Heterocyclic PAD4 inhibitors

Abstract

The present invention generally relates to substituted heterocyclic compounds of formula (Ia) as inhibitors of PAD4, methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and uses of these compounds in treating diseases or disorders associated with PAD4 enzyme activity. wherein is and X1 to X6 and R1 to R8 and other variables are as defined herein.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] The present application claims priority from Indian Patent Application No. 202041006146 filed on February 12, 2020, each of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present invention generally relates to substituted heterocyclic compounds, methods of preparing these compounds, pharmaceutical compositions containing these compounds, and the use of these compounds in treating diseases or disorders associated with PAD4 enzyme activity. Background Art

[0004] PAD4 is a member of the peptide tyrosine deiminase (PAD) family of enzymes that catalyzes the conversion of arginine to citrulline within peptide sequences. PAD4 causes deimination or citrullination of a variety of proteins in vitro and in vivo, with consequences for different functional responses in a variety of diseases (Jones JE et al., Curr. Opin. Drug Discov. Devel., 12(5), (2009), 616-627). Examples of exemplary diseases or conditions include rheumatoid arthritis, diseases with neutrophil contributions to pathogenesis other than oncological indications (e.g., vasculitis, systemic lupus erythematosus, ulcerative colitis). PAD4 inhibitors also have broader applicability as tools and therapies for human diseases and conditions via epigenetic mechanisms.

[0005] PAD4 inhibitors have potential to treat rheumatoid arthritis (RA). RA is an autoimmune disease that affects approximately 1% of the population (Wegner N. et al., Immunol. Rev., 233(1), (2010), 34-54). It is characterized by joint inflammation leading to debilitating destruction of bone and cartilage. Although inconsistent, a weak genetic association between PAD4 polymorphism and susceptibility to RA has been proposed in many 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 deimination of various joint proteins. It is hypothesized that this process leads to a breakdown of tolerance to citrullinated substrates (such as fibrinogen, vimentin, and collagen in RA joints) and the initiation of an immune response to citrullinated substrates. These anti-citrullinated protein antibodies (ACPAs) contribute to disease pathogenesis and can also be used as a diagnostic test for RA (e.g., the commercially available CCP2 or cyclic citrullinated protein 2 test). Additionally, increased citrullination may also provide an additional direct contribution to disease pathogenesis through its ability to directly affect the function of several joints and inflammatory mediators (e.g., fibrinogen, antithrombin, various chemokines). In a smaller subset of RA patients, anti-PAD4 antibodies can be measured and may be associated with a more aggressive form of the disease.

[0006] PAD4 inhibitors are also useful in reducing pathological neutrophil activity in various diseases. Studies have shown that the formation of neutrophil extracellular traps (NETs), an innate defense mechanism by which neutrophils can immobilize and kill pathogens, is associated with histone citrullination and is deficient in PAD4 knockout mice (Neeli I. et al., J. Immunol., 180, (2008), 1895-1902 and Li P. et al., J. Exp. Med., 207(9), (2010), 1853-1862). Therefore, PAD4 inhibitors may be useful in diseases in which 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 et al., J. Allergy Clin. Immunol., 127(5), (2011), 1260-6), T. et al., Proc. Natl. Acad. Sci. USA, 107(36), (2010), 15880-5), radiculitis (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. In addition, there are indications that NETs may contribute to pathology in diseases affecting the skin, 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), and therefore PAD4 inhibitors may show benefit in treating NET skin diseases when administered via systemic or cutaneous routes. PAD4 inhibitors may affect additional functions within neutrophils and have broader applicability to neutrophil diseases.

[0007] Studies have demonstrated the efficacy of tool PAD inhibitors (e.g., chloramidine) in a number of animal models of disease, including collagen-induced arthritis (Willis VC et al., J. Immunol., 186(7), (2011), 4396-4404), dextran sulfate sodium (DSS)-induced experimental colitis (Chumanevich AA et al., Am. J. Physiol. Gastrointest. Liver Physiol., 300(6), (2011), G929-G938), spinal cord repair (Lange S. et al., Dev. Biol., 355(2), (2011), 205-14), and experimental autoimmune encephalomyelitis (EAE). DSS colitis reports also demonstrated that chloramidine 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 useful in 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 anti-proliferative effects of PAD4 inhibitors have been suggested by the observation that PAD4 citrullinates arginine residues in histones at the promoters of p53-target genes such as p21, which are involved in cell cycle arrest and induction of apoptosis (Li P. et al., Mol. Cell Biol., 28(15), (2008), 4745-4758).

[0009] The aforementioned role of PAD4 in the deimination of arginine residues in histones may indicate that PAD4 plays a role in epigenetic regulation of gene expression. PAD4 is the main PAD family member observed to reside in the nucleus and cytoplasm. Early evidence that PAD4 can act as a histone demethyliminase and deiminase is inconsistent and unconfirmed. However, it can indirectly reduce histone arginine methylation (and therefore reduce the epigenetic regulation associated with this mark) by eliminating available arginine residues through conversion to citrulline. PAD4 inhibitors are used as epigenetic tools or therapies to affect the expression of target genes that change in additional disease settings. Through such mechanisms, PAD4 inhibitors can also effectively control the citrullination level of stem cells and therefore can therapeutically affect the pluripotency state and differentiation potential of different stem cells, including but not limited to embryonic stem cells, neural stem cells, hematopoietic stem cells and cancer stem cells. Therefore, there is still an unmet need to identify and develop PAD4 inhibitors for the treatment of PAD4-mediated diseases or conditions. Summary of the Invention

[0010] Thus, there is provided a compound of formula (Ia):

[0011]

[0012] or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof.

[0013] In another general aspect, pharmaceutical compositions are provided comprising at least one compound of formula (I) or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

[0014] In another general aspect, provided is a method of treating a disease or condition associated with PAD4 enzyme activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof.

[0015] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the following description, including the claims.

[0016] Implementation Method

[0017] 1. Definition

[0018] The following are definitions of the terms used in this specification. Unless otherwise specified, the initial definitions provided for groups or terms herein apply to groups or terms throughout the present invention, either individually or as part of another group. Although the present invention is described with reference to exemplary embodiments, it should be understood that this is not intended to limit the scope of the invention. Numerous changes and other modifications to the inventive features of the present invention can be envisioned by those skilled in the art, and the present invention is possessed. All such changes and modifications are considered to be within the scope of the present invention. It must be noted that, unless the context clearly indicates otherwise, as used in this specification and the appended claims, the singular forms "a", "an" and "said" include plural referents. All references cited in this specification, including patents, patent applications and documents, are expressly incorporated herein by reference in their entirety.

[0019] As used herein, the term “C 1-6 "Alkyl" refers to and includes cyclic, straight-chain and branched hydrocarbon groups containing 1 to 6 carbon atoms. 1-6Representative, non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0020] As used herein, the term "alkenyl" refers to and includes straight or branched chain hydrocarbon groups containing 2 to 20 carbon atoms, including 1 to 6 double bonds. Typical non-limiting examples of alkenyl groups include ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, and the like.

[0021] As used herein, the term "alkynyl" refers to and includes straight or branched chain hydrocarbon groups containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Typical non-limiting examples of alkynyl groups include ethynyl, 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, and the like.

[0022] As used herein, the term "cycloalkyl" refers to and includes saturated or partially unsaturated (containing 1 or 2 double bonds) cycloalkyl containing 1 to 3 rings (e.g., monocyclic, bicyclic or tricyclic) and containing a total of 3 to 20 carbon atoms forming the ring. Cycloalkyl can be optionally substituted. The ring of polycyclic cycloalkyl can be fused, bridged and / or connected via one or more spiro rings to 1 or 2 aromatic cycloalkyls or heterocycles. Typical non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl and similar groups.

[0023] As used herein, the term "heterocyclic," "heterocyclyl," or "heterocycle" refers to and includes an optionally substituted saturated, unsaturated, or partially unsaturated 3-20 membered cyclic group (e.g., a 3-13 membered monocyclic, 7-17 membered bicyclic, or 10-20 membered tricyclic ring system) having at least one heteroatom in at least one carbon atom-containing ring. The heteroatoms are selected from nitrogen, oxygen, and / or sulfur atoms. Each ring of the heterocyclyl group may have 1, 2, 3, 4, or 5 heteroatoms, subject to the condition that at least one ring contains at least one heteroatom. The nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The rings of the polycyclic heterocycle may be fused, bridged, and / or connected via one or more spirocyclic junctions. Representative, non-limiting examples of heterocyclyl groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxythiophenyl, and the like.

[0024] As used herein, the term "aryl" refers to and includes aromatic homocyclic (i.e., hydrocarbon) monocyclic, bicyclic, or tricyclic aromatic groups containing 6 to 14 carbon atoms in the ring portion, and may optionally include one to three additional rings (cycloalkyl, heterocyclic, or heteroaryl) fused thereto. Typical non-limiting examples of aryl groups include phenyl, biphenyl, naphthyl (including 1-naphthyl and 2-naphthyl), anthracenyl, and the like.

[0025] The groups defined above may optionally have one or more hydrogen atoms attached to the carbon atom substituted with any group known to those skilled in the art. Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.

[0026] As used herein, the term "subject" refers to and includes any human or non-human organism that can potentially benefit from treatment with a PAD4 inhibitor. Exemplary subjects include humans and animals.

[0027] As used herein, the term "treating" or "treatment" refers to and includes treating a disease condition in a subject, e.g., a human or animal, and includes: (a) inhibiting the disease condition, i.e., arresting its development; (b) relieving the disease condition, i.e., causing regression of the disease condition; and / or (c) preventing the occurrence of the disease condition in a subject.

[0028] As used herein, the term "preventing" or "prevention" refers to and includes prophylactic treatment (i.e., prevention and / or risk reduction) of subclinical disease conditions in an individual, e.g., a human or animal, that is intended to reduce the chance of the occurrence of a clinical disease condition. An individual can be selected for prophylactic therapy based on factors known to increase the risk of developing a clinical disease condition compared to the general population. "Preventive" therapies can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment in an individual who has not yet presented with a clinical disease condition, while secondary prevention is defined as preventing the second occurrence of the same or similar clinical disease condition.

[0029] The term "therapeutically effective amount" refers to and includes an amount of a compound or composition according to the present invention that is effective, when administered alone or in combination, to prevent or treat a disease or condition associated with PAD4 enzyme activity. When applied to a combination, the term refers to combined amounts of the active ingredients that produce a prophylactic or therapeutic effect, whether administered in combination, sequentially, or simultaneously.

[0030] A "pharmaceutically acceptable carrier" refers to a medium generally recognized in the art for delivering biologically active agents to humans and / or animals. Pharmaceutically acceptable carriers are formulated based on a number of factors within the purview of one of ordinary skill in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to whom the composition containing the agent is to be administered; the desired route of administration of the compound or composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous solutions and anhydrous liquid media. Such carriers may include a variety of different ingredients and additives other than the active agent, such additional ingredients being included in the formulation for a variety of reasons well known to one of ordinary skill in the art, such as stabilizing the active agent, binders, and the like. Typical, non-limiting examples of such carriers include diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispensing agents, coating agents, and the like. Descriptions of suitable pharmaceutically acceptable carriers and factors involved in their selection are found in a variety of readily available sources, such as Allen, LV, Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd ed., Pharmaceutical Press (2012).

[0031] Prodrugs and solvates of the compounds of the present invention are also encompassed herein. As used herein, the term "prodrug" refers to a compound that undergoes chemical transformation by metabolic or chemical processes upon administration to a subject to produce a compound of formula (I) and its salts and / or solvates. Solvates of compounds of formula (I) include hydrates.

[0032] Any tautomers that may exist are also encompassed herein as part of the present invention. All stereoisomers of compounds of formula (I), including enantiomeric formulas (which may exist even in the absence of an asymmetric carbon, such as asymmetric isomers) and diastereomeric formulas (such as those that may exist due to an asymmetric carbon) are encompassed within the scope of the present invention. Individual stereoisomers of compounds of formula (I) may, for example, be substantially free of other isomers, or may be mixed, for example, in racemic form or with all other or other selected stereoisomers. The chiral centers in these compounds may have an S or R configuration as defined by the IUPAC 1974 recommendations. In general, for convenience, compounds of the present invention may be described herein without specific stereochemistry; however, all stereoisomers are encompassed within the scope of the present invention.

[0033] The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms that have the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium (symbol D or 2 H) and tritium (symbol T or 3 H). For example, a methyl group can be represented by CH3 or CD3. Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed.

[0034] Formula (I) compounds form salts, which are also within the scope of the present invention. Unless otherwise specified, references to formula (I) compounds herein are understood to include references to their salts. As used herein, the term "salt" refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, when the formula (I) compound contains both a basic moiety and an acidic moiety, a zwitterion ("inner salt") may be formed and is included within the term "salt" as used herein. Pharmaceutically acceptable salts include salts that are generally acceptable in the art of pharmaceutical science for administration to individuals including humans and animals. In general, pharmaceutically acceptable salts are non-toxic and physiologically acceptable salts. Salts of compounds according to the present invention can be formed, for example, by reacting the compound with an amount of acid or base (such as an equivalent) in a medium (such as a medium for salt precipitation) or in an aqueous medium followed by freeze drying.

