4-aminophenol (6.76 mg, 0.062 mmol), cesium carbonate (40.4 mg, 0.124 mmol), and second-generation X-Phos precatalyst (3.25 mg, 4.13 μmol). Cap the vial and anaerobically circulate the reaction mixture using a pump / backfill nitrogen cycle (5×). Stir the reaction mixture overnight at 70 °C. After cooling, the mixture was diluted with EtOAc and dried (MgSO4), filtered, and concentrated. The resulting residue was dissolved in CH2Cl2 (1 mL) and treated with TFA (0.5 mL, 6.49 mmol). The mixture was stirred at room temperature for 2 hours, followed by concentration. The resulting residue was dissolved in DMF and purified by preparative LC / MS under the following conditions: column: XBridge C18, 200 mm × 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: 0 min at 17% B, 20 min at 17–57% B, followed by 4 min at 100% B; flow rate: 20 mL / min; column temperature: 25 °C. The eluent was collected by MS and UV signal triggering. The eluents containing the desired product were combined and evaporated to dryness by centrifugation. The purified substance was then diluted with DMF, treated with Si-pyridine, and shaken for at least 2 hours. The resulting mixture was filtered and dried by centrifugation and evaporation to give ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-((4-hydroxyphenyl)amino)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) ketone (13.8 mg, 0.024 mmol, 57.8% yield): 1H NMR (500MHz, DMSO-d6) δ8.83 (s, 1H), 7.75 (d, J = 8.5Hz, 1H), 7.56 (br d, J = 8.9Hz, 2H), 7.40-7.27 (m, 1H), 6.89-6.79 (m, 2H), 6.68 (br d, J=8.9Hz, 2H), 6.59 (d, J=8.5Hz, 1H), 4.39 (brd, J=6.7Hz, 2H), 4.08 (s, 3H), 3.93 (s, 3H), 3.73 (br 3.65-3.42 (m, 1H), 3.16-2.95 (m, 2H), 2.22-2.07 (m, 1H), 2.00-1.87 (m, 2H), 1.77-1.60 (m, 1H), 1.44-1.28 (m, 1H), 1.11 (br s, 1H), 0.25 (br d, J = 7.9 Hz, 2H), 0.13 (br d, J = 4.0 Hz, 2H); LC / MS(M+H) = 578.26; retention time = 1.41 min (Method 1).

[0621] Intermediate 4

[0622] 2-(5-((1R,4R,7R)-7-((tert-butoxycarbonyl)amino)-2-azabicyclo[2.2.1]heptane-2-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-1-(cyclopropylmethyl)-1H-indole-6-carboxylic acid

[0623]

[0624] Intermediate 4

[0625] CO(g) was bubbled into a solution of ((1R,4R,7R)-2-(2-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-2-azabicyclo[2.2.1]hept-7-yl)carbamate tert-butyl (0.36 g, 0.555 mmol), DPPF (0.062 g, 0.111 mmol), and TEA (0.232 mL, 1.665 mmol) in DMF (2 mL) and MeOH (0.500 mL) for 5 min, followed by treatment of the reaction solution with palladium(II) acetate (0.037 g, 0.056 mmol). CO(g) was then bubbled again for one minute. A sealed vial containing carbon monoxide was connected to the vial via a needle. The vial was then stirred at 90 °C.

[0626] After stirring overnight, the reaction was found to be incomplete. Additional amounts of DPPF (0.062 g, 0.111 mmol), MeOH (0.500 mL), and palladium(II) acetate (0.037 g, 0.056 mmol) were added to the reactants, and the solution was saturated with CO(g) by bubbling for 5 min. The vial was sealed and a CO(g) balloon was attached. The mixture was stirred at 90 °C for another 18 hours. After cooling, the reaction mixture was diluted with EtOAc and filtered through diatomaceous earth. The mixture was then washed with 10% LiCl (aqueous solution) (2×), followed by washing with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by rapid chromatography (EtOAc / hexane) to give a brown oily methyl ester, which was then dissolved in THF (2 mL) and MeOH (0.5 mL). The solution was treated with 2M LiOH aqueous solution (0.555 mL, 1.110 mmol). The reaction mixture was stirred at 70 °C for 2 h. The temperature was then increased to 80 °C. After 1 h, the reaction was still not complete, and 2M LiOH aqueous solution (0.278 mL, 0.555 mmol) was added, and stirring was continued at 80 °C. Saponification was complete after 7 h. After cooling, the mixture was diluted with EtOAc and 2M HCl (pH = 5) was added. The organic layer was separated and then washed with brine. The product was dried (MgSO4), filtered, and concentrated to obtain intermediate 2-(5-((1R,4R,7R)-7-((tert-butoxycarbonyl)amino)-2-azabicyclo[2.2.1]heptane-2-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-1-(cyclopropylmethyl)-1H-indole-6-carboxylic acid: LC / MS (M+H) = 614.3; retention time = 0.87 min (Method 3).

[0627] Example 6

[0628] 2-(5-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-1-(cyclopropylmethyl)-N-(pyridin-4-yl)-1H-indole-6-carboxamide

[0629]

[0630] Example 6

[0631] A mixture of 2-(5-((1R,4R,7R)-7-((tert-butoxycarbonyl)amino)-2-azabicyclo[2.2.1]heptane-2-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-1-(cyclopropylmethyl)-1H-indole-6-carboxylic acid (30 mg, 0.049 mmol - from above procedure), 4-aminopyridine (4.38 μl, 0.059 mmol), and Huenig's base (0.026 mL, 0.147 mmol) in DMF (1 mL) was treated with HATU (22.30 mg, 0.059 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with EtOAc and washed with 10% LiCl (aqueous solution), followed by washing with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated. The resulting residue was dissolved in CH₂Cl₂ (1 mL) and treated with TFA (0.5 mL, 6.49 mmol). After stirring for 1 h, the reaction mixture was evaporated. This residue was dissolved in DMF and purified by preparative LC / MS under the following conditions: column: XBridge C18, 19 × 200 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: 14–54% B for 20 min, followed by 100% B for 4 min; flow rate: 20 mL / min. The eluates containing the desired product were combined and evaporated to dryness by centrifugation. The purified substance was then diluted with DMF, treated with Si-pyridine, and shaken for at least 2 h. The resulting mixture was filtered and dried by centrifugation and evaporation to give 2-(5-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-1-(cyclopropylmethyl)-N-(pyridin-4-yl)-1H-indole-6-carboxamide (5.9 mg, 10.01 μmol, 20.47% yield): 1H NMR (500MHz, DMSO-d6) δ8.45 (brt, J=5.4Hz, 1H), 8.16-8.13 (m, 1H), 7.71-7.67 (m, 1H), 7.65-7.60(m, 1H), 7.44-7.31(m, 1H), 7.02(s, 1H), 6.95-6.88(m, 1H), 4.41(br d, J=6.7Hz, 2H), 4.13 (br d, J=8.3Hz, 1H), 4.06 (s, 3H), 3.95 (s, 3H), 3.78-3.66 (m, 3H), 3.61 (q, J=7.7Hz, 1H), 3.49 (br dd, J = 8.3, 5.4 Hz, 1H), 3.34-3.22 (m, 1H), 3.04 (br d, J = 11.5 Hz, 1H), 2.52 (br s, 2H), 2.24-2.12 (m, 1H), 2.02-1.88 (m, 3H), 1.78-1.68 (m, 1H), 1.62 (dq, J = 12.9, 6.5 Hz, 1H), 1.42 (br s, 1H), 1.20 (br s, 1H), 1.06 (br s, 1H), 0.28 (br d, J = 7.8 Hz, 2H), 0.00 (br s, 2H); LC / MS(M+H) = 590.36; retention time = 1.25 min (Method 3).