[0035] Compounds of formula (Ia) containing a basic moiety can form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acids (e.g., trifluoroacetic acid)), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride (formed with hydrochloric acid), hydrobromide (formed with hydrogen bromide), hydroiodide, 2-hydroxyethanesulfonate , lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, peroxysulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylate, undecanoates, and the like.

[0036] Compounds of formula (Ia) containing an acidic moiety can form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts; alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; salts with organic bases (e.g., organic amines) such as benzathine, dicyclohexylamine, hydrazine (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine; and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can be quaternized by reagents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long-chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and other reagents.

[0037] The present invention encompasses compounds of formula (I), including stereoisomers, enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts thereof; methods for preparing these compounds; pharmaceutical compositions containing these compounds; and the use of these compounds in treating diseases or conditions associated with PAD4 enzyme activity.

[0038] 2. Description of Certain Aspects of the Invention

[0039] In a first aspect, the present invention provides a compound of formula (I):

[0040]

[0041] or a pharmaceutically acceptable salt thereof, wherein:

[0042] Independently selected from and

[0043] X1 and X2 are independently selected from CH and N;

[0044] X3 is independently selected from O and S;

[0045] X4 is independently selected from CR2 and N; with the proviso that X1 and X4 are not both N;

[0046] R1 is independently selected from -NH-C optionally substituted with one or more substituents selected from F, Cl and NH2 1-5 alkyl, 4-10 membered heterocyclyl and -NH-4-10 membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of 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;

[0047] R2 is independently selected from H, F, Cl, C 1-4 Alkyl, and -OC 1-4 alkyl;

[0048] R3 is independently selected from H, F, Cl, CN, -C(=O)OR b , and C optionally substituted with one or more substituents selected from F, Cl, and OH 1-3 alkyl;

[0049] R4 is independently selected from H, F, Cl, Br, -C(=O)R b , C optionally substituted with one or more substituents selected from F, Cl, and OH 1-6 Alkyl, optionally substituted with one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted -NH-C 1-6alkyl, optionally substituted with one or more R5 -(CH2) r -aryl, optionally substituted with one or more R5-OC 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -C 3-12 Cycloalkyl, and -(CH2) containing carbon atoms and 1 to 5 heteroatoms selected from N, NR6, O and S and optionally substituted with one or more R5 r -4-10 membered heterocyclic group;

[0050] R5 is independently selected from H, F, Cl, Br, CN, ═O, optionally substituted with one or more R e Substituted C 1-4 Alkyl, optionally substituted with one or more R e Substituted C 2-4 Alkenyl, optionally substituted with one or more R e Substituted C 2-4 Alkynyl, -(CR d R d ) r OR b 、-(CR d R d ) r S(O) p R c 、-(CR d R d ) r S(O) p NR a R a 、-(CR d R d ) r NR a S(O) p R c 、-(CR d R d ) r NR a R a 、-(CR d R d ) r NR a C(=O)R b 、-(CR d R d ) r NR a C(=O)OR b 、-(CR d R d ) r NR a C(=O)NRa R a 、-(CR d R d ) r C(=O)R b 、-(CR d R d ) r C(=O)OR b 、-(CR d R d ) r C(=O)NR a R a 、-(CR d R d ) r OC(=O)R b 、-(CR d R d ) r OC(=O)OR b 、-(CR d R d ) r O(CH2) r C(=O)NR a R a , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0051] R6 is independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, -S(O) p R c 、-S(O) p NR a R a 、-C(=O)R b 、-C(=O)OR b 、-C(=O)NR a R a , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0052] R7 is independently selected from H, F and Cl;

[0053] R8 is independently selected from H and optionally substituted by one or more selected from F, Cl and C3-6 Substituents of cycloalkyl substituted C 1-6 alkyl;

[0054] R a Independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group and optionally one or more R e Substituted -(CH2) r -heterocyclyl; or R a and R a Together with the nitrogen atom to which they are attached, they form a e substituted heterocycles;

[0055] R b Independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclic group;

[0056] R c Independently selected from optionally one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclic group;

[0057] Rd independently selected from H and optionally substituted with one or more R e Substituted C 1-6 alkyl;

[0058] R e Independently selected from F, Cl, Br, CN, NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, =O, OH, -OC 1-6 Alkyl, -CO2H, optionally with one or more R f Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted with one or more R f Substituted -(CH2) r -C 3-6 Cycloalkyl, optionally substituted with one or more R f Substituted -(CH2) r -aryl, and optionally one or more R f Substituted -(CH2) r -heterocyclic group;

[0059] R f independently selected from F, Cl, Br, CN, OH, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 cycloalkyl, and phenyl;

[0060] p is independently selected at each occurrence from 0, 1, and 2; and

[0061] r is independently selected from 0, 1, 2, 3 and 4 at each occurrence.

[0062] In a second aspect, the present invention provides compounds of formula (II):

[0063]

[0064] or a pharmaceutically acceptable salt thereof, within the scope of the first aspect, wherein:

[0065] X2 is independently selected from CH and N;

[0066] R1 is independently selected from

[0067] and

[0068] R2 is independently selected from H, F, Cl, -CH3 and -OCH3;

[0069] R3 is independently selected from H, F, Cl, -CN, CH3 and CH2OH;

[0070] R4 is independently selected from H, C optionally substituted with one or more substituents selected from F, Cl and OH 1-5 alkyl, phenyl optionally substituted with one or more R5, C 3-6 Cycloalkyl and 4-10 membered heterocyclyl comprising carbon atoms and 1 to 5 heteroatoms selected from N, NR6, O and S and optionally substituted with one or more R5;

[0071] R5 is independently selected from H, F, Cl, Br, CN, ═O, optionally substituted with one or more R e Substituted C 1-4 Alkyl, C optionally substituted with one or more Re 2-4 Alkenyl, -(CHR d ) r OR b 、–(CHR d ) r S(O) p R c 、-(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 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 ;

[0072] R6 is independently selected from H, optionally substituted with one or more R e Substituted C 1-4 alkyl;

[0073] R8 is independently selected from H and -CH2-C 3-6 Cycloalkyl;

[0074] R a independently selected from H and optionally substituted with one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted –(CH2) r –C 3-10 Carbocyclic group, optionally substituted with one or more R e Substituted (CH2) r heterocyclic group; or R a and R a Together with the nitrogen atom to which they are attached, they form a e substituted heterocycles;

[0075] R b Independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r heterocyclic group;

[0076] R c Independently selected from optionally one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclic group;

[0077] R d independently selected from H and optionally substituted with one or more R e Substituted C 1-4 alkyl.

[0078] R eIndependently selected from F, Cl, Br, -CN, NO2, =O, OH, OC 1-4 Alkyl, optionally substituted with one or more R f Substituted C 1-4 Alkyl, optionally substituted with one or more R f Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R f Substituted -(CH2) r -aryl, and optionally one or more R f Substituted -(CH2) r -heterocyclic group;

[0079] R f independently selected from F, Cl, Br, -CN and -OH;

[0080] p is independently selected at each occurrence from 0, 1, and 2; and

[0081] r is independently selected from 0, 1, 2, 3 and 4 at each occurrence.

[0082] In a third aspect, the present invention provides compounds within the scope of the second aspect,

[0083] or a pharmaceutically acceptable salt thereof, wherein:

[0084] R1 is independently selected from and

[0085] R2 is independently selected from H, F, -CH3 and -OCH3;

[0086] R3 is independently selected from H, Cl, CH3 and CH2OH;

[0087] R4 is independently selected from H, C optionally substituted with one or more substituents selected from F, Cl and OH 1-5 alkyl, phenyl optionally substituted with one or more R5, C 3-6 Cycloalkyl and 4-10 membered heterocyclyl comprising carbon atoms and 1 to 5 heteroatoms selected from N, NR6, O and S and optionally substituted with one or more R5;

[0088] R5 is independently selected from H, F, Cl, -CN, =O, optionally substituted with one or more R e Substituted C 1-4 Alkyl, -(CH2) r OR b 、–(CH2) r NR a S(O) p R c 、-(CH2) r NRa 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 C(=O)NR a R a 、-(CH2) r OC(=O)R b 、-(CH2) r OC(=O)OR b , and -(CH2) r O(CH2) r C(=O)NR a R a ;

[0089] R6 is independently selected from H, optionally substituted with one or more R e Substituted C 1-3 alkyl;

[0090] R8 is -CH2cyclopropyl;

[0091] R a independently selected from H and optionally substituted with one or more R e Substituted C 1-6 Alkyl; or R a and R a Together with the nitrogen atom to which they are attached, they form a e substituted heterocycles;

[0092] R b Independently selected from H, optionally through one or more R e Substituted C 1-6 alkyl;

[0093] R c Independently selected from optionally one or more R e Substituted C 1-6 alkyl;

[0094] R eIndependently selected from F, Cl, Br, -CN, =O, OH, OC 1-3 Alkyl, optionally substituted with one or more R f Substituted C 1-3 Alkyl, optionally substituted with one or more R f Substituted -C 3-6 Cycloalkyl, optionally substituted with one or more R f Substituted -(CH2) r -aryl, and optionally one or more R f Substituted -(CH2) r -heterocyclic group;

[0095] R f independently selected from F, Cl, Br, -CN and -OH;

[0096] p is independently selected at each occurrence from 0, 1, and 2; and

[0097] r is independently selected from 0, 1, 2, 3 and 4 at each occurrence.

[0098] In a fourth aspect, the present invention provides a compound according to the third aspect,

[0099] or a pharmaceutically acceptable salt thereof, wherein:

[0100] R1 is independently selected from and R2 is independently selected from H, F, and OC 1-3 ;

[0101] R3 is CH3;

[0102] R4 is independently selected from F, Cl, C 1-3 alkyl;

[0103]

[0104]

[0105]

[0106] and

[0107] R5 is independently selected at each occurrence from H, F, Cl, =O, optionally substituted with one or more R e Substituted C 1-4 Alkyl, -OR b 、-NR a S(O)2R c 、-NR a R a 、-NR a C(=O)Rb 、-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 and -OC(=O)OR b ;

[0108] R6 is independently selected from H and C 1-3 alkyl;

[0109] R a Independently selected from H and C 1-5 Alkyl; or R a and R a Together with the nitrogen atom to which they are attached, they form a e substituted heterocycles;

[0110] R b independently selected from H and optionally substituted with one or more R e Substituted C 1-5 alkyl;

[0111] R c is optionally passed through one or more R e Substituted C 1-5 alkyl;

[0112] R e Independently selected from F, Cl, Br, -CN, =O, OH, optionally through one or more R f Substituted C 1-4 Alkyl, optionally substituted with one or more R f Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R f substituted aryl, and optionally substituted by one or more R f substituted heterocyclic groups;

[0113] R f Independently selected from F, Cl, Br, -CN and OH.

[0114] In a fifth aspect, the present invention provides a compound according to the fourth aspect,

[0115] or a pharmaceutically acceptable salt thereof, wherein:

[0116] R4 is selected from C 1-2 alkyl,

[0117] and

[0118] R5 is independently selected from H, F, Cl, =O, optionally substituted by one or more R e Substituted C 1-4 Alkyl, -OR b 、-NR a S(O)2R c 、-NR a R a 、-NR a C(=O)R b and C(=O)NR a R a ;

[0119] R6 is independently selected from H, C optionally substituted with one or more F, Cl, and OH 1-4 alkyl;

[0120] R a Independently selected from H, optionally substituted with one or more R e Substituted C 1-4 alkyl;

[0121] R b Independently selected from H, optionally substituted with one or more R e Substituted C 1-4 alkyl;

[0122] R c Independently selected from H, optionally substituted with one or more R e Substituted C 1-4 alkyl; and

[0123] R e independently selected from F, Cl, Br, -CN, =O, OH and C 1-6 alkyl.

[0124] In a sixth aspect, the present invention provides a compound according to the fifth aspect, or a pharmaceutically acceptable salt thereof, wherein:

[0125] R4 is independently selected from CH3,

[0126] and

[0127] R5 is independently selected from F, Cl, -OH and C(=O)NH2.

[0128] In a seventh aspect, the present invention provides compounds having formula (III):

[0129]

[0130] or a pharmaceutically acceptable salt thereof, within the scope of the first aspect, wherein:

[0131] X2 is independently selected from CH and N;

[0132] R1 is independently selected from

[0133] and

[0134] R2 is independently selected from H, F, Cl, -CH3 and -OCH3;

[0135] R3 is independently selected from H, F, Cl, -CN, -CH3 and -CH2OH;

[0136] R4 is independently selected from H, F, Cl, C 1-3 alkyl,

[0137]

[0138] and

[0139] R5 is independently selected from H, F, Cl, ═O, —OH, —OCHF2, C(═O)NH2, and —NHS(O)2C 1-4 alkyl;

[0140] R6 is independently selected from H, C optionally substituted with one or more substituents selected from F, Cl, OH 1-4 alkyl;

[0141] R8 is -CH2cyclopropyl;

[0142] R a Independently selected from H, optionally through one or more R e Substituted C 1-4 alkyl;

[0143] R b Independently selected from H, optionally through one or more R e Substituted C 1-4 alkyl; and

[0144] R e independently selected from F, Cl, Br, -CN, =O, OH and C 1-6 alkyl.

[0145] In an eighth aspect, the present invention provides a compound having formula (IV),

[0146]

[0147] or a pharmaceutically acceptable salt thereof, within the scope of the first aspect, wherein:

[0148] X2 is independently selected from CH and N;

[0149] R1 is independently selected from -NHCH2CHFCH2NH2, and

[0150] R2 is independently selected from H, F, Cl, -CH3 and -OCH3;

[0151] R3 is independently selected from H, F, Cl, -CN, -CH3 and -CH2OH;

[0152] R4 is independently selected from H, F, Cl and C 1-3 alkyl; and

[0153] R8 is -CH2cyclopropyl.

[0154] In a ninth aspect, the present invention provides a compound having formula (V):

[0155]

[0156] or a pharmaceutically acceptable salt thereof, within the scope of the first aspect, wherein:

[0157] X2 is independently selected from CH and N;

[0158] R1 is independently selected from and R2 is independently selected from F, Cl, -CH3 and -OCH3;

[0159] R3 is independently selected from H, F, Cl, -CN, -CH3 and -CH2OH;

[0160] R4 is independently selected from H, F, Cl, Br, C 1-3 alkyl,

[0161]

[0162] and R5 is independently selected from H, H, F, Cl, =O, -OH, -OCHF2, NH2 and C(=O)NH2; R6 is independently selected from H, C, optionally substituted with one or more substituents of F, Cl and OH. 1-4 Alkyl; R8 is -CH2cyclopropyl;

[0163] R a Independently selected from H, optionally through one or more Re Substituted C 1-4 alkyl;

[0164] R b Independently selected from H, optionally through one or more R e Substituted C 1-4 alkyl;

[0165] R e independently selected from F, Cl, Br, -CN, =O, OH and C 1-6 alkyl.

[0166] In a tenth aspect, the present invention provides a compound having formula (VI):

[0167]

[0168]

[0169] or a pharmaceutically acceptable salt thereof, wherein:

[0170] X2 is independently selected from CH and N;

[0171] R1 is independently selected from

[0172] and

[0173] R2 is independently selected from H, F, Cl, -CH3 and -OCH3;

[0174] R3 is independently selected from H, F, Cl, -CN, -CH3 and -CH2OH;

[0175] R4 is independently selected from H, F, Cl, C 1-3 alkyl、

[0176]

[0177] and

[0178] R5 is independently selected from H, F, Cl, ═O, —OH, —OCHF2, and —C(═O)NH2;

[0179] R6 is independently selected from H, C optionally substituted with one or more substituents selected from F, Cl, OH 1-4 alkyl;

[0180] R8 is -CH2cyclopropyl;

[0181] R a Independently selected from H, optionally substituted with one or more R eSubstituted C 1-4 alkyl;

[0182] R b Independently selected from H, optionally through one or more R e Substituted C 1-4 alkyl;

[0183] R e independently selected from F, Cl, Br, -CN, =O, OH and C 1-6 alkyl.

[0184] In an eleventh aspect, the present invention provides a compound within the tenth category, or a pharmaceutically acceptable salt thereof, wherein:

[0185] R1 is independently selected from and

[0186] R2 is independently selected from H, F and OCH3;

[0187] R3 is CH3;

[0188] R4 is independently selected from

[0189] and and

[0190] R5 is independently selected from F, Cl, -OH, -NH2, -OC 1-4 Alkyl and C(=O)NH2.

[0191] In one aspect, the present invention provides a compound of formula (Ia):

[0192]

[0193] or its stereoisomers, enantiomers, diastereomers, tautomers or pharmaceutically acceptable

[0194] Acceptable salts, of which:

[0195] Selected from and

[0196] Selected from and

[0197] X1 is independently selected from CR2 and N;

[0198] X2 is independently selected from CR4 and N;

[0199] X3 is independently selected from O and S;

[0200] X4 is independently selected from CR2 and N; provided that X1 and X4 are not N at the same time;

[0201] X5 is independently selected from O and S;

[0202] X6 is independently selected from CR4 and N; assuming 1) X2 and X6 are not N at the same time; 2) when X2 and X6 are

[0203] In case of CR4, one of R4 is H;

[0204] R1 is independently selected from -NH-C optionally substituted with one or more substituents selected from F, Cl and NH2 1-5 alkyl, 4-10 membered heterocyclic group and -NH-4-10 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with one or more selected from 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 group and heterocyclic group are substituted by substituents.

[0205] R2 is independently selected from H, F, Cl, C optionally substituted with one or more substituents selected from F, Cl and OH 1-4 Alkyl and -OC 1-4 alkyl;

[0206] R3 is independently selected from H, F, Cl, CN, -C(=O)OR b , C optionally substituted with one or more substituents selected from F, Cl, OH, NH2 and N3 1-3 alkyl;

[0207] R4 is independently selected from H, F, Cl, Br, -C(=O)R b , optionally through one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted C 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -aryl, optionally substituted with one or more R5-(CH2) r –C 3-12 cycloalkyl, and -(CH2)r-4-10 membered heterocyclyl comprising carbon atoms and 1 to 5 heteroatoms selected from N, NR6, O and S and optionally substituted with one or more R5.

[0208] R5 is independently selected from H, F, Cl, Br, CN, ═O, optionally substituted with one or more R e Substituted C 1-4 Alkyl, optionally substituted with one or more R e Substituted C 2-4 Alkenyl, optionally substituted with one or more R e Substituted C 2-4 Alkynyl, –(CR d R d ) r OR b 、–(CR d R d ) r S(O) p R c 、–(CR d R d ) r S(O) p NR a R a 、–(CR d R d ) r NR a S(O) p R c 、–(CR d R d ) r NR a R a 、–(CR d R d ) r NR a C(=O)R b 、–(CR d R d ) r NR a C(=O)OR b 、–(CR d R d ) r NR a C(=O)NR a R a 、–(CR d R d ) r C(=O)R b 、–(CR d R d ) r C(=O)OR b 、–(CR d R d ) rC(=O)NR a R a 、–(CR d R d ) r OC(=O)R b 、–(CR d R d ) r OC(=O)OR b 、–(CR d R d ) r O(CH2) r C(=O)NR a R a , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0209] R6 is independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, -S(O) p R c 、-S(O) p NR a R a 、-C(=O)R b 、–C(=O)OR b 、-C(=O)NR a R a , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0210] R7 is independently selected from H, F and Cl;

[0211] R8 is independently selected from H and optionally substituted by one or more selected from F, Cl and C 3-6 Substituents of cycloalkyl substituted C 1-6 Alkyl, and C 3-6 Cycloalkyl;

[0212] R a Independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more Re Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclyl; or R a and R a Together with the nitrogen atom to which they are attached, they form a e substituted heterocycles;

[0213] R b Independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r heterocyclic group;

[0214] R c Independently selected from optionally one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclic group;

[0215] R d Independently selected from H, optionally through one or more R e Substituted C 1-6 alkyl;

[0216] R e Independently selected from F, Cl, Br, CN, NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, =O, OH, -OC 1-6Alkyl, -CO2H, optionally with one or more R f Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted with one or more R f Substituted -(CH2) r -C 3-6 Cycloalkyl, optionally substituted with one or more R f Substituted -(CH2) r -aryl, and optionally one or more R f Substituted -(CH2) r -heterocyclic group;

[0217] R f Independently selected from F, Cl, Br, CN, OH, OC 1-5 Alkyl, optionally OH-substituted C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 cycloalkyl, and phenyl;

[0218] p is independently selected at each occurrence from 0, 1, and 2; and

[0219] r is independently selected from 0, 1, 2, 3 and 4 at each occurrence.

[0220] In another aspect, the present invention provides compounds having formula (IIa)-(XIII):

[0221]

[0222]

[0223] or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof. R1, R2, R3, R4, R7 and R8 are as defined in formula (Ia).

[0224] In another aspect, the present invention provides compounds having formula (IIa):

[0225]

[0226] or its stereoisomers, enantiomers, diastereomers, tautomers or pharmaceutically acceptable

[0227] Acceptable salts, of which:

[0228] R1 is independently selected from and

[0229] R2 is independently selected from H, F, Cl, optionally substituted with one or more selected from F, Cl, OH and OC 1-3 Alkyl substituents substituted C 1-3 alkyl;

[0230] R3 is independently selected from H, F, Cl, CH3 and CH2OH;

[0231] R4 is independently selected from H, F, Cl, -C(=O)R b , optionally through one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted C 1-6 Alkyl, optionally substituted with one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted -NH-C 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -aryl, optionally substituted with one or more R5-OC 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -C 3-12 Cycloalkyl, and -(CH2) containing carbon atoms and 1 to 5 heteroatoms selected from N, NR6, O and S and optionally substituted with one or more R5 r -4-10 membered heterocyclic group;

[0232] R5 is independently selected from H, F, Cl, ═O, optionally substituted with one or more R e Substituted C 1-4 Alkyl, –(CH2) 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 aC(=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 、–(CH2) r OC(=O)OR b 、–(CH2) r O(CH2) r C(=O)NR a R a , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0233] R6 is independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, -C(=O)R b 、-C(=O)NR a R a , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0234] R7 is independently selected from H, F and Cl;

[0235] R8 is independently selected from H and optionally substituted by one or more selected from F, Cl and C 3-6 Substituents of cycloalkyl substituted C 1-6 alkyl;

[0236] R a Independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl; or R a and R a Together with the nitrogen atom to which they are attached, they form a e substituted heterocycles;

[0237] R bIndependently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r heterocyclic group;

[0238] R c Independently selected from optionally one or more R e Substituted C 1-6 Aryl, optionally with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclic group;

[0239] R e Independently selected from F, Cl, Br, NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, =O, OH, -OC 1-6 Alkyl, optionally substituted with one or more R f Substituted C 1-6 Alkyl, optionally substituted with one or more R f Substituted -(CH2) r -C 3-6 Cycloalkyl, optionally substituted with one or more R f Substituted -(CH2) r -aryl, and optionally one or more R f Substituted -(CH2) r -heterocyclic group;

[0240] R f Independently selected from F, Cl, OH, OC 1-5 Alkyl, optionally OH-substituted C 1-5 Alkyl, C 3-6 cycloalkyl, and phenyl;

[0241] p is independently selected at each occurrence from 0, 1, and 2; and

[0242] r is independently selected from 0, 1, 2, 3 and 4 at each occurrence.

[0243] In another aspect, the present invention provides compounds having formula (IIIa):

[0244]

[0245] or its stereoisomers, enantiomers, diastereomers, tautomers or pharmaceutically acceptable

[0246] Acceptable salts, of which:

[0247] R1 is independently selected from and

[0248] R2 is independently selected from H, F, Cl, C optionally substituted with one or more substituents selected from F, Cl and OH 1-3 Alkyl, and OC 1-3 alkyl;

[0249] R3 is independently selected from H, F, Cl, and C optionally substituted with one or more substituents selected from F, Cl and OH. 1-3 alkyl;;

[0250] R4 is independently selected from H, F, Cl, -C(=O)R b , optionally through one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted C 1-6 Alkyl, optionally substituted with one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted -NH-C 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -aryl, optionally substituted with one or more R5-OC 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -C 3-12 Cycloalkyl, and -(CH2) containing carbon atoms and 1 to 5 heteroatoms selected from N, NR6, O and S and optionally substituted with one or more R5 r -4-10 membered heterocyclic group;

[0251] R5 is independently selected from H, F, Cl, ═O, optionally substituted with one or more R e Substituted C 1-4 Alkyl, –(CH2) 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 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 , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0252] R6 is independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, --C(=O)R b 、–C(=O)OR b 、-C(=O)NR a R a , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0253] R7 is independently selected from H, F and Cl;

[0254] R8 is independently selected from H and optionally substituted by one or more selected from F, Cl and C 3-6 Substituents of cycloalkyl substituted C 1-6 alkyl;

[0255] R a Independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl; or R a and R a Together with the nitrogen atom to which they are attached, they form a e substituted heterocycles;

[0256] R b Independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r heterocyclic group;

[0257] R c Independently selected from optionally one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclic group;

[0258] R e Independently selected from F, Cl, Br, CN, NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, =O, OH, -OC 1-6 Alkyl, optionally substituted with one or more R f Substituted C 1-6 Alkyl, optionally substituted with one or more R f Substituted -(CH2) r -C 3-6 Cycloalkyl, optionally substituted with one or more R f Substituted -(CH2) r -aryl, and optionally one or more R f Substituted -(CH2) r -heterocyclic group;

[0259] R fIndependently selected from F, Cl, OH, OC 1-5 Alkyl, optionally OH-substituted C 1-5 Alkyl, C 3-6 cycloalkyl, and phenyl;

[0260] p is independently selected at each occurrence from 0, 1, and 2; and

[0261] r is independently selected from 0, 1, 2, 3 and 4 at each occurrence.