[0632] Example 7

[0633] 6-(2-(5-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,4-dihydroquinoline-2(1H)-one

[0634]

[0635] Example 7

[0636] Add 125 mg (0.248 mmol) of ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone and 6-(4,4,5,5-tetramethyl) to a 2dr vial. The reaction mixture consisted of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (81 mg, 0.297 mmol), 3 M tripotassium phosphate solution (0.248 mL, 0.743 mmol), and 2 mL of THF containing 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (20.21 mg, 0.025 mmol). The vials were capped and the reaction mixture was anaerobic by a pump / backfill nitrogen circulation (5×). The reaction mixture was stirred overnight at 70 °C. After cooling, the mixture was concentrated and dried under vacuum. It was dissolved in DMF and purified by preparative HPLC. Preparative HPLC conditions: Initial %B = 20, Final %B = 70, Gradient time = 15 min, Flow rate = 30 mL / min, Wavelength = 254 nm, Solvent pair = MeCN-H2O-TFA; Solvent A = 0.1% TFA / water; Solvent B = 0.1% TFA / MeCN; Column 2 = 1: Luna 5uC18 30×100 mm. The product was eluted at 7.92 min. The desired eluates were combined and diluted with EtOAc, followed by washing with 1.5 M K2HPO4 (aqueous solution), and then with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was dissolved in DCM-MeOH and treated with 25 mg Py resin. The mixture was shaken for 2 h, then filtered and concentrated. The residue was dissolved in a mixture of water and acetonitrile, frozen, and lyophilized to give a white, fluffy solid of 6-(2-(5-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,4-dihydroquinoline-2(1H)-one (55 mg, 0.086 mmol, 34.6% yield): 1H NMR (500MHz, DMSO-d6) δ10.08 (s, 1H), 8.15 (d, J = 8.2Hz, 1H), 8.02-7.97 (m, 2H), 7.89-7.78 (m , 1H), 7.76-7.69 (m, 2H), 7.45 (brd, J=8.6Hz, 1H), 7.10 (s, 1H), 7.01 (d, J=8.2Hz, 1H), 4.64 (br d, J=7.0Hz, 2H), 3.99 (s, 3H), 3.74 (br s, 1H), 3.63-3.48 (m, 1H), 3.35-3.27 (m, 1H), 3.17-3.04 (m, 1H), 3.01 (br t, J = 7.5 Hz, 2H), 2.56-2.52 (m, 3H), 2.23 (br s, 1H), 2.06-1.91 (m, 2H), 1.72 (br t, J = 9.3 Hz, 1H), 1.49-1.39 (m, 1H), 1.23 (br d, J = 8.4 Hz, 1H), 0.32 (br d, J = 7.8 Hz, 2H), 0.23 (br s, 2H) LCMS = (M + H) + = 616.3; retention time = 0.7 min (Method 3).

[0637] Example 8

[0638] ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(oxacyclobutane-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone

[0639]

[0640] Example 8

[0641] ((1R,4R,7R)-2-(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-2-azabicyclo[2.2.1]hept-7-yl) tert-butyl carbamate (30 mg, 0.050 mmol) was dissolved in dioxane (0.5 mL), followed by the addition of 3-bromooxycyclobutane (6.79 mg, 0.050 mmol) and (Ir[DF [(CF3)PPY]2(DTBPY))PF6 (1.112 mg, 0.992 μmol), sodium carbonate (0.011 mL, 0.198 mmol), 4,4′-di-tert-butyl-2,2′-bipyridine (0.798 mg, 2.97 μmol), tris(trimethylsilyl)silane (0.023 mL, 0.074 mmol), nickel(II) glycol dimethyl ether complex (0.545 mg, 2.479 μmol), and then purged with nitrogen. The mixture was stirred overnight with the reaction vial cooled by a fan in front of two Kessil lamps. After cooling, EtOAc was added, and the mixture was filtered and concentrated. The resulting residue was dissolved in DCM (1 mL), followed by the addition of T-FA (2 mL). After 30 min, the mixture was concentrated. The residue was purified by preparative LC / MS under the following conditions: Column: XBridge C18, 200 mm × 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water + 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water + 0.1% trifluoroacetic acid; Gradient: 0 min at 10% B, 20 min at 10–50% B, followed by 4 min at 100% B; Flow rate: 20 mL / min; Column temperature: 25 °C. The eluent was collected by MS and UV signal triggering. The eluents containing the desired product were combined and evaporated to dryness by centrifugation. The purified substance was then diluted with DMF, treated with Si-pyridine, and shaken for at least 2 h. The resulting mixture was filtered and dried by centrifugation and evaporation to give ((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(oxecyclobutane-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone (5.8 mg, 0.01 mmol, 22.2%): 1¹H NMR (500MHz, DMSO-d6, rotational isomer) δ 8.07–8.00 (m, 1H), 7.44 (m, 0.33H), 7.36–7.31 (m, 0.71H), 7.14–7.08 (m, 1H), 7.03–6.99 (m, 1H), 6.95–6.85 (m, 1H), 4.94–4.89 (m, 2H), 4.88–4.83 (m, 2H), 4.52–4.42 (m, 3H), 4.14 (m, 0.25H), 4.07 (s, 3H), 3.94 (s, 3H), 3.79–3.72 (m , 0.53H), 3.52-3.38 (m, 1H), 3.18-3.11 (m, 0.49H), 3.07-2.95 (m, 1H), 2.22 (m, 0.76H), 2.14 (m, 0.41H), 1.99-1.78 (m, 2H), 1.77-1.62 (m, 1H), 1.48-1.30 (m, 1H), 1.13-1.01 (m, 1H), 0.32-0.20 (m, 2H), 0.17-0.06 (m, 2H); LCMS(M+H)+=527.4; retention time: 1.37min (Method 1).

[0642] The examples in the table below were prepared in the same manner as those described in Examples 1 to 8 above.

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733] Other embodiments regarding experimental details are shown below with reference to Examples 445 to 448.

[0734] Example 445

[0735] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(1,1-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone

[0736]

[0737] Example 445

[0738] Step A: methyl 2-(6-acetyl-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazolium-5-carboxylate

[0739]

[0740] Example 445A

[0741] A mixture of 2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazolium-5-carboxylate (890 mg, 2.095 mmol) [for this starting material, see: WO 2017 / 0100594], 1-ethoxyvinyl tert-butyltin (0.856 mL, 2.51 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (364 mg, 0.628 mmol) and Pd2(dba)3 (192 mg, 0.209 mmol) in degassed dioxane (10 mL) was stirred at 100 °C under nitrogen for 18 hours. The mixture was then cooled to rt. Add 1.0 M HCl aqueous solution (2.095 mL, 2.095 mmol) and stir the mixture at room temperature for 1 hour. Dilute the reaction mixture with EtOAc (15 mL) and wash with saturated sodium bicarbonate aqueous solution (2 × 15 mL). Dry the organic layer with sodium sulfate and concentrate. Perform ISCO rapid chromatography (silica gel / hexane-EtOAc 100:0 to 0:100 gradient) on the resulting residue to give methyl 2-(6-acetyl-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazolium-5-carboxylate 445A (850 mg, 1.769 mmol, 84% yield) as a light brown solid: LCMS(M+H) = 433.4, retention time = 1.06 min (Method 3).

[0742] Step B: (E)-2-(1-(cyclopropylmethyl)-6-(1-(hydroxyimino)ethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazolium-5-carboxylic acid methyl ester

[0743]

[0744] Example 4445B

[0745] A mixture of 2-(6-acetyl-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazolium-5-carboxylate 445A (400 mg, 0.925 mmol), hydroxylamine hydrochloride (70.7 mg, 1.017 mmol), and MeOH (12 mL) was stirred at 60 °C for 3 hours (J. Med. Chem. 2012, 55, 3364). The mixture was concentrated. The reaction mixture was diluted with EtOAc (15 mL) and washed with saturated aqueous sodium bicarbonate solution (2 × 15 mL). The organic layer was dried and concentrated with sodium sulfate to obtain crude (E)-2-(1-(cyclopropylmethyl)-6-(1-(hydroxyimino)ethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazolium-5-carboxylate 445B, a grayish-white solid, with LCMS(M+H) = 448.5 and retention time = 0.95 min (Method 3), which was used in the next step.

[0746] Step C: methyl 2-(1-(cyclopropylmethyl)-6-(1,1-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazolium-5-carboxylate

[0747]

[0748] Example 445C

[0749] Under nitrogen atmosphere at -78°C, 70% HF-pyridine (1310 mg, 9.25 mmol) was added to a solution of (E)-2-(1-(cyclopropylmethyl)-6-(1-(hydroxyimino)ethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazolium-5-carboxylate 445B in DCM (5.0 mL), and the mixture was stirred at -78°C for 15 min. A solution of tert-butyl nitrite (286 mg, 2.77 mmol) in DCM (5.0 mL) was added dropwise to the mixture, and the reaction mixture was stirred at -78°C for 30 min and then at room temperature for 1 h. The mixture was then added to sulfuric acid (1.0 mL) and ice water (200 g), and the mixture was stirred at room temperature for 30 min. The organic layer was collected and washed with a saturated aqueous solution of sodium bicarbonate (35 mL). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was subjected to ISCO rapid chromatography (silica gel / hexane-EtOAc 100:0 to 50:50 gradient) to give methyl 2-(1-(cyclopropylmethyl)-6-(1,1-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazolium-5-carboxylate 445C (92 mg, 0.192 mmol, 20.79% yield) as a white solid. 1 ¹H NMR (499 MHz, chloroform-d) δ 8.23 ​​(d, J = 1.2 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.52–7.47 (m, 1H), 6.84 (s, 1H), 4.55 (d, J = 7.2 Hz, 2H), 4.18 (s, 3H), 4.09–4.06 (m, 3H), 3.99 (s, 3H), 2.16 (t, J = 18.5 Hz, 3H), 1.22–1.12 (m, 1H), 0.39–0.31 (m, 2H), 0.23–0.17 (m, 2H); LCMS (M+H) = 455.4, retention time = 1.09 min (Method 3).

[0750] Step D: 2-(1-(cyclopropylmethyl)-6-(1,1-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carboxylic acid

[0751]

[0752] Example 445D

[0753] A mixture of methyl 2-(1-(cyclopropylmethyl)-6-(1,1-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazolium-5-carboxylate 445C (102 mg, 0.224 mmol) and 2.0 M lithium hydroxide aqueous solution (561 μl, 1.122 mmol) in THF (5.0 mL) was stirred at 50 °C for 18 hours. A 1.0 M HCl aqueous solution (1.20 mL) was added, and the mixture was concentrated. The mixture was extracted with EtOAc (2 × 15 mL), and the ethyl acetate layer was dried over sodium sulfate and concentrated to give crude 2-(1-(cyclopropylmethyl)-6-(1,1-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carboxylic acid 445D (101 mg, 0.218 mmol, 97% yield) as a white solid. LCMS (M+H) = 441.4, retention time = 0.96 min (Method 3).

[0754] Example 445: ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(1,1-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone

[0755]

[0756] Example 445

[0757] A mixture of 2-(1-(cyclopropylmethyl)-6-(1,1-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carboxylic acid 445D (20 mg, 0.045 mmol), ((3R,5R)-5-fluoropiperidin-3-yl)carbamate tert-butyl ester (9.91 mg, 0.045 mmol), BOP (22.09 mg, 0.050 mmol), and TEA (31.6 μl, 0.227 mmol) in DMF (1.0 mL) was stirred for 2 hours at room temperature. The mixture was diluted with EtOAc (5 mL) and washed with saturated aqueous sodium bicarbonate solution (2 × 5 mL). The organic layer was dried over sodium sulfate and concentrated to obtain crude ((3R,5R)-1-(2-(1-(cyclopropylmethyl)-6-(1,1-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-5-fluoropiperidin-3-yl) tert-butyl carbamate: LCMS(M+H) = 641.6, retention time = 1.00 min (Method 3), which was used in the next step.

[0758] A mixture of (3R,5R)-1-(2-(1-(cyclopropylmethyl)-6-(1,1-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-5-fluoropiperidin-3-yl) tert-butyl carbamate in DCM (1.0 mL) and TFA (1.0 mL) was stirred at room temperature for 30 min. The mixture was concentrated. The residue was purified by preparative HPLC (Phenomenex, Luna 5 μm 30 × 250 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)). The purified product eluent was loaded onto a Strata-XC 33 μm cationic mixed-mode polymer filter cartridge (0.30 g), washed with methanol (20 mL), and eluted with methanol containing 0.5 N NH3 (5.0 mL). The NH3 eluent was concentrated and the purified product was lyophilized with ACN / H2O (1:1, 10 mL) to give 445 (16.90 mg, 0.031 mmol, 67.5% yield) of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(1,1-difluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone as a white powder. 1 ¹H NMR (499 MHz, methanol-d⁴) δ 8.22 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.44 (s, 1H), 7.05 (s, 1H), 7.02–6.95 (m, 1H), 4.82–4.64 (m, 1H), 4.48 (d, J = 7.2 Hz, 2H), 4.06 (s, 7H), 3.43–3.35 (m, 2H), 3.26– 3.06 (m, 1H), 3.01-2.53 (m, 1H), 2.45-2.28 (m, 1H), 2.12 (t, J = 18.5 Hz, 3H), 1.72-1.50 (m, 1H), 1.05-0.97 (m, 1H), 0.38-0.30 (m, 2H), 0.14-0.04 (m, 2H); LCMS(M+H) = 541.5, retention time = 0.83 min (Method 3).