[0262] In another aspect, the present invention provides a compound having formula (IIa)-(IIIa), or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0263] R1 is independently selected from and

[0264] R2 is independently selected from H, F, Cl, CH3 and OCH3;

[0265] R3 is independently selected from H, F, Cl, CH3 and CH2OH;

[0266] R4 is independently selected from H, F, Cl, optionally substituted with one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted C 1-5 alkyl, optionally substituted with one or more R5 -(CH2) r -aryl, optionally substituted with one or more R5-OC 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -C 3-12 Cycloalkyl, and -(CH2) containing carbon atoms and 1 to 5 heteroatoms selected from N, NR6, O and S and optionally substituted with one or more R5 r -4-10 membered heterocyclic group;

[0267] R5 is independently selected from H, F, Cl, ═O, optionally substituted with one or more R e Substituted C 1-4 Alkyl, –(CH2) r OR b 、–(CH2) r S(O)2R c 、–(CH2) r S(O) p NR a R a 、–(CH2) r NR a S(O)2R 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 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 , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0268] R6 is independently selected from H, optionally substituted with one or more R e Substituted C 1-65 alkyl;

[0269] R7 is independently selected from H;

[0270] R8 is independently selected from 3-6 Cycloalkyl substituted C 1-3 alkyl;

[0271] R a Independently selected from H, C 1-4 alkyl;

[0272] R b Independently selected from H, C 1-4 alkyl;

[0273] R c C 1-4 alkyl;

[0274] r is independently selected from 0, 1 and 2 at each occurrence.

[0275] In another aspect, the present invention provides a compound having formula (IIa)-(IIIa), or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0276] R4 is independently selected from H, F, Cl, C optionally substituted with one or more substituents selected from F, Cl and OH 1-5 Alkyl, C 3-6 Cycloalkyl,

[0277]

[0278]

[0279] and

[0280] R5 is independently selected from H, F, Cl, ═O, optionally substituted with one or more R e Substituted C 1-4 Alkyl, –(CH2) 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)ORb 、–(CH2) 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 , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclyl; and

[0281] R6 is independently selected from H and C 1-5 alkyl; and the other variables are as defined in Formulas (IIa)-(IIIa).

[0282] In another aspect, the present invention provides a compound having formula (IIa)-(IIIa), or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0283] R4 is independently selected from

[0284]

[0285]

[0286] and and the other variables are defined in formulas (IIa)-(IIIa).

[0287] In another aspect, the present invention provides compounds having formula (IVa):

[0288]

[0289]

[0290] or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0291] R1 is independently selected from and

[0292] R2 is independently selected from H, F, Cl, optionally substituted with one or more substituents selected from F, Cl and OH.

[0293] Generation C 1-3 Alkyl, and OC 1-3 alkyl;

[0294] R3 is independently selected from H, F, Cl, optionally substituted with one or more substituents selected from F, Cl and OH.

[0295] Generation C 1-3 alkyl;

[0296] R4 is independently selected from H, F, Cl, -C(=O)R b , optionally through one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted C 1-6 Alkyl, optionally substituted with one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted -NH-C 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -aryl, optionally substituted with one or more R5-OC 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -C 3-12 Cycloalkyl, and -(CH2) containing carbon atoms and 1 to 5 heteroatoms selected from N, NR6, O and S and optionally substituted with one or more R5 r -4-10 membered heterocyclic group;

[0297] R5 is independently selected from H, F, Cl, ═O, optionally substituted with one or more R e Substituted C 1-4 Alkyl, –(CH2) 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)Rb 、–(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 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 , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0298] R6 is independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, -S(O) p R c 、-S(O) p NR a R a 、-C(=O)R b 、–C(=O)OR b 、-C(=O)NR a R a , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0299] R7 is independently selected from H, F and Cl;

[0300] R8 is independently selected from H and optionally substituted by one or more selected from F, Cl and C 3-6 Substituents of cycloalkyl substituted C 1-6 alkyl;

[0301] R a Independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group and optionally one or more R e Substituted -(CH2)r-heterocyclyl; or R a and R a Together with the nitrogen atom to which they are attached, they form a e substituted heterocycles;

[0302] R b Independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e substituted -(CH2)r heterocyclyl;

[0303] R c Independently selected from optionally one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclic group;

[0304] R e Independently selected from F, Cl, Br, NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, =O, OH, -OC 1-6 Alkyl, optionally substituted with one or more R f Substituted C 1-6 Alkyl, optionally substituted with one or more R f Substituted -(CH2) r -C 3-6 Cycloalkyl, optionally substituted with one or more R f Substituted -(CH2) r -aryl, and optionally one or more R f Substituted -(CH2) r -heterocyclic group;

[0305] R f independently selected from F, Cl, OH, C optionally substituted with OH 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 cycloalkyl, and phenyl;

[0306] p is independently selected at each occurrence from 0, 1, and 2; and

[0307] r is independently selected from 0, 1, 2, 3 and 4 at each occurrence.

[0308] In another aspect, the present invention provides a compound having formula (IVa), or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0309] R1 is independently selected from and

[0310] R2 is independently selected from H, F, Cl and OCH3;

[0311] R3 is independently selected from F, Cl and CH3;

[0312] R4 is independently selected from H, and

[0313] R5 is independently selected from H, =O, C 1-4 Alkyl, OH and NH2;

[0314] R6 is independently selected from H, optionally substituted with one or more R e Substituted C 1-5 Alkyl and -C(=O)R b ;

[0315] R7 is H;

[0316] R8 is independently selected from C optionally substituted by cyclopropyl 1-2 alkyl;

[0317] R b Independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r heterocyclic group;

[0318] R e independently selected from NH2 and optionally one or more R f Substituted C 1-5 alkyl;

[0319] R f Independently selected from F, Cl, OH and OC 1-5 alkyl;

[0320] In another aspect, the present invention provides a compound having formula (IIa)-(IIIa), or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0321] R4 is independently selected from and and the other variables are defined in formulas (IIa)-(IIIa).

[0322] In another aspect, the present invention provides compounds having formula (Va),

[0323]

[0324] or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0325] R1 is independently selected from and

[0326] R2 is independently selected from H, F, Cl, CH3 and OCH3;

[0327] R3 is independently selected from H, F, Cl, CH3 and CH2OH;

[0328] R4 is independently selected from H, F, Cl, -C(=O)R b , optionally through one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted C 1-6 Alkyl, optionally substituted with one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted -NH-C 1-6 alkyl, -(CH2)r-aryl optionally substituted with one or more R5, -OC 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -C 3-12Cycloalkyl, and -(CH2) containing carbon atoms and 1 to 5 heteroatoms selected from N, NR6, O and S and optionally substituted with one or more R5 r -4-10 membered heterocyclic group;

[0329] R5 is independently selected from H, F, Cl, ═O, optionally substituted with one or more R e Substituted C 1-4 Alkyl, optionally substituted with one or more R e Substituted C 2-4 Alkenyl, optionally substituted with one or more R e Substituted C 2-4 Alkynyl, –(CH2) 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 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 , optionally through one or more R e Substituted C3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0330] R6 is independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, -C(=O)R b 、–C(=O)OR b 、-C(=O)NR a R a , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0331] R7 is independently selected from H, F and Cl;

[0332] R8 is independently selected from H and optionally substituted by one or more selected from F, Cl and C 3-6 Substituents of cycloalkyl substituted C 1-6 alkyl;

[0333] R a Independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group and optionally one or more R e Substituted -(CH2) r -heterocyclyl; or R a and R a Together with the nitrogen atom to which they are attached, they form a e substituted heterocycles;

[0334] R b Independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r heterocyclic group;

[0335] R c Independently selected from optionally one or more R eSubstituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclic group;

[0336] R e Independently selected from F, Cl, Br, NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, =O, OH, -OC 1-6 Alkyl, -CO2H, optionally with one or more R f Substituted C 1-6 Alkyl, optionally substituted with one or more R f Substituted -(CH2) r -C 3-6 Cycloalkyl, optionally substituted with one or more R f Substituted -(CH2) r -aryl, and optionally one or more R f Substituted -(CH2) r -heterocyclic group;

[0337] R f independently selected from F, Cl, Br, CN, OH, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 cycloalkyl, and phenyl;

[0338] p is independently selected at each occurrence from 0, 1, and 2; and

[0339] r is independently selected from 0, 1, 2, 3 and 4 at each occurrence.

[0340] In another aspect, the present invention provides a compound having formula (Va), or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0341] R1 is independently selected from and

[0342] R2 is CH3;

[0343] R3 is CH3; and

[0344] R4 is independently selected from and

[0345] R7 is H;

[0346] R8 is optionally selected from C 1-2 alkyl;

[0347] In another aspect, the present invention provides a compound having formula (VIa),

[0348]

[0349] or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0350] R1 is independently selected from and

[0351] R3 is independently selected from H, F and CH3;

[0352] R4 is independently selected from H, F, Cl, -C(=O)R b , optionally through one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted C 1-6 Alkyl, optionally substituted with one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted -NH-C 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -aryl, optionally substituted with one or more R5-OC 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -C 3-12 Cycloalkyl, and -(CH2) containing carbon atoms and 1 to 5 heteroatoms selected from N, NR6, O and S and optionally substituted with one or more R5 r -4-10 membered heterocyclic group;

[0353] R5 is independently selected from H, F, Cl, Br, CN, ═O, optionally substituted with one or more R e Substituted C 1-4 Alkyl, optionally substituted with one or more R e Substituted C 2-4 Alkenyl, optionally substituted with one or more R e Substituted C 2-4 Alkynyl, –(CH2) 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 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 , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0354] R6 is independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, -C(=O)R b 、–C(=O)OR b 、-C(=O)NR a R a , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0355] R7 is independently selected from H, F and Cl;

[0356] R8 is independently selected from H and optionally substituted by one or more selected from F, Cl and C 3-6 Substituents of cycloalkyl substituted C 1-6 alkyl;

[0357] R a Independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group and optionally one or more R e Substituted -(CH2) r -heterocyclyl; or R a and R a Together with the nitrogen atom to which they are attached, they form a e substituted heterocycles;

[0358] R b Independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r heterocyclic group;

[0359] R c Independently selected from optionally one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclic group;

[0360] R e Independently selected from F, Cl, Br, CN, NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, =O, OH, -OC 1-6 Alkyl, -CO2H, optionally with one or more R f Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted with one or more R f Substituted -(CH2) r -C 3-6 Cycloalkyl, optionally substituted with one or more R f Substituted -(CH2) r -aryl, and optionally one or more R f Substituted -(CH2) r -heterocyclic group;

[0361] R f independently selected from F, Cl, Br, CN, OH, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 cycloalkyl, and phenyl;

[0362] p is independently selected at each occurrence from 0, 1, and 2; and

[0363] r is independently selected from 0, 1, 2, 3 and 4 at each occurrence.

[0364] In another aspect, the present invention provides a compound having formula (VIa), or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0365] R1 is independently selected from and

[0366] R3 is CH3;

[0367] R4 is independently selected from F, Cl, and

[0368] R7 is H; and

[0369] R8 is optionally selected from C 1-2 alkyl;

[0370] In another aspect, the present invention provides compounds having formula (VII),

[0371]

[0372] or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0373] R1 is independently selected from and

[0374] R2 is independently selected from H, F, Cl, CH3 and OCH3;

[0375] R3 is independently selected from H, F and CH3;

[0376] R4 is independently selected from H, F, Cl, Br, -C(=O)R b , optionally through one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted C 1-6 Alkyl, optionally substituted by one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted -NH-C 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -aryl, optionally substituted with one or more R5-OC 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -C 3-12 cycloalkyl, and -(CH2) containing carbon atoms and 1 to 5 heteroatoms selected from N, NR6, O and S and optionally substituted with one or more R5 r -4-10 membered heterocyclic group;

[0377] R5 is independently selected from H, F, Cl, Br, CN, ═O, optionally substituted by one or more R e Substituted C 1-4 Alkyl, optionally with one or more R e Substituted C 2-4 Alkenyl, optionally with one or more R e Substituted C 2-4 Alkynyl, -(CH2) 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 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 , as appropriate, through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0378] R6 is independently selected from H, optionally substituted by one or more R e Substituted C 1-6 Alkyl, -S(O) p R c 、-S(O) p NR a R a 、-C(=O)R b 、-C(=O)OR b 、-C(=O)NR a R a , as appropriate, through one or more R e Substituted C 3-6Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0379] R7 is independently selected from H, F and Cl;

[0380] R8 is independently selected from H and optionally substituted by one or more selected from F, Cl and C 3-6 Substituents of cycloalkyl substituted C 1-6 alkyl;

[0381] R a independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally with one or more R e Substituted C 2-6 Alkenyl, optionally with one or more R e Substituted C 2-6 Alkynyl, optionally with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group and optionally one or more R e Substituted -(CH2) r -heterocyclyl; or R a and R a Together with the nitrogen atom to which they are attached, they form optionally one or more R e substituted heterocycles;

[0382] R b independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally with one or more R e Substituted C 2-6 Alkenyl, optionally with one or more R e Substituted C 2-6 Alkynyl, optionally with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r heterocyclic group;

[0383] R c Independently selected from optionally one or more R e Substituted C 1-6 Alkyl, optionally with one or more R e Substituted C 2-6 Alkenyl, optionally with one or more R e Substituted C 2-6Alkynyl, optionally with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclic group;

[0384] R e Independently selected from F, Cl, Br, CN, NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, =O, OH, -OC 1-6 Alkyl, -CO2H, optionally with one or more R f Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally with one or more R f Substituted -(CH2) r -C 3-6 Cycloalkyl, optionally substituted with one or more R f Substituted -(CH2) r -aryl, and optionally one or more R f Substituted -(CH2) r -heterocyclic group;

[0385] R f independently selected from F, Cl, Br, CN, OH, C optionally substituted with OH 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 cycloalkyl, and phenyl;

[0386] p is independently selected at each occurrence from 0, 1, and 2; and

[0387] r is independently selected from 0, 1, 2, 3 and 4 at each occurrence.