[0759] Example 446

[0760] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(6-(1-cyclobutyl-1-hydroxyethyl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone

[0761]

[0762] Example 446

[0763] Step A: ((3R,5R)-1-(2-(6-acetyl-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-5-fluoropiperidin-3-yl)tert-butyl carbamate

[0764]

[0765] Example 446A

[0766] Using the procedure of step A in Example 445, but starting with ((3R,5R)-1-(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-5-fluoropiperidin-3-yl)carbamate tert-butyl carbamate, the preparation of ((3R,5R)-1-(2-(6-acetyl-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy- 1-Methyl-1H-benzo[d]imidazol-5-carbonyl)-5-fluoropiperidin-3-yl)tert-butyl carbamate was used to obtain ((3R,5R)-1-(2-(6-acetyl-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-5-fluoropiperidin-3-yl)tert-butyl carbamate 446A: LCMS(M+H) = 619.4, retention time = 0.89 min (Method 3).

[0767] Example 446: ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(6-(1-cyclobutyl-1-hydroxyethyl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone

[0768]

[0769] Example 446

[0770] A solution of 0.5 M cyclobutyl magnesium bromide in 2-methyltetrahydrofuran (194 μl, 0.097 mmol) was added to a solution of ((3R,5R)-1-(2-(6-acetyl-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-5-fluoropiperidin-3-yl)carbamate 446A (20 mg, 0.032 mmol) in THF (1.0 mL), and the mixture was stirred at room temperature for 60 min. The mixture was then added to a 10% ammonium chloride aqueous solution (10 mL). The mixture was extracted with EtOAc (15 mL). The organic layer was dried over sodium sulfate and concentrated to obtain crude ((3R,5R)-1-(2-(6-(1-cyclobutyl-1-hydroxyethyl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-5-fluoropiperidin-3-yl) tert-butyl carbamate: LCMS(M+H) = 675.4, retention time = 0.94 min (Method 3), which was used in the next step.

[0771] A mixture of (3R, 5R)-1-(2-(6-(1-cyclobutyl-1-hydroxyethyl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-5-fluoropiperidin-3-yl) tert-butyl carbamate in DCM (1.0 mL) and TFA (0.40 mL) was stirred at room temperature for 30 min. The mixture was concentrated. The residue was purified by preparative HPLC (Phenomenex, Luna 5 μm 30 × 250 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)). The purified product eluent was loaded onto a Strata-XC 33 μm cationic mixed-mode polymer filter cartridge (0.30 g), washed with methanol (20 mL), and then eluted with methanol containing 0.5 N NH3 (5.0 mL). The NH3 eluent was concentrated and the product was lyophilized with ACN / H2O (1:1, 5 mL) to give a white powder of ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(6-(1-cyclobutyl-1-hydroxyethyl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone 446 (8.19 mg, 0.014 mmol, 41.9% yield): 1¹H NMR (499 MHz, methanol-d⁴) δ 8.08 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 8.3 Hz, 2H), 6.99–6.95 (m, 2H), 4.83–4.63 (m, 1H), 4.48 (br) s, 2H), 4.26-3.96 (m, 7H), 3.47-3.35 (m, 1H), 3.24-3.15 (m, 1H), 3.03-2.92 (m, 1H), 2.79-2.53 (m, 1H), 2.46-2.14 (m, 2H), 2.05-1.93 (m, 2H), 1.88-1.75 (m, 1H), 1.74-1.46 (m, 7H), 1.03-0.91 (m, 1H), 0.33 (br d, J = 8.1Hz, 2H), 0.07 (br d, J = 4.1Hz, 2H); LCMS(M+H) = 575.4, retention time = 0.91 min (Method 3).

[0772] Example 447

[0773] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(1,3-difluoro-2-hydroxypropane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone

[0774]

[0775] Example 447

[0776] Step A: ((3R,5R)-1-(2-(1-(cyclopropylmethyl)-6-(1,3-difluoro-2-hydroxypropane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-5-fluoropiperidin-3-yl)tert-butyl carbamate

[0777]

[0778] Example 447A

[0779] A solution of 1.60 M n-butyllithium in hexane (203 μl, 0.324 mmol) was added to a solution of ((3R,5R)-1-(2-(6-bromo-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-5-fluoropiperidin-3-yl) tert-butyl carbamate (85 mg, 0.130 mmol) [prepared in a manner similar to intermediate 2, but starting with ethyl 6-bromo-1H-pyrrolo[2,3-b]pyridin-2-carboxylate] in anhydrous diethyl ether (10 mL) and anhydrous THF (3.0 mL) under nitrogen atmosphere at -78 °C. The mixture was stirred for 30 min at -78 °C. 1,3-Difluoroprop-2-one (14.63 mg, 0.156 mmol) was then added to the mixture at -78 °C, and the mixture was stirred at -78 °C for 10 min and then stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (15 mL) and washed with a saturated aqueous solution of sodium bicarbonate (2 × 15 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was subjected to ISCO rapid chromatography (silica gel / hexane-5% EtOAc 100:0 to 0:100 gradient) to give ((3R,5R)-1-(2-(1-(cyclopropylmethyl)-6-(1,3-difluoro-2-hydroxypropane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-5-fluoropiperidin-3-yl) tert-butyl carbamate 447A (35 mg, 0.052 mmol, 40.2% yield): LCMS (M+H) = 671.5, retention time = 0.86 min (Method 3).

[0780] Example 447: ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(1,3-difluoro-2-hydroxypropane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone

[0781]

[0782] Example 447

[0783] A mixture of (3R,5R)-1-(2-(1-(cyclopropylmethyl)-6-(1,3-difluoro-2-hydroxypropane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-5-fluoropiperidin-3-yl) tert-butyl carbamate 447A (35 mg, 0.052 mmol, 40.2% yield) in DCM (1.0 mL) and TFA (1.0 mL) was stirred for 30 min at room temperature. The concentrated solution was purified by preparative HPLC (Phenomenex, Luna 5 μm 30 × 250 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)). The purified product eluent was loaded onto a Strata-XC 33 μm cationic mixed-mode polymer filter cartridge (0.30 g), washed with methanol (20 mL), and then eluted with methanol containing 0.5 N NH₃ (5.0 mL). The product was concentrated using NH3 as eluent and lyophilized with ACN / H2O (1:1, 5 mL) to give ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(1,3-difluoro-2-hydroxypropane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone 447 (16.30 mg, 0.029 mmol, 22.03% yield): 1 ¹H NMR (500MHz, DMSO-d⁶) δ 7.97 (d, J = 8.2Hz, 1H), 7.36 (d, J = 8.2Hz, 1H), 7.13 (s, 1H), 6.87 (s, 1H), 6.66 (s, 1H), 4.92–4.48 (m, 6H), 4.44–4.17 (m, 3H), 4.01–3.62 (m, 6H), 2.79–2.43 (m, 2H), 2.04–1.88 (m, 1H), 1.47–1.16 (m, 1H), 1.08–0.87 (m, 2H), 0.19–0.10 (m, 4H); LCMS (M+H) = 571.3, retention time = 1.39 min (Method 2).

[0784] Example 448

[0785] 2-(4-(2-(5-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)phenoxy)acetamide

[0786]

[0787] Example 448

[0788] In 2dr vials, p-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) methyl ketone (1.5 g, 2.495 mmol), 4,4,4′,4′,5,5,5′,5′ A mixture of octamethyl-2,2′-bis(1,3,2-dioxaborane) (0.760 g, 2.99 mmol) and potassium acetate (0.612 g, 6.24 mmol) in dioxane (12 ml) was sonicated and treated with a 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (0.102 g, 0.125 mmol), and the vial was capped. The reaction mixture was anaerobic by a pump / backfill nitrogen circulation (5×). It was set to be stirred at 90 °C for 5 h until the starting material was depleted. The reaction mixture was evaporated and dried under vacuum. The resulting brown solid was used or used in the next step. A portion of this substance (45 mg, 0.047 mmol), 2-(4-bromophenoxy)acetamide (13.08 mg, 0.057 mmol), 2N sodium carbonate aqueous solution (0.071 mL, 0.142 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (3.87 mg, 4.74 μmol) were dissolved in DMF (1 mL). The vial was capped and the reaction mixture was anaerobic by pump / backfill nitrogen circulation (5×). The reaction mixture was stirred overnight at 70 °C. After cooling to rt, the solution was diluted with DMF, filtered, and purified by preparative LC / MS under the following conditions: column: XBridge C18, 200 mm × 19 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile:water + 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water + 0.1% trifluoroacetic acid; gradient: 0 min at 11% B, 20 min at 11-51% B, followed by 4 min at 100% B; flow rate: 20 mL / min; column temperature: 25 °C. The eluent was collected triggered by the MS signal of the product. The eluents containing the desired product were combined and dried by centrifugation. The purified product was then diluted with DMF, treated with Si-pyridine, and shaken for at least 2 h. The resulting mixture was filtered and dried by centrifugation and evaporation to give 2-(4-(2-(5-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)phenoxy)acetamide 448 (20.6 mg): 1H NMR (500MHz, DMSO-d6) δ8.17-8.13(m, 3H), 7.95-7.92(m, 1H), 7.78-7.74(m, 1H), 7.62-7.53(m, 2H), 7.44-7 .40(m,1H),7.11-7.08(m,2H),7.08-7.06(m,1H),7.02-6.94(m,1H),4.57-4.52(m,2H),4.52-4.50(m,2H),4 0.18-4.12 (m, 3H), 4.03-3.95 (m, 3H), 3.83-3.71 (m, 1H), 3.66-3.54 (m, 1H), 3.53-3.44 (m, 1H), 3.22-3.15 (m, 1H), 2.69-2.57 (m, 1H), 2.02-1.85 (m, 3H), 1.74-1.59 (m, 1H), 1.28-1.11 (m, 2H), 0.35-0.29 (m, 2H), 0.20 (br s, 2H); LCMS(M+H) = 620.0, retention time = 1.58 min (Method 1).

[0789] The following compounds were synthesized using the methods described above.

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

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[0851]

[0852]

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[0862]

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[0871]

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[0893]

[0894]

[0895]

[0896]

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[0898]

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[0900]

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[0903]

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[0906]

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[0998]

[0999]

[1000]

[1001]

[1002]

[1003]

[1004]

[1005]

[1006]

[1007] Bioanalysis

[1008] The compounds of the present invention were analyzed as inhibitors of PAD4 using the analytical methods described below.

[1009] RFMS Human PAD4 Functional Analysis:

[1010] The compound was dissolved in 100% DMSO to achieve a concentration of 10 mM. The stock solution was stored at room temperature. A series of dilutions were prepared in DMSO and mixed eight times with a 20 μL mixing volume. The highest final concentration of the compound in the analysis was 50 μM. The final analytical conditions were as follows:

[1011] Reaction volume: 26 μl

[1012] Analysis 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

[1013] Final concentration: 5 nM hPAD4 enzyme, 250 μM BAEE and 0.5% DMSO

[1014] Total incubation time: pre-incubate the compound and enzyme at 37℃ for 30 min, perform the enzyme / substrate reaction for 90 min, and react with phenylglyoxal at 37℃ for 30 min.

[1015] Stop solution: ACN containing 40 μl of 5% TCA

[1016] 0.13 μL of the compound solution was added to 13 μL of 10 nMP AD4 in the analysis buffer. After 30 minutes, 13 μL of 500 μM BAEE 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, and 5 μM TPEN. The reaction was incubated at 37 °C for 90 minutes. The enzyme reaction was quenched by adding 15 μL of 6.1N TCA to achieve a final concentration of 20% (100%). Subsequently, 35 μL of 8.5 mM phenylglyoxal (final concentration 4 mM) was added, and the reaction was incubated at 37 °C for 30 minutes.

[1017] After 30 minutes, the culture dish was briefly centrifuged to remove all precipitate. The enzyme reaction was quenched with an equal volume of methanol containing the internal standard (modified citrulline). The sample was loaded onto an Agilent RF300 system, initially aspirated for 1000 ms, and then directly loaded into a C18 separation cartridge with a mixture of acetonitrile and 0.01% formic acid for 3000 ms desalting. The mobile phase flow rate was 1.5 mL / min. Once the sample was eluted from the cartridge, it was transferred to the mass spectrometer with a mobile phase of acetonitrile and 0.01% formic acid at a flow rate of 1.25 mL / min for 4000 ms. A Sciex API5500 triple quadrupole mass spectrometer (Applied Biosystems) equipped with ESI was used to analyze peptidylcitrulline and the internal standard ion.

[1018] The MRM transitions and internal standard of the products were monitored at m / z 424.5 to 350.4 and m / z 293 to 247, respectively. The residence time for each transition was set to 200 ms, and the ESI voltage was set at 5500 Ω at a source temperature of 400 °C. The extracted ion peaks for each transition were integrated using rapid-fire integrator software. The peak area of ​​the analyte was normalized using the internal standard.

[1019] For the given compound examples, the table below shows the IC50 of human PAD4 (hPAD4) in rapid radio mass spectrometry (RFMS) analysis.

[1020] Table 11. PAD4 Activity

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029]

[1030]

[1031]

[1032]

Claims

1. A compound of formula (I): Or its pharmaceutically acceptable salt. in: Q is selected from N and CH; Selected from and ; R1 is selected from CH3 and CD3; R2 is selected from methyl, ethyl, and compounds with 0 to 3 R groups. e Substituted -CH2-cyclopropyl; R3 is selected from H, F, Cl, Br and -OC. 1-4 alkyl; L does not exist or is selected from -NR d -, -O-, -C(=O)NH-, -S- and -S(O)2-; R4 is selected from: ， ； R5 is independently selected from H, F, Cl, Br, CN, =O, via 0 to 5 Rs each time it appears. e Replacement C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -(CHR) d ) r OR b -(CH2) r S(O)pR c -(CH2) r S(O)pNR a R a -(CH2) r NR a S(O)pR c -(CH2) r NR a R a -(CH2) r NR a C(=O)R b -(CH2) r NR a C(=O)OR b -(CH2) r NR a C(=O)NR a R a -(CH2) r C(=O)R b -(CH2) r C(=O)OR b -(CHR) d ) r C(=O)NR a R a -(CH2) r OC(=O)R b -(CH2) r OC(=O)OR b -(CH2) r O(CH2) r C(=O)NR a R a , through 0 to 4 R e Replacement C 3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups; R6 is independently selected from H, through 0 to 4 Rs each time it appears. e Replacement C 1-3 Alkyl, -S(O)pR c -C(=O)R b -(CH2) r C(=O)OR b -(CH2) r C(=O)(CH2) r NR a R a -C(=O)(CH2) r NR a C(=O)R b -S(O)pNR a R a , through 0 to 4 R e Substituted -(CH2) r -Aryl and 0 to 4 R e Substituted -(CH2) r - Heterocyclic group; R a Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; or R a and R a Together with the nitrogen atom it is attached to, they form a structure with 0 to 5 R atoms. e Substituted heterocycles; R b Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; R c Each occurrence is independently selected from 0 to 5 R values. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-6 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; R d Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl groups and OH groups; R e Each occurrence is independently selected from 0 to 5 R values. f Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -Aryl, -(CH2) r -Heterocyclic groups, F, Cl, Br, CN, NO2, =O, -NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl group 2, -C(=O)OH, -C(=O)OC 1-4 Alkyl group, -(CH2) r OH and -(CH2) r OC 1-4 alkyl; R f Each time it appears, it is independently selected from H, F, Cl, Br, CN, OH, C. 1-5 Alkyl, C 3-6 Cycloalkyl, phenyl and OH-substituted C 1-5 alkyl; p is independently selected from 0, 1, and 2 each time it appears; and r is independently selected from 0, 1, 2, 3, and 4 each time it appears.