[0388] In another aspect, the present invention provides compounds having formula (VIII),

[0389]

[0390] or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0391] R1 is independently selected from and

[0392] R2 is independently selected from H, F and OCH3;

[0393] R3 is independently selected from H, F and CH3;

[0394] R4 is independently selected from H, F, Cl, Br, -C(=O)R b , optionally through one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted C 1-6 Alkyl, optionally substituted by one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted -NH-C 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -aryl, optionally substituted with one or more R5-OC 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -C 3-12 cycloalkyl, and -(CH2) containing carbon atoms and 1 to 5 heteroatoms selected from N, NR6, O and S and optionally substituted with one or more R5 r -4-10 membered heterocyclic group;

[0395] R5 is independently selected from H, F, Cl, Br, CN, ═O, optionally substituted by one or more R e Substituted C 1-4 Alkyl, optionally with one or more R e Substituted C 2-4 Alkenyl, optionally with one or more R e Substituted C 2-4 Alkynyl, -(CH2) 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)NRa 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 、-(CH2) r OC(=O)OR b 、-(CH2) r O(CH2) r C(=O)NR a R a , as appropriate, through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0396] R6 is independently selected from H, optionally substituted by one or more R e Substituted C 1-6 Alkyl, -C(=O)R b 、-C(=O)OR b 、-C(=O)NR a R a , as appropriate, through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0397] R7 is independently selected from H, F and Cl;

[0398] R8 is independently selected from H and optionally substituted by one or more selected from F, Cl and C 3-6 Substituents of cycloalkyl substituted C 1-6 alkyl;

[0399] R a independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally with one or more R e Substituted C 2-6 Alkenyl, optionally with one or more R e Substituted C 2-6 Alkynyl, optionally with one or more R eSubstituted -(CH2) r -C 3-10 Carbocyclic group and optionally one or more R e Substituted -(CH2) r -heterocyclyl; or R a and R a Together with the nitrogen atom to which they are attached, they form optionally one or more R e substituted heterocycles;

[0400] R b independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally with one or more R e Substituted C 2-6 Alkenyl, optionally with one or more R e Substituted C 2-6 Alkynyl, optionally with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r heterocyclic group;

[0401] R c Independently selected from optionally one or more R e Substituted C 1-6 Alkyl, optionally with one or more R e Substituted C 2-6 Alkenyl, optionally with one or more R e Substituted C 2-6 Alkynyl, optionally with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclic group;

[0402] R d independently selected from H and optionally one or more R e Substituted C 1-6 alkyl;

[0403] R e Independently selected from F, Cl, Br, CN, NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, =O, OH, -OC 1-6 Alkyl, -CO2H, optionally with one or more R f Substituted C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted with one or more Rf -(CH2) r -C 3-6 Cycloalkyl, optionally substituted with one or more R f Substituted -(CH2) r -aryl, and optionally one or more R f Substituted -(CH2) r -heterocyclic group;

[0404] R f independently selected from F, Cl, Br, CN, OH, C optionally substituted with OH 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 cycloalkyl, and phenyl;

[0405] p is independently selected at each occurrence from 0, 1, and 2; and

[0406] r is independently selected from 0, 1, 2, 3 and 4 at each occurrence.

[0407] In another aspect, the present invention provides compounds having formula (IX),

[0408]

[0409] or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0410] R1 is independently selected from and

[0411] R2 is independently selected from H, F, CH3, CH2OH, CH2CH2OH and OCH3;

[0412] R3 is independently selected from H, F, Cl, CH3, CH2OH, CH2CH2OH, CH2NH3, CH2CH2NH2 and CH2CH2N3;

[0413] R4 is independently selected from H, F, Cl, Br, -C(=O)R b , optionally through one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted C 1-6 Alkyl, optionally substituted by one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted -NH-C 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r-aryl, optionally substituted with one or more R5-OC 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -C 3-12 cycloalkyl, and -(CH2) containing carbon atoms and 1 to 5 heteroatoms selected from N, NR6, O and S and optionally substituted with one or more R5 r -4-10 membered heterocyclic group;

[0414] R5 is independently selected from H, F, Cl, Br, CN, ═O, optionally substituted by one or more R e Substituted C 1-4 Alkyl, optionally with one or more R e Substituted C 2-4 Alkenyl, optionally with one or more R e Substituted C 2-4 Alkynyl, -(CH2) 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 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 , as appropriate, through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0415] R6 is independently selected from H, optionally substituted by one or more R e Substituted C 1-6 Alkyl, -S(O) p R c 、-S(O) p NR a R a 、-C(=O)R b 、-C(=O)OR b 、-C(=O)NR a R a , as appropriate, through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0416] R7 is independently selected from H, F and Cl;

[0417] R8 is independently selected from H and optionally substituted by one or more selected from F, Cl and C 3-6 Substituents of cycloalkyl substituted C 1-6 alkyl;

[0418] R a independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally with one or more R e Substituted C 2-6 Alkenyl, optionally with one or more R e Substituted C 2-6 Alkynyl, optionally with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group and optionally one or more R e Substituted -(CH2) r -heterocyclyl; or R a and R a Together with the nitrogen atom to which they are attached, they form optionally one or more R e substituted heterocycles;

[0419] R b independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally with one or more R e Substituted C 2-6 Alkenyl, optionally with one or more R e Substituted C 2-6 Alkynyl, optionally with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r heterocyclic group;

[0420] R c Independently selected from optionally one or more R e Substituted C 1-6 Alkyl, optionally with one or more R e Substituted C 2-6 Alkenyl, optionally with one or more R e Substituted C 2-6 Alkynyl, optionally with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclic group;

[0421] R e Independently selected from F, Cl, Br, CN, NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, =O, OH, -OC 1-6 Alkyl, -CO2H, optionally with one or more R f Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally with one or more R f Substituted -(CH2) r -C 3-6 Cycloalkyl, optionally substituted with one or more R f Substituted -(CH2) r -aryl, and optionally one or more R f Substituted -(CH2) r -heterocyclic group;

[0422] R findependently selected from F, Cl, Br, CN, OH, C optionally substituted with OH 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 cycloalkyl, and phenyl;

[0423] p is independently selected at each occurrence from 0, 1, and 2; and

[0424] r is independently selected from 0, 1, 2, 3 and 4 at each occurrence.

[0425] In another aspect, the present invention provides compounds having formula (X),

[0426]

[0427] or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0428] R1 is independently selected from and

[0429] R2 is independently selected from H, F, CH3, CH2OH, CH2CH2OH and OCH3;

[0430] R3 is independently selected from H, F, CH3, CH2OH, CH2CH2OH, CH2NH3, CH2CH2NH2 and CH2CH2N3;

[0431] R4 is independently selected from H, F, Cl, Br, -C(=O)R b , optionally through one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted C 1-6 Alkyl, optionally substituted by one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted -NH-C 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -aryl, optionally substituted with one or more R5-OC 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -C 3-12 cycloalkyl, and -(CH2) containing carbon atoms and 1 to 5 heteroatoms selected from N, NR6, O and S and optionally substituted with one or more R5 r -4-10 membered heterocyclic group;

[0432] R5 is independently selected from H, F, Cl, Br, CN, ═O, optionally substituted by one or more R eSubstituted C 1-4 Alkyl, optionally with one or more R e Substituted C 2-4 Alkenyl, optionally with one or more R e Substituted C 2-4 Alkynyl, -(CH2) 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 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 , as appropriate, through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0433] R6 is independently selected from H, optionally substituted by one or more R e Substituted C1-6 Alkyl, -S(O) p R c 、-S(O) p NR a R a 、-C(=O)R b 、-C(=O)OR b 、-C(=O)NR a R a , as appropriate, through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0434] R7 is independently selected from H, F and Cl;

[0435] R8 is independently selected from H and optionally substituted by one or more selected from F, Cl and C 3-6 Substituents of cycloalkyl substituted C 1-6 alkyl;

[0436] R a independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally with one or more R e Substituted C 2-6 Alkenyl, optionally with one or more R e Substituted C 2-6 Alkynyl, optionally with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group and optionally one or more R e Substituted -(CH2) r -heterocyclyl; or R a and R a Together with the nitrogen atom to which they are attached, they form optionally one or more R e substituted heterocycles;

[0437] R b independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally with one or more R e Substituted C 2-6 Alkenyl, optionally with one or more R e Substituted C 2-6 Alkynyl, optionally with one or more R e Substituted -(CH2) r -C 3-10Carbocyclic group, and optionally one or more R e Substituted -(CH2) r heterocyclic group;

[0438] R c Independently selected from optionally one or more R e Substituted C 1-6 Alkyl, optionally with one or more R e Substituted C 2-6 Alkenyl, optionally with one or more R e Substituted C 2-6 Alkynyl, optionally with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclic group;

[0439] R e Independently selected from F, Cl, Br, CN, NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, =O, OH, -OC 1-6 Alkyl, -CO2H, optionally with one or more R f Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally with one or more R f Substituted -(CH2) r -C 3-6 Cycloalkyl, optionally substituted with one or more R f Substituted -(CH2) r -aryl, and optionally one or more R f Substituted -(CH2) r -heterocyclic group;

[0440] R f independently selected from F, Cl, Br, CN, OH, C optionally substituted with OH 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 cycloalkyl, and phenyl;

[0441] p is independently selected at each occurrence from 0, 1, and 2; and

[0442] r is independently selected from 0, 1, 2, 3 and 4 at each occurrence.

[0443] In another aspect, the present invention provides compounds having formula (XI),

[0444]

[0445] or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0446] R1 is independently selected from and

[0447] R2 is independently selected from H, F, CH3, CH2OH, CH2CH2OH and OCH3;

[0448] R3 is independently selected from H, F, CH3, CH2OH, CH2CH2OH, CH2NH3, CH2CH2NH2 and CH2CH2N3;

[0449] R4 is independently selected from H, F, Cl, Br, -C(=O)R b , optionally through one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted C 1-6 Alkyl, optionally substituted with one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted -NH-C 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -aryl, optionally substituted with one or more R5-OC 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -C 3-12 Cycloalkyl, and -(CH2) containing carbon atoms and 1 to 5 heteroatoms selected from N, NR6, O and S and optionally substituted with one or more R5 r -4-10 membered heterocyclic group;

[0450] R5 is independently selected from H, F, Cl, Br, CN, ═O, optionally substituted with one or more R e Substituted C 1-4 Alkyl, optionally substituted with one or more R e Substituted C 2-4 Alkenyl, optionally substituted with one or more R e Substituted C 2-4 Alkynyl, -(CH2) r OR b 、-(CH2) r S(O) p R c 、-(CH2) r S(O) p NR a Ra 、-(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 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 , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0451] R6 is independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, -S(O) p R c 、-S(O) p NR a R a 、-C(=O)R b 、-C(=O)OR b 、-C(=O)NR a R a , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R esubstituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0452] R7 is independently selected from H, F and Cl;

[0453] R8 is independently selected from H and optionally substituted by one or more selected from F, Cl and C 3-6 Substituents of cycloalkyl substituted C 1-6 alkyl;

[0454] R a Independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group and optionally one or more R e Substituted -(CH2) r -heterocyclyl; or R a and R a Together with the nitrogen atom to which they are attached, they form a e substituted heterocycles;

[0455] R b Independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r heterocyclic group;

[0456] R c Independently selected from optionally one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R eSubstituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclic group;

[0457] R d independently selected from H and optionally substituted with one or more R e Substituted C 1-6 alkyl;

[0458] R e Independently selected from F, Cl, Br, CN, NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, =O, OH, -OC 1-6 Alkyl, -CO2H, optionally with one or more R f Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted with one or more R f Substituted -(CH2) r -C 3-6 Cycloalkyl, optionally substituted with one or more R f Substituted -(CH2) r -aryl, and optionally one or more R f Substituted -(CH2) r -heterocyclic group;

[0459] R f independently selected from F, Cl, Br, CN, OH, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 cycloalkyl, and phenyl;

[0460] p is independently selected at each occurrence from 0, 1, and 2; and

[0461] r is independently selected from 0, 1, 2, 3 and 4 at each occurrence.

[0462] In another aspect, the present invention provides compounds having formula (XII),

[0463]

[0464] or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0465] R1 is independently selected from and

[0466] R2 is independently selected from H, F, CH3, CH2OH, CH2CH2OH and OCH3;

[0467] R3 is independently selected from H, F, CH3, CH2OH, CH2CH2OH, CH2NH3, CH2CH2NH2 and CH2CH2N3;

[0468] R4 is independently selected from H, F, Cl, Br, -C(=O)R b , optionally through one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted C 1-6 Alkyl, optionally substituted with one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted -NH-C 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -aryl, optionally substituted with one or more R5-OC 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -C 3-12 Cycloalkyl, and -(CH2) containing carbon atoms and 1 to 5 heteroatoms selected from N, NR6, O and S and optionally substituted with one or more R5 r -4-10 membered heterocyclic group;

[0469] R5 is independently selected from H, F, Cl, Br, CN, ═O, optionally substituted with one or more R e Substituted C 1-4 Alkyl, optionally substituted with one or more R e Substituted C 2-4 Alkenyl, optionally substituted with one or more R e Substituted C 2-4 Alkynyl, -(CH2) 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)Rb 、-(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 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 , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0470] R6 is independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, -S(O) p R c 、-S(O) p NR a R a 、-C(=O)R b 、-C(=O)OR b 、-C(=O)NR a R a , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0471] R7 is independently selected from H, F and Cl;

[0472] R8 is independently selected from H and optionally substituted by one or more selected from F, Cl and C 3-6 Substituents of cycloalkyl substituted C 1-6 alkyl;

[0473] R a Independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group and optionally one or more R e Substituted -(CH2) r -heterocyclyl; or R a and R a Together with the nitrogen atom to which they are attached, they form a e substituted heterocycles;

[0474] R b Independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r heterocyclic group;

[0475] R c Independently selected from optionally one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclic group;

[0476] R d independently selected from H and optionally substituted with one or more R e Substituted C1-6 alkyl;

[0477] R e Independently selected from F, Cl, Br, CN, NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, =O, OH, -OC 1-6 Alkyl, -CO2H, optionally with one or more R f Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted with one or more R f Substituted -(CH2) r -C 3-6 Cycloalkyl, optionally substituted with one or more R f Substituted -(CH2) r -aryl, and optionally one or more R f Substituted -(CH2) r -heterocyclic group;

[0478] R f independently selected from F, Cl, Br, CN, OH, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 cycloalkyl, and phenyl;

[0479] p is independently selected at each occurrence from 0, 1, and 2; and

[0480] r is independently selected from 0, 1, 2, 3 and 4 at each occurrence.

[0481] In another aspect, the present invention provides compounds having formula (IX) to (XII), or stereoisomers, enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof, wherein;

[0482] R4 is independently selected from H, F, Cl, Br,

[0483]

[0484]

[0485] and and other variations defined by formula (IX) to formula (XII).

[0486] In another aspect, the present invention provides compounds having formula (XIII),

[0487]

[0488] or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0489] R1 is independently selected from and

[0490] R2 is independently selected from H, F, CH3 and OCH3;

[0491] R3 is independently selected from H, F and CH3;

[0492] R4 is independently selected from H, F, Cl, Br, -C(=O)R b , optionally through one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted C 1-6 Alkyl, optionally substituted with one or more selected from F, Cl, OH and C 3-6 Substituents of cycloalkyl substituted -NH-C 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -aryl, optionally substituted with one or more R5-OC 1-6 alkyl, optionally substituted with one or more R5 -(CH2) r -C 3-12 Cycloalkyl, and -(CH2) containing carbon atoms and 1 to 5 heteroatoms selected from N, NR6, O and S and optionally substituted with one or more R5 r -4-10 membered heterocyclic group;

[0493] R5 is independently selected from H, F, Cl, Br, CN, ═O, optionally substituted with one or more R e Substituted C 1-4 Alkyl, optionally substituted with one or more R e Substituted C 2-4 Alkenyl, optionally substituted with one or more R e Substituted C 2-4 Alkynyl, -(CH2) 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 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 , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0494] R6 is independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, -S(O) p R c 、-S(O) p NR a R a 、-C(=O)R b 、-C(=O)OR b 、-C(=O)NR a R a , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic groups;

[0495] R8 is independently selected from H and optionally substituted by one or more selected from F, Cl and C3-6 Substituents of cycloalkyl substituted C 1-6 alkyl;

[0496] R a Independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group and optionally one or more R e Substituted -(CH2) r -heterocyclyl; or R a and R a Together with the nitrogen atom to which they are attached, they form a e substituted heterocycles;

[0497] R b Independently selected from H, optionally substituted with one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r heterocyclic group;

[0498] R c Independently selected from optionally one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclic group;

[0499] Rd independently selected from H and optionally substituted with one or more R e Substituted C 1-6 alkyl;

[0500] R e Independently selected from F, Cl, Br, CN, NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, =O, OH, -OC 1-6 Alkyl, -CO2H, optionally with one or more R f Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted with one or more R f Substituted -(CH2) r -C 3-6 Cycloalkyl, optionally substituted with one or more Rf -(CH2) r -aryl, and -(CH2) optionally substituted with one or more Rf r -heterocyclic group;

[0501] R f independently selected from F, Cl, Br, CN, OH, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 cycloalkyl, and phenyl;

[0502] p is independently selected at each occurrence from 0, 1, and 2; and

[0503] r is independently selected from 0, 1, 2, 3 and 4 at each occurrence.

[0504] In another aspect, the present invention provides compounds having formula (XIV),

[0505]

[0506] or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0507] X2 is independently selected from CR4 and N;

[0508] X3 is independently selected from O and S;

[0509] R1 is independently selected from and

[0510] R2 is independently selected from CH2OH, CH2CH2OH and OCH3;

[0511] R3 is independently selected from CH2OH, CH2CH2OH, CH2NH2, CH2CH2NH2 and CH2CH2N3;

[0512] R4 is independently selected from H and -OC optionally substituted with one or more R5 1-4 Alkyl; with the limitation that R4 is not all -OC optionally substituted with one or more R5 1-4 alkyl;

[0513] R5 is independently selected from OH and optionally substituted by one or more R e substituted heterocyclic groups;

[0514] R8 is independently selected from H and optionally C 3-6 Cycloalkyl substituted C 1-6 alkyl; and

[0515] R e Independently selected from NH2 and C 1-3 alkyl.

[0516] In another aspect, the present invention provides compounds having formula (XV),

[0517]

[0518] or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0519] R4 is independently selected from H, OCH3, OCH2CH2OH,

[0520] and

[0521] R8 is C 3-6 Cycloalkyl substituted C 1-3 alkyl; and

[0522] R e Independently selected from NH2 and C 1-3 alkyl; and a variant as defined in formula (XIV).

[0523] Representative non-limiting examples of compounds of the present invention include:

[0524] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (1);

[0525] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (2);

[0526] 6-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one (3);

[0527] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (4);

[0528] 5-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one (5);

[0529] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-cyclopropyl-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (6);

[0530] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(1-isopropyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (7);

[0531] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (8);

[0532] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (9);

[0533] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-fluoro-4-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (10);

[0534] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-(difluoromethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (11);

[0535] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (12);

[0536] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methoxyazetidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (13);

[0537] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (14);

[0538] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (15);

[0539] 6-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one (16);

[0540] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)-methanone (17);

[0541] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (18);

[0542] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(6-cyclopropyl-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (19);

[0543] 5-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one (20);

[0544] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (21);

[0545] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (22);

[0546] 6-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one (23);

[0547] 5-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one (24);

[0548] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (25);

[0549] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-(difluoromethoxy)phenyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (26);

[0550] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-methyl-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (27);

[0551] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-cyclopropyl-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (28);

[0552] 6-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one (29);

[0553] 5-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one (30);

[0554] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (31);

[0555] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (32);

[0556] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(3-(methoxymethyl)-azetidin-1-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (33);

[0557] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(6-((3R,5R)-3-amino-5-fluoropiperidin-1-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (34);

[0558] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (35);

[0559] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(((R)-2-fluoro-3-hydroxy-3-methylbutyl)amino)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (36);

[0560] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (37);

[0561] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (38);

[0562] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (39);

[0563] 3((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (40);

[0564] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-cyclopropyl-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (41);

[0565] 5-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one (42);

[0566] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (43);

[0567] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (44);

[0568] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(5-fluoro-2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (45);

[0569] 6-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one (46);

[0570] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-(difluoromethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (47);

[0571] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-fluoro-4-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (48);

[0572] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (49);

[0573] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methoxyazetidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (50);

[0574] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-((R)-3-hydroxypiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (51);

[0575] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (52);

[0576] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (53);

[0577] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (54);

[0578] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (55);

[0579] 4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-fluorobenzamide (56);

[0580] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(6-cyclopropyl-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (57);

[0581] N-(7-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide (58);

[0582] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (59);

[0583] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-fluoro-4-hydroxyphenyl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (60);

[0584] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-fluoro-3-hydroxyphenyl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (61);

[0585] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (62);

[0586] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (63);

[0587] 5-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one (64);

[0588] 6-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one (65);

[0589] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (66);

[0590] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-fluoro-4-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (67);

[0591] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (68);

[0592] 4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-fluorobenzamide (69);

[0593] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (70);

[0594] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-cyclopropyl-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (71);

[0595] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(5-fluoro-2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (72);

[0596] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-(difluoromethoxy)-3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (73);

[0597] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3,5-difluoro-4-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (74);

[0598] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-fluoro-3-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (75);

[0599] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (76);

[0600] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-hydroxypiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (77);

[0601] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-((R)-3-hydroxypiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (78);

[0602] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methoxyazetidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (79);

[0603] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (80);

[0604] 5-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one (81);

[0605] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (82);

[0606] 6-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one (83);

[0607] 4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-fluorobenzamide (84);

[0608] 4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-chlorobenzamide (85);

[0609] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (86);

[0610] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (87);

[0611] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(4-hydroxypiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (88);

[0612] 6-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one (89);

[0613] 5-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one (90);

[0614] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (91);

[0615] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (92);

[0616] 4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)-2-fluorobenzamide (93);

[0617] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(3-fluoro-4-hydroxyphenyl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (94);

[0618] 5-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one (95);

[0619] 6-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one (96);

[0620] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (97);

[0621] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (98);

[0622] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (99);

[0623] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (100);

[0624] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (101);

[0625] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (102);

[0626] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (103);

[0627] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(1-hydroxyethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (104);

[0628] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (105);

[0629] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (106, 107, as diastereomers);

[0630] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyrimidin-6-yl)methanone (108);

[0631] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyrimidin-6-yl)methanone (109);

[0632] 6-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyrimidin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one (110);

[0633] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-fluoro-4-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyrimidin-6-yl)methanone (111);

[0634] 4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyrimidin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-fluorobenzamide (112);

[0635] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyrazin-6-yl)methanone (113);

[0636] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyrazin-6-yl)methanone (114);

[0637] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyrazin-6-yl)methanone (115);

[0638] (2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyrazin-6-yl)(2,6-diazaspiro[3.3]hept-2-yl)methanone (116);

[0639] (R)-N-(3-amino-2-fluoropropyl)-2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyrazine-6-carboxamide (117);

[0640] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylbenzo[b]thiophen-6-yl)methanone (118);

[0641] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylbenzo[b]thiophen-6-yl)methanone (119);

[0642] 6-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylbenzo[b]thiophen-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one (120);

[0643] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-indol-2-yl)-4-methoxy-3-methylbenzo[b]thiophen-6-yl)methanone (121);

[0644] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-indol-2-yl)-4-methoxy-3-methylbenzo[b]thiophen-6-yl)methanone (122);

[0645] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-fluoro-4-hydroxyphenyl)-1H-indol-2-yl)-4-methoxy-3-methylbenzo[b]thiophen-6-yl)methanone (123);

[0646] 4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylbenzo[b]thiophen-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)-2-fluorobenzamide (124);

[0647] 4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylbenzo[b]thiophen-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)-2-chlorobenzamide (125);

[0648] 5-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylbenzo[b]thiophen-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one (126);

[0649] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-methyl-1H-indol-2-yl)-4-methoxy-3-methylbenzo[b]thiophen-6-yl)methanone (127);

[0650] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-fluoro-2-methylphenyl)-1H-indol-2-yl)-4-methoxy-3-methylbenzo[b]thiophen-6-yl)methanone (128);