2. The compound of claim 1, having formula (II): Or its pharmaceutically acceptable salt. in: Selected from ； R2 is selected from CH3, CH2CH3 and -CH2-cyclopropyl groups substituted with 0 to 2 F, Cl and CH3 groups; R3 is selected from H, F and -OC. 1-4 alkyl; R4 is selected from ， ； R5 is independently selected from H, F, Cl, Br, CN, =O, via 0 to 4 Rs each time it appears. e Replacement C 1-4 Alkyl, -(CHR) d ) r OR b -(CH2) r S(O)pR c -S(O)pNR a R a -(CH2) r NR a S(O)pR c -(CH2) r NR a R a -(CH2) r NR a C(=O)R b -NR a C(=O)OR b -NR a C(=O)NR a R a -(CH2) r C(=O)R b -(CH2) r C(=O)OR b -(CHR) d ) r C(=O)NR a R a -(CH2) r OC(=O)R b -(CH2) r OC(=O)OR b -(CH2) r O(CH2) r C(=O)NR a R a , through 0 to 4 R e Replacement C 3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups; R6 is independently selected from H, through 0 to 4 Rs each time it appears. e Replacement C 1-3 Alkyl, -S(O)pR c -C(=O)R b -(CH2) r C(=O)OR b -(CH2) r C(=O)NR a R a -C(=O)(CH2) r NR a C(=O)R b -S(O)pNR a R a , through 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups; R a Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; or R a and R a Together with the nitrogen atom it is attached to, they form a structure with 0 to 5 R atoms. e Substituted heterocycles; R b Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Substituted -(CH2) r -C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; R c Each occurrence is independently selected from 0 to 5 R values. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-6 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; R d Each occurrence is independently selected from H and via 0 to 5 R. e Replacement C 1-6 alkyl; R e Each occurrence is independently selected from 0 to 5 R values. f Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -Aryl, -(CH2) r -Heterocyclic groups, F, Cl, Br, CN, NO2, =O, -NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl group 2, -C(=O)OH, -C(=O)OC 1-4 Alkyl group, -(CH2) r OH and -(CH2) r OC 1-4 alkyl; R f Each time it appears, it is independently selected from H, F, Cl, Br, CN, OH, C. 1-5 Alkyl, C 3-6 Cycloalkyl, phenyl and OH-substituted C 1-5 alkyl; p is independently selected from 0, 1, and 2 each time it appears; and r is independently selected from 0, 1, 2, 3, and 4 each time it appears.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein: Selected from ； R2 is -CH2-cyclopropyl; R3 is -OC 1-4 alkyl; R4 is selected from ； R5 is independently selected from H, F, Cl, Br, CN, and C each time it appears. 1-4 Alkyl, -OR b -S(O)pR c -(CH2) r NR a S(O)pR c -(CH2) r NR a R a -(CH2) r NR a C(=O)R b -NR a C(=O)OR b -C(=O)OR b C(=O)NR a R a , through 0 to 4 R e Replacement C 3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups; R6 is independently selected from H, through 0 to 4 Rs each time it appears. e Replacement C 1-3 Alkyl, -S(O)pR c -C(=O)R b -C(=O)OR b -(CH2) r -C(=O)NR a R a -C(=O)(CH2) r NR a C(=O)R b -S(O)pNR a R a , through 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups; R a Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; or R a and R a Together with the nitrogen atom it is attached to, they form a structure with 0 to 5 R atoms. e Substituted heterocycles; R b Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Substituted -(CH2) r -C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; R c Each occurrence is independently selected from 0 to 5 R values. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-6 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; R e Each occurrence is independently selected from 0 to 5 R values. f Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -aryl, F, Cl, Br, CN, NO2, =O, -NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl group 2, -C(=O)OH, -C(=O)OC 1-4 Alkyl group, -(CH2) r OH and -(CH2) r OC 1-4 alkyl; R f Each time it appears, it is independently selected from H, F, Cl, Br, CN, OH, C. 1-5 Alkyl, C 3-6 Cycloalkyl, phenyl and OH-substituted C 1-5 alkyl; p is independently selected from 0, 1, and 2 each time it appears; and r is independently selected from 0, 1, 2, 3, and 4 each time it appears.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein: R4 is selected from ， ;and R5 is selected independently from H, F, Cl, Br, and C each time it appears. 1-4 Alkyl groups, OH groups, and -C(=O)OH groups.

5. The compound of claim 1, having formula (IV): Or its pharmaceutically acceptable salt. in: Selected from ； R2 is selected from CH3 and -CH2-cyclopropyl; R3 is selected from H, F and -OC. 1-4 alkyl; R4 is ； R5 is independently selected from H, F, Cl, Br, CN, and C each time it appears. 1-4 Alkyl group, -(CH2) r OR b -NR a S(O)pR c -NR a R a -NR a C(=O)R b -NR a C(=O)OR b -C(=O)OR b -C(=O)NR a R a -NR a C(=O)NR a R a , through 0 to 4 R e Replacement C 3-6 cycloalkyl, via 0 to 4 R e Substituted aryl groups and those with 0 to 4 R groups e Substituted heterocyclic groups; R6 is selected independently from H and C each time it appears. 1-3 alkyl; R a Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; R b Each occurrence is independently selected from H, via 0 to 5 R. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-10 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; R c Each occurrence is independently selected from 0 to 5 R values. e Replacement C 1-6 Alkyl, via 0 to 5 R e Replacement C 2-6 alkenyl, via 0 to 5 R e Replacement C 2-6 Alkyne group, with 0 to 5 R groups e Substituted -(CH2) r -C 3-6 Carbocyclic groups and those with 0 to 5 R groups e Substituted -(CH2) r - Heterocyclic group; R d Each time it appears, it is independently selected from H and C. 1-3 alkyl; R e Each occurrence is independently selected from 0 to 5 R values. f Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -Aryl, F, Cl, Br, CN, NO2, =O, N(C) 1-4 Alkyl group 2, -C(=O)OH, -C(=O)OC 1-4 Alkyl group, -(CH2) r OH and -(CH2) r OC 1-4 alkyl; R f Each time it appears, it is independently selected from H, F, Cl, Br, CN, OH, C. 1-5 Alkyl, C 3-6 Cycloalkyl, phenyl and OH-substituted C 1-5 alkyl; p is independently selected from 0, 1, and 2 each time it appears; and r is independently selected from 0, 1, 2, 3, and 4 each time it appears.