[0651] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-methoxypyridin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylbenzo[b]thiophen-6-yl)methanone (129);

[0652] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-(4-aminopiperidin-1-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylbenzo[b]thiophen-6-yl)methanone (130);

[0653] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-indol-2-yl)-4-methoxy-3-methylbenzo[b]thiophen-6-yl)methanone (131);

[0654] 5-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylbenzo-[b]thiophen-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one (132);

[0655] 4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylbenzo[b]thiophen-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-fluorobenzamide (133);

[0656] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylbenzo[b]thiophen-6-yl)methanone (134);

[0657] 6-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylbenzo[b]thiophen-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one (135);

[0658] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-fluoro-4-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylbenzo[b]thiophen-6-yl)methanone (136);

[0659] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylbenzo[b]thiophen-6-yl)methanone (137);

[0660] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylbenzo[b]thiophen-6-yl)methanone (138);

[0661] 5-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylbenzo[b]thiophen-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one (139);

[0662] 6-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylbenzo[b]thiophen-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one (140);

[0663] 4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylbenzo[b]thiophen-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-fluorobenzamide (141);

[0664] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylbenzo[b]thiophen-6-yl)methanone (142);

[0665] 6-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylbenzo[b]thiophen-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one (143);

[0666] 5-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylbenzo[b]thiophen-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one (144);

[0667] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylbenzofuran-6-yl)methanone (145);

[0668] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylbenzofuran-6-yl)methanone (146);

[0669] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylbenzofuran-6-yl)methanone (147);

[0670] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylbenzofuran-6-yl)methanone (148);

[0671] 5-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one (149);

[0672] 6-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one (150);

[0673] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-methyl-1H-indol-2-yl)-4-methoxy-3-methylbenzofuran-6-yl)methanone (151);

[0674] 4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)-2-fluorobenzamide (152);

[0675] 4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)-2-chlorobenzamide (153);

[0676] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-fluoro-4-hydroxyphenyl)-1H-indol-2-yl)-4-methoxy-3-methylbenzofuran-6-yl)methanone (154);

[0677] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (155);

[0678] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-cyclopropyl-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylbenzofuran-6-yl)methanone (156);

[0679] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-indol-2-yl)-4-methoxy-3-methylbenzofuran-6-yl)methanone (157);

[0680] 3-((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-ethoxypiperidin-1-yl)-1H-indol-2-yl)-4-methoxy-3-methylbenzofuran-6-yl)methanone (158);

[0681] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-indol-2-yl)-4-methoxy-3-methylbenzofuran-6-yl)methanone (159);

[0682] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-(4-aminopiperidin-1-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylbenzofuran-6-yl)methanone (160);

[0683] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylbenzofuran-6-yl)methanone (161);

[0684] 4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)-2-chlorobenzamide (162);

[0685] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-indol-2-yl)-4-methoxy-3-methylbenzofuran-6-yl)methanone (163);

[0686] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylbenzofuran-6-yl)methanone (164);

[0687] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylbenzofuran-6-yl)methanone (165);

[0688] 6-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one (166);

[0689] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylbenzofuran-6-yl)methanone cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one (167);

[0690] 5-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one (168);

[0691] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylbenzofuran-6-yl)methanone (169);

[0692] 4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-fluorobenzamide (170);

[0693] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylbenzofuran-6-yl)methanone (171);

[0694] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylbenzofuran-6-yl)methanone (172);

[0695] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methoxyazetidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylbenzofuran-6-yl)methanone (173);

[0696] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylbenzofuran-6-yl)methanone (174);

[0697] 6-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one (175);

[0698] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (176);

[0699] 6-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one (177);

[0700] 5-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one (178);

[0701] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (179);

[0702] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (180);

[0703] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (181);

[0704] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-fluoro-4-hydroxyphenyl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (182);

[0705] 4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)-2-chlorobenzamide (183);

[0706] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-methyl-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (184);

[0707] 4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)-2-fluorobenzamide (185);

[0708] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-methoxypyridin-4-yl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (186);

[0709] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-cyclopropyl-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (187);

[0710] 5-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)-3-methylpicolinamide (188);

[0711] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (189);

[0712] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methoxyazetidin-1-yl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (190);

[0713] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-(4-aminopiperidin-1-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (191);

[0714] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(piperazin-1-yl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (192);

[0715] 1-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)piperazin-2-one (193);

[0716] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (194);

[0717] 5-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one (195);

[0718] 4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)-2-fluorobenzamide (196);

[0719] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (197);

[0720] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (198);

[0721] 4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)-2-chlorobenzamide (199);

[0722] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (200);

[0723] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(piperazin-1-yl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (201);

[0724] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(6-(4-aminopiperidin-1-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (202);

[0725] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylbenzofuran-6-yl)methanone (203);

[0726] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone (204);

[0727] 1-[2-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl-imidazolidin-2-one (205);

[0728] 4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-methylbenzamide (206);

[0729] 4-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-fluoro-5-methylbenzamide (207);

[0730] 4-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-fluoro-5-methylbenzamide (208);

[0731] [2-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methanol (209);

[0732] [3-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methanol (210);

[0733] N-{[3-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methyl}methanesulfonamide (211);

[0734] (3R,5R)-1-{2-[1-(cyclopropylmethyl)-6-(3-methoxyphenyl)-1H-indol-2-yl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-5-fluoropiperidin-3-amine (212);

[0735] N-[3-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methanesulfonamide (213);

[0736] N-[4-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]acetamide (214);

[0737] N-{[3-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methyl}acetamide (215);

[0738] N-[4-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methanesulfonamide (216);

[0739] 4-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-N,N-dimethylbenzamide (217);

[0740] (3R,5R)-1-{2-[1-(cyclopropylmethyl)-6-(1H-indazol-5-yl)-1H-indol-2-yl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-5-fluoropiperidin-3-amine (218);

[0741] (3R,5R)-1-{2-[1-(cyclopropylmethyl)-6-(1-methyl-1H-indazol-5-yl)-1H-indol-2-yl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-5-fluoropiperidin-3-amine (219);

[0742] (3R,5R)-1-{2-[1-(cyclopropylmethyl)-6-[3-(2H-1,2,3,4-tetrazol-5-yl)phenyl]-1H-indol-2-yl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-5-fluoropiperidin-3-amine (220);

[0743] N-{[4-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methyl}acetamide (221);

[0744] (3R,5R)-1-{2-[1-(cyclopropylmethyl)-6-(1H-indazol-4-yl)-1H-indol-2-yl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-5-fluoropiperidin-3-amine (222);

[0745] 2-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)benzamide (223);

[0746] N-{[4-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methyl}methanesulfonamide (224);

[0747] 6-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-8-fluoro-5-methyl-1,2-dihydroquinolin-2-one (225);

[0748] N-[5-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)pyridin-2-yl]acetamide (226);

[0749] [3-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methanol (227);

[0750] N-{[4-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methyl}acetamide (228);

[0751] 4-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)benzamide (229);

[0752] 4-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-N,N-dimethylbenzamide (230);

[0753] N-[4-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methanesulfonamide (231);

[0754] N-{[3-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methyl}acetamide (232);

[0755] [2-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methanol (233);

[0756] N-{[4-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methyl}methanesulfonamide (234);

[0757] N-{[3-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methyl}methanesulfonamide (235);

[0758] [3-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methanol (236);

[0759] 2-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)benzamide (237);

[0760] (3R)-1-{2-[1-(cyclopropylmethyl)-6-(1H-indazol-4-yl)-1H-indol-2-yl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}piperidin-3-amine (238);

[0761] 6-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-8-fluoro-5-methyl-1,2-dihydroquinolin-2-one (239);

[0762] N-[5-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)pyridin-2-yl]acetamide (240);

[0763] (3R,5R)-1-{2-[1-(cyclopropylmethyl)-6-(4-methanesulfonylpiperidin-1-yl)-1H-indol-2-yl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-5-fluoropiperidin-3-amine (241);

[0764] 1-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-N,N-dimethylpiperidine-4-carboxamide (242);

[0765] N-[1-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-N-methylacetamide (243);

[0766] N-[1-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-N-methylacetamide (244);

[0767] Methyl N-[1-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-N-methylcarbamate (245);

[0768] N-[1-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-N-methylmethanesulfonamide (246);

[0769] N-[1-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)azetidin-3-yl]-N-methylmethanesulfonamide (247);

[0770] (3R)-1-{2-[1-(cyclopropylmethyl)-6-(4-methanesulfonylpiperidin-1-yl)-1H-indol-2-yl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}piperidin-3-amine (248);

[0771] (3R)-1-{2-[1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-indol-2-yl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}piperidin-3-amine (249);

[0772] 2-[1-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-N,N-dimethylacetamide (250);

[0773] (3R)-1-{2-[1-(cyclopropylmethyl)-6-[4-(3-methoxyazetidine-1-carbonyl)piperidin-1-yl]-1H-indol-2-yl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}piperidin-3-amine (251);

[0774] N-[1-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-N-methylacetamide (252);

[0775] N-[1-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-N-methylacetamide (253);

[0776] N-[1-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-N-methylmethanesulfonamide (254);

[0777] Methyl N-[1-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-N-methylcarbamate (255);

[0778] N-[1-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)azetidin-3-yl]-N-methylmethanesulfonamide (256);

[0779] 1-[2-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl-imidazolidin-2-one (257);

[0780] 1-[4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl]pyrrolidin-2-one (258);

[0781] 3-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-methylphenol (259);

[0782] 4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-fluoro-5-methylbenzamide (260);

[0783] 1-[4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl-imidazolidin-2-one (261);

[0784] 4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-methylbenzamide (262);

[0785] 4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)benzamide (263);

[0786] 5-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-N-methylpyridine-2-carboxamide (264);

[0787] ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-((R)-3-hydroxypiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (265);

[0788] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (266);

[0789] 4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholin-3-one (267);

[0790] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(4-methanesulfonylpiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (268);

[0791] 8-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one (269);

[0792] (3R)-1-{2-[1-(cyclopropylmethyl)-6-(4-methanesulfonylpiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}piperidin-3-amine (270);

[0793] N-[1-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-4-yl]-N-methylacetamide (271);

[0794] Methyl N-[1-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-4-yl]-N-methylcarbamate (272);

[0795] 1-[1-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-4-yl]pyrrolidin-2-one (273);

[0796] (5S)-5-{[(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]methyl}pyrrolidin-2-one (274);

[0797] 4-{[(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]methyl}pyrrolidin-2-one (275);

[0798] (3R)-1-{4-chloro-2-[1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}piperidin-3-amine (276);

[0799] 4-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-fluoro-5-methylbenzamide (277);

[0800] 3-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-chlorophenol (278);

[0801] 4-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-fluorobenzamide (279);

[0802] 1-[4-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl-imidazolidin-2-one (280);

[0803] 1-[2-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl-imidazolidin-2-one (281);

[0804] 3-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-methylphenol (282);

[0805] 3-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-fluorophenol (283);

[0806] 5-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2,3-dihydro-1H-isoindol-1-one (284);

[0807] 6-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2,3-dihydro-1H-isoindol-1-one (285);

[0808] 4-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-methylbenzamide (286);

[0809] 5-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-N-methylpyridine-2-carboxamide (287);

[0810] (3R)-1-{2-[1-(cyclopropylmethyl)-6-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl}-1H-pyrrolo[2,3-b]pyridin-2-yl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}piperidin-3-amine (288);

[0811] (3R,5R)-1-{4-chloro-2-[6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-5-fluoropiperidin-3-amine (289);

[0812] (3R,5R)-1-{4-chloro-2-[1-(cyclopropylmethyl)-6-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-5-fluoropiperidin-3-amine (290);

[0813] (3R)-1-{4-chloro-2-[6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}piperidin-3-amine (291);

[0814] (3R)-1-{4-chloro-2-[1-(cyclopropylmethyl)-6-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}piperidin-3-amine (292);

[0815] 5-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-2,3-dihydro-1H-isoindol-1-one (293);

[0816] 4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-3-chlorobenzamide (294);

[0817] (7R)-2-{2-[1-(cyclopropylmethyl)-6-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl}-1H-indol-2-yl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (295);

[0818] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(3-methoxyazetidin-1-yl)-1H-indol-2-yl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (296);

[0819] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(3-fluoro-1H-indazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (297);

[0820] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(1H-indazol-6-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (298);

[0821] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(1H-indazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (299);

[0822] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (300);

[0823] 3-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-methylphenol (301);

[0824] 1-[2-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl-imidazolidin-2-one (302);

[0825] 4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-methoxybenzamide (303);

[0826] 1-[4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl]pyrrolidin-2-one (304);

[0827] 4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-fluoro-5-methylbenzamide (305);

[0828] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(7-fluoro-1H-indazol-6-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (306);

[0829] 5-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-N-methylpyridine-2-carboxamide (307);

[0830] Methyl N-[5-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)pyridin-2-yl]carbamate (308);

[0831] (3R)-1-{2-[1-(cyclopropylmethyl)-6-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}piperidin-3-amine (309);