6. A compound as claimed in claim 1, wherein: 6-(2-(5-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,4-dihydroquinoline-2(1H)-one 6-(2-(5-((1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,4-dihydroquinoline-2(1H)-one (1R,4R,7R)-2-{2-[1-(cyclopropylmethyl)-6-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-7-methoxy-1-methyl-1H-1,3-benzodiazole-5-carbonyl}-2-azabicyclo[2.2.1]heptane-7-amine 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline-1-one (1R,4R,7R)-2-{2-[1-(cyclopropylmethyl)-6-(2,3-dihydro-1,4-benzodioxane-6-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-7-methoxy-1-methyl-1H-1,3-benzodiazole-5-carbonyl}-2-azabicyclo[2.2.1]heptane-7-amine 6-[(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino]-1,2,3,4-tetrahydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-1,2,3,4-tetrahydroquinoline-2-one 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-4-methyl-1,2-dihydroquinoline-2-one 7-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methyl-1,2,3,4-tetrahydroquinazolin-2-one 5-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroquinazolin-2,4-dione 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-oxo-1,2-dihydroquinoline-4-carboxylic acid methyl ester 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-4-hydroxy-3-methyl-1,2-dihydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2-dihydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-2-oxo-1,2-dihydroquinoline-4-carboxylic acid methyl ester 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-4-hydroxy-3-methyl-1,2-dihydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-1,2-dihydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydro-1,8-naphthidin-2-one 7-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2-dihydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2-dihydroisoquinoline-1-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-1,2-dihydroisoquinoline-1-one 7-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-1,2-dihydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-3-methyl-1,2,3,4-tetrahydroquinazolin-2-one 5-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-1,2,3,4-tetrahydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-2-one 7-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-1,2,3,4-tetrahydroquinazolin-2,4-dione 7-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroquinazolin-2,4-dione 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-4-(hydroxymethyl)-1,2-dihydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-fluoro-8-methyl-1,2-dihydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-4-methyl-1,2-dihydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-4-(hydroxymethyl)-1,2-dihydroquinoline-2-one 7-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-1,2,3,4-tetrahydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-1,2,3,4-tetrahydroquinazolin-2,4-dione 7-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,4-dihydro-2H-1,4-benzoxazine-3-one 5-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroquinazoline-2,4-dione 7-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-3,4-dihydro-2H-1,4-benzoxazin-3-one 5-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-1,2,3,4-tetrahydroquinazolin-2,4-dione 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-4-hydroxy-3-methyl-1,2-dihydroquinoline-2-one 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroquinazolin-2,4-dione (1R,4R,7R)-2-{2-[1-(cyclopropylmethyl)-6-(isoquinoline-6-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-7-methoxy-1-methyl-1H-1,3-benzodiazole-5-carbonyl}-2-azabicyclo[2.2.1]heptane-7-amine 7-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline-1-one 7-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-1,2,3,4-tetrahydroisoquinoline-1-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-4-hydroxy-1,2-dihydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)quinoline-4-ol 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-4-hydroxyquinoline-2-carboxylic acid methyl ester 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-4-hydroxy-1,2-dihydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)quinoline-4-ol (1R,4R,7R)-2-{2-[1-(cyclopropylmethyl)-6-(quinolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-7-methoxy-1-methyl-1H-1,3-benzodiazole-5-carbonyl}-2-azabicyclo[2.2.1]heptane-7-amine (1R,4R,7R)-2-{2-[1-(cyclopropylmethyl)-6-(quinolin-6-yl)-1H-indol-2-yl]-7-methoxy-1-methyl-1H-1,3-benzodiazole-5-carbonyl}-2-azabicyclo[2.2.1]heptane-7-amine 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroquinoline-2-one (1R,4R,7R)-2-{2-[1-(cyclopropylmethyl)-6-(quinolin-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-7-methoxy-1-methyl-1H-1,3-benzodiazole-5-carbonyl}-2-azabicyclo[2.2.1]heptane-7-amine (1R,4R,7R)-2-{2-[1-(cyclopropylmethyl)-6-(2-methylquinolin-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-7-methoxy-1-methyl-1H-1,3-benzodiazole-5-carbonyl}-2-azabicyclo[2.2.1]heptane-7-amine (1R,4R,7R)-2-{2-[1-(cyclopropylmethyl)-6-(quinolin-5-yl)-1H-indol-2-yl]-7-methoxy-1-methyl-1H-1,3-benzodiazole-5-carbonyl}-2-azabicyclo[2.2.1]heptane-7-amine (1R,4R,7R)-2-{2-[1-(cyclopropylmethyl)-6-(2-methylquinolin-5-yl)-1H-indol-2-yl]-7-methoxy-1-methyl-1H-1,3-benzodiazole-5-carbonyl}-2-azabicyclo[2.2.1]heptane-7-amine 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)quinoline-1-onthium-1-olate 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-4-hydroxyquinoline-3-carboxylic acid 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-8-fluoro-1,2,3,4-tetrahydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)quinoline-1-onthium-1-olate 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-4-hydroxyquinoline-3-carboxylic acid 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-8-fluoro-1,2,3,4-tetrahydroquinoline-2-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)quinoline-2-carboxynitrile 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)quinoline-2-carboxylonitrile (1R,4R,7R)-2-{2-[1-(cyclopropylmethyl)-6-(quinoxolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-7-methoxy-1-methyl-1H-1,3-benzodiazole-5-carbonyl}-2-azabicyclo[2.2.1]heptane-7-amine 6-(2-{5-[(2S,5R)-5-amino-2-methylpiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2-dihydroisoquinoline-1-one 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)quinazolin-4-ol 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)quinoxalin-2-ol 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)methyl quinoline-2-carboxylate 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)quinoxalin-2-ol 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)methyl quinoline-2-carboxylate 6-(2-{5-[(1R,4R,7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl) cinnamyl-4-ol 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)quinazolin-4-ol 6-(2-(5-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)-1-methyl-1H-benzo[c][1,2]thiazine-4(3H)-one 2,2-dioxide 7-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)isoquinoline-2-onthium-2-ol 6-(2-(5-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1-methyl-1H-benzo[c][1,2]thiazine-4(3H)-one 2,2-dioxide 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl) cinnamyl-4-ol 7-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoquinoline-2-onthium-2-ol 7-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)quinazolin-4-ol 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-7-methoxy-1,2,3,4-tetrahydroquinoline-2-one 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-7-hydroxy-1,2,3,4-tetrahydroquinoline-2-one 5-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2-dihydroquinoline-2-one 7-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-4-hydroxyquinoline-3-carboxylic acid ethyl ester 7-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)quinoline-4-ol 7-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)quinoline-4-ol 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-1,8-naphthidium-2-ol 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,8-naphthidium-2-ol 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)quinoline-2-carboxamide 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-4-hydroxyquinoline-2-carboxylic acid 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-4-hydroxyquinoline-2-carboxylic acid ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-hydroxyquinoline-7-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-(methyl-d3)-1H-benzo[d]imidazol-5-yl) methyl ketone 5-(2-(5-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-7-methoxy-1-(methyl-d3)-1H-benzo[d]imidazol-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)quinoline-2(1H)-one 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-4-hydroxyquinoline-3-carboxynitrile 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-4-hydroxyquinoline-3-carboxylic acid ethyl ester 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-4-hydroxyquinoline-3-carboxynitrile 5-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoquinoline-1-ol 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1-(2-hydroxy-2-methylpropyl)-1,2-dihydroquinoline-2-one 5-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)isoquinoline-1-ol 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-1-(2-hydroxy-2-methylpropyl)-1,2-dihydroquinoline-2-one 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline-1-one 7-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline-3-one 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroquinazolin-2-one 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-7-fluoro-1,2,3,4-tetrahydroquinoline-2-one 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-1,2,3,4-tetrahydroquinazolin-2-one 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-7-fluoro-1,2,3,4-tetrahydroquinoline-2-one 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-7-methoxy-1,2,3,4-tetrahydroquinoline-2-one 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2,4-dihydro-1H-3,1-benzoxazin-2-one 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-2,4-dihydro-1H-3,1-benzoxazin-2-one 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-4-methyl-1,2-dihydroquinoline-2-one 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2,4-dihydro-1H-3,1-benzoxazin-2-one 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-7-hydroxy-1,2,3,4-tetrahydroquinoline-2-one 7-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)quinoline-4-ol 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2-dihydroquinazolin-2-one 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,8-naphthyl-2-ol 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)quinoline-2-ol 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)quinoline-2,4-diol 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-methylquinoline-4-ol 5-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoquinoline-1-ol 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-methylquinoline-4-ol 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)quinoline-1-onthium-1-ol 7-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoquinoline-2-onthium-2-ol 7-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)quinazolin-4-ol 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)quinoxaline-2-ol 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2-dihydroisoquinoline-1-one 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-8-fluoro-1,2-dihydroquinoline-2-one 7-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroquinazolin-2,4-dione 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-7-methoxy-1,2,3,4-tetrahydroquinoline-2-one 5-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline-1-one 5-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroquinazolin-2,4-dione (3R,5R)-1-{2-[1-(cyclopropylmethyl)-6-{2H,3H,4H-pyrido[3,2-b][1,4]oxazin-7-yl}-1H-pyrrolo[2,3-b]pyridin-2-yl]-7-methoxy-1-methyl-1H-1,3-benzodiazole-5-carbonyl}-5-fluoropiperidine-3-amine (7R)-2-{2-[1-(cyclopropylmethyl)-6-{2H,3H,4H-pyrido[3,2-b][1,4]oxazin-7-yl}-1H-pyrrolo[2,3-b]pyridin-2-yl]-7-methoxy-1-methyl-1H-1,3-benzodiazole-5-carbonyl}-2-azabicyclo[2.2.1]heptane-7-amine 8-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-6-fluoro-3-methyl-1,2-dihydroquinoxalin-2-one 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-8-fluoro-1,2,3,4-tetrahydroquinoline-2-one 7-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline-1-one 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydro-1,8-naphthidin-2-one 7-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-3-one 7-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-2-one 7-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,4-dihydro-2H-1,4-benzoxazine-3-one 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,4-dihydro-2H-1,4-benzoxazine-3-one 7-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-3-one 7-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-2-one 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,4-dihydro-2H-1,4-benzoxazin-3-one (3R,5R)-1-{2-[1-(cyclopropylmethyl)-6-(2,3-dihydro-1,4-benzodioxane-6-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-7-methoxy-1-methyl-1H-1,3-benzodiazole-5-carbonyl}-5-fluoropiperidine-3-amine (3R,5R)-1-{2-[1-(cyclopropylmethyl)-6-{2H,3H,4H-pyrido[3,2-b][1,4]oxazin-6-yl}-1H-pyrrolo[2,3-b]pyridin-2-yl]-7-methoxy-1-methyl-1H-1,3-benzodiazole-5-carbonyl}-5-fluoropiperidine-3-amine 7-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2,5-dione 7-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2,5-dione 7-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)quinoline-2-ol 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoquinoline-3-ol (3R,5R)-1-{2-[1-(cyclopropylmethyl)-6-{2H,3H,4H-pyrido[3,2-b][1,4]oxazin-7-yl}-1H-indol-2-yl]-7-methoxy-1-methyl-1H-1,3-benzodiazole-5-carbonyl}-5-fluoropiperidine-3-amine 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)quinoline-1-onthium-1-olate 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-1,2,3,4-tetrahydro-1,8-naphthidin-2-one 7-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)isoquinoline-2-onthium-2-ol 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl) cinnamyl-4-ol 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-4-hydroxyquinoline-3-carboxylic acid 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)quinoline-2-ol 7-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-3-one 7-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2,5-dione 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-8-fluoro-4-hydroxyquinoline-3-carboxylic acid 6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-8-fluoro-4-hydroxyquinoline-3-carboxylic acid 2-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline-1-one 6-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-fluoro-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)quinazolin-2,4-diol 7-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one 8-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,4-dihydro-2H-1,4-benzoxazine-3-one 1-[5-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroquinolin-1-yl]ethane-1-one (3R,5R)-1-{2-[6-(1,2,4-benzotriazine-6-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-7-methoxy-1-methyl-1H-1,3-benzodiazole-5-carbonyl}-5-fluoropiperidine-3-amine 1-[5-(2-{5-[(3R,5R)-3-amino-5-fluoropiperidin-1-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline-2-yl]ethane-1-one 1-[6-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-2-yl]ethane-1-one 1-[5-(2-{5-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-7-methoxy-1-methyl-1H-1,3-benzodiazol-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline-2-yl]ethane-1-one.

7. A pharmaceutically acceptable composition comprising a compound as claimed in any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

8. A pharmaceutically acceptable composition comprising a compound as claimed in any one of claims 1 to 6 and a pharmaceutically acceptable adjuvant.

9. A pharmaceutically acceptable composition comprising a compound as claimed in any one of claims 1 to 6 and a pharmaceutically acceptable mediator.

10. The composition of any one of claims 7 to 9, in combination with an additional therapeutic agent.

11. The use of the composition of any one of claims 7 to 10 in the preparation of a medicament for treating a patient suffering from a PAD4-mediated disease, condition, or symptom, wherein the disease, condition, or symptom is selected from ankylosing spondylitis, cancer, colitis, lupus, rheumatoid arthritis, and multiple sclerosis, wherein the use comprises the step of administering the composition of claim 7 or 8 to the individual.

12. The use of claim 11, wherein the cancer is acute lymphoblastic leukemia.

13. The use of claim 11, wherein the cancer is chronic lymphocytic leukemia.

14. The use as claimed in claim 11, wherein the colitis is ulcerative colitis.

15. The use as claimed in claim 11, wherein the PAD4-mediated disease, condition, or symptom is selected from rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, and cancer.

16. The use as claimed in claim 11, wherein the PAD4-mediated disease, condition, or symptom is cutaneous lupus erythematosus.

17. A compound of any one of claims 1 to 6 or a composition of any one of claims 7 to 10, used in a therapeutic manner.

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