[0832] (3R)-1-{2-[1-(cyclopropylmethyl)-6-(1H-indazol-6-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}piperidin-3-amine (310);

[0833] (3R)-1-{2-[1-(cyclopropylmethyl)-6-(1H-indazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}piperidin-3-amine (311);

[0834] 6-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-8-fluoro-5-methyl-1,2-dihydroquinolin-2-one (312);

[0835] 3-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-chlorophenol (313);

[0836] 3-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-fluorophenol (314);

[0837] 6-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2,3-dihydro-1H-isoindol-1-one (315);

[0838] 4-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-methylbenzamide (316);

[0839] 5-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2,3-dihydro-1H-isoindol-1-one (317);

[0840] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (318);

[0841] 4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholin-3-one (319);

[0842] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(4-methanesulfonylpiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (320);

[0843] (3R,5R)-1-{2-[1-(cyclopropylmethyl)-6-(1H-indazol-6-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-5-fluoropiperidin-3-amine (321);

[0844] (3R,5R)-1-{2-[1-(cyclopropylmethyl)-6-(1H-indazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-5-fluoropiperidin-3-amine (322);

[0845] (3R,5R)-1-{2-[1-(cyclopropylmethyl)-6-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-5-fluoropiperidin-3-amine (323);

[0846] 6-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-8-fluoro-5-methyl-1,2-dihydroquinolin-2-one (324);

[0847] Methyl N-[1-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-4-yl]-N-methylcarbamate (325);

[0848] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(7-fluoro-1H-indazol-4-yl)-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (326);

[0849] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(3-fluoro-1H-indazol-4-yl)-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (327);

[0850] 1-[4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl-imidazolidin-2-one (328);

[0851] 1-[4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]pyrrolidin-2-one (329);

[0852] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(7-fluoro-1H-indazol-6-yl)-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (330);

[0853] 4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-5-fluoro-2-methylbenzamide (331);

[0854] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(1H-indazol-6-yl)-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (332);

[0855] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(1H-indazol-5-yl)-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (333);

[0856] 4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-2-methylbenzamide (334);

[0857] 4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-3-(trifluoromethyl)benzamide (335);

[0858] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(7-fluoro-1H-indazol-6-yl)-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (336);

[0859] N-[7-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-4-chloro-1-methyl-1H-indazol-3-yl]methanesulfonamide (337);

[0860] 1-[2-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl-imidazolidin-2-one (338);

[0861] 4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-2-chlorobenzamide (339);

[0862] 5-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-N-methylpyridine-2-carboxamide (340);

[0863] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(1H-pyrazol-4-yl)-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (341);

[0864] N-{[4-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methyl}methanesulfonamide (342);

[0865] N-{[3-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methyl}acetamide (343);

[0866] [3-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methanol (344);

[0867] (3R)-1-{2-[1'-(cyclopropylmethyl)-1H,1'H-[5,6'-diindolyl]-2'-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}piperidin-3-amine (345);

[0868] 6-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-8-fluoro-5-methyl-1,2-dihydroquinolin-2-one (346);

[0869] N-[4-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methanesulfonamide (347);

[0870] N-[5-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)pyridin-2-yl]acetamide (348);

[0871] (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (349);

[0872] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(morpholin-4-yl)-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (350);

[0873] (7R)-2-{2-[1-(cyclopropylmethyl)-6-(4-methanesulfonylpiperidin-1-yl)-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine (351);

[0874] Methyl N-[1-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-N-methylcarbamate (352);

[0875] N-[1-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-N-methylacetamide (353);

[0876] N-[1-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-N-methylmethanesulfonamide (354);

[0877] (3R,5R)-1-{2-[1-(cyclopropylmethyl)-6-[4-(pyrrolidine-1-carbonyl)piperidin-1-yl]-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-5-fluoropiperidin-3-amine (355);

[0878] 1-[1-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]pyrrolidin-2-one (356);

[0879] 3-[1-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-1,3-oxazolidin-2-one (357);

[0880] Methyl N-[1-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-N-methylcarbamate (358);

[0881] N-[1-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-N-methylacetamide (359);

[0882] N-[1-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-N-methylmethanesulfonamide (360);

[0883] (3R)-1-{2-[1-(cyclopropylmethyl)-6-[4-(pyrrolidine-1-carbonyl)piperidin-1-yl]-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}piperidin-3-amine (361);

[0884] N-[1-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-N-methylmethanesulfonamide (362);

[0885] 1-[1-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]pyrrolidin-2-one (363);

[0886] 3-[1-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-1,3-oxazolidin-2-one (364);

[0887] (3R)-1-{2-[1-(cyclopropylmethyl)-6-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}piperidin-3-amine (365);

[0888] N-[1-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)azetidin-3-yl]-N-methylmethanesulfonamide (366);

[0889] N-{[3-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methyl}methanesulfonamide (367);

[0890] (3R,5R)-1-{2-[1-(cyclopropylmethyl)-6-[3-(2H-1,2,3,4-tetrazol-5-yl)phenyl]-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-5-fluoropiperidin-3-amine (368);

[0891] N-[4-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methanesulfonamide (369);

[0892] N-{[4-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methyl}methanesulfonamide (370);

[0893] [3-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methanol (371);

[0894] 2-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)benzamide (372);

[0895] 4-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)benzamide (373);

[0896] (3R,5R)-1-{2-[1'-(cyclopropylmethyl)-1H,1'H-[5,6'-diindolyl]-2'-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-5-fluoropiperidin-3-amine (374);

[0897] [4-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-2-chloro-5-fluorophenyl]methanol (375);

[0898] 6-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-8-fluoro-5-methyl-1,2-dihydroquinolin-2-one (376);

[0899] 4-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-3-chlorobenzamide (377);

[0900] 4-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-2-methylbenzamide (378);

[0901] (3R,5R)-1-{2-[1-(cyclopropylmethyl)-6-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl}-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-5-fluoropiperidin-3-amine (379);

[0902] 2-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)propan-2-ol (homochiral) (380);

[0903] 2-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,1-difluoropropan-2-ol (diastereoisomer mixture) (381);

[0904] 2-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,1,1-trifluoropropan-2-ol (diastereoisomer mixture) (382);

[0905] 2-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,1,1-trifluoropropan-2-ol (383);

[0906] 1-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1-cyclopropylethan-1-ol (384);

[0907] 1-(2-{6-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)ethan-1-ol (diastereoisomer mixture) (385);

[0908] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(tetrahydro-2H-pyran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (386);

[0909] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(tetrahydro-2H-pyran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (387);

[0910] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(tetrahydro-2H-pyran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (388);

[0911] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(tetrahydro-2H-pyran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (389);

[0912] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxycyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (390);

[0913] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1r,4r)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (391);

[0914] (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxycyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (392);

[0915] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxycyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (393);

[0916] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(tetrahydrofuran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (394);

[0917] (R)-1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one (395);

[0918] (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxycyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (396);

[0919] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(tetrahydrofuran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (397);

[0920] (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (398);

[0921] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (399);

[0922] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(tetrahydrofuran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (400);

[0923] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxyethan-1-one (401);

[0924] (R)-1-(4-(2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one (402);

[0925] (S)-1-(4-(2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one (403);

[0926] (S)-1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one (404);

[0927] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxyethan-1-one (405);

[0928] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (406);

[0929] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (407);

[0930] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1r,4r)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (408);

[0931] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1r,4r)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (409);

[0932] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)ethan-1-one (410);

[0933] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)ethan-1-one (411);

[0934] 1-(4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)ethan-1-one (412);

[0935] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)ethan-1-one (413);

[0936] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1r,4r)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (414);

[0937] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1r,4r)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (415);

[0938] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (416);

[0939] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxy-2-methylpropan-1-one (417);

[0940] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxy-2-methylpropan-1-one (418);

[0941] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxycyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (419);

[0942] (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxycyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (420);

[0943] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (421);

[0944] (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (422);

[0945] (S)-1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one (423);

[0946] (S)-1-(4-(2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one (424);

[0947] (R)-1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one (425);

[0948] (R)-1-(4-(2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one (426);

[0949] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)ethan-1-one (427);

[0950] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxyethan-1-one (428);

[0951] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxyethan-1-one (429);

[0952] 2-(7-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridine-6-carboxylic acid ethyl ester (430);

[0953] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-3-hydroxypropan-1-one (430);

[0954] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-isopropoxyethan-1-one (431);

[0955] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-isopropoxyethan-1-one (432);

[0956] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one (433);

[0957] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one (434);

[0958] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-hydroxy-2-methylpropan-1-one (435);

[0959] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-hydroxy-2-methylpropan-1-one (436);

[0960] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-3-hydroxypropan-1-one (437);

[0961] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-hydroxyethan-1-one (438);

[0962] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-hydroxyethan-1-one (439);

[0963] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1R,3S)-3-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (440);

[0964] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-ethoxyethan-1-one (441);

[0965] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-ethoxyethan-1-one (442);

[0966] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1r,4r)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (443);

[0967] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (444);

[0968] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-3-methylbutan-1-one (445);

[0969] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-3-methylbutan-1-one (446);

[0970] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1S,3R)-3-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (447);

[0971] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1S,3R)-3-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (448);

[0972] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1R,3S)-3-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (449);

[0973] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (450);

[0974] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1r,4r)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (451);

[0975] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)ethan-1-one (452);

[0976] 1-(4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxyethan-1-one (453);

[0977] (S)-1-(4-(2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one (454);

[0978] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxyethan-1-one (455);

[0979] (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (456);

[0980] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(tetrahydro-2H-pyran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (457);

[0981] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(tetrahydro-2H-pyran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (458);

[0982] (S)-1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one (459);

[0983] (R)-1-(4-(2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one (460);

[0984] (R)-1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one (461);

[0985] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(tetrahydrofuran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (462);

[0986] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(tetrahydrofuran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (463);

[0987] (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(thiophene-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (464);

[0988] (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxycyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (465);

[0989] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxycyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (466);

[0990] (4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)(3-hydroxycyclobutyl)methanone (467);

[0991] (R)-methyl 4-(2-(6-(3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidine-1-carboxylate (468);

[0992] 4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidine-1-carboxylic acid methyl ester (469);

[0993] 4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidine-1-carboxylic acid methyl ester (470);

[0994] (R)-1-(4-(2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-hydroxypropan-1-one (471);

[0995] (R)-1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-hydroxypropan-1-one (472);

[0996] (2R)-1-(4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-hydroxypropan-1-one (473);

[0997] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(thiophene-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (474);

[0998] (4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)(thiophen-2-yl)methanone (475);

[0999] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)ethan-1-one (476);

[1000] 1-(4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)ethan-1-one (477);

[1001] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxyethan-1-one (478);

[1002] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)ethan-1-one (479);

[1003] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)-2-methoxyethan-1-one (480);

[1004] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)-2-methoxyethan-1-one (481);

[1005] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)ethan-1-one (482);

[1006] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)ethan-1-one (483);

[1007] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-7-(1-((1r,4r)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (484);

[1008] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-7-(1-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (485);

[1009] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-7-(1-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (486);

[1010] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-7-(1-((1r,4r)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (487);

[1011] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-7-(1-(tetrahydrofuran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (488);

[1012] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-7-(1-(tetrahydrofuran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (489);

[1013] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-7-(1-(tetrahydrofuran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (490);

[1014] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-7-(1-(tetrahydrofuran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (491);

[1015] (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-7-(1-(3-hydroxycyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (492);

[1016] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)-2-methoxy-2-methylpropan-1-one (493);

[1017] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)-3-methylbutan-1-one (494);

[1018] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)-3-methylbutan-1-one (495);

[1019] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-7-(1-(3-hydroxycyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (496);

[1020] (R)-1-(4-(2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one (497);

[1021] (R)-1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one (498);

[1022] (S)-1-(4-(2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one (499);

[1023] (S)-1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one (500);

[1024] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)-2-methoxy-2-methylpropan-1-one (501);

[1025] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)-2-methoxyethan-1-one (502);

[1026] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)-2-methoxyethan-1-one (503);

[1027] (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-7-(1-(3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (504);

[1028] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-7-(1-(3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (505);

[1029] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)ethan-1-one (506);

[1030] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)ethan-1-one (507);

[1031] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-7-(1-(tetrahydro-2H-pyran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (508);

[1032] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-7-(1-(tetrahydro-2H-pyran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (509);

[1033] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperidin-1-yl)-2-methoxyethan-1-one (510);

[1034] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperidin-1-yl)-2-methoxyethan-1-one (511);

[1035] (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperidin-1-yl)-2-methoxyethan-1-one (512);

[1036] 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperidin-1-yl)-2-methoxyethan-1-one (513);

[1037] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1r,4r)-4-hydroxycyclohexane-1-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (514);

[1038] (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (515);

[1039] (R)-1-(3-(2-(6-(3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)-2-methoxy-2-methylpropan-1-one (516);

[1040] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1r,4r)-4-hydroxycyclohexane-1-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (517);

[1041] 1-(3-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)-2-methoxy-2-methylpropan-1-one (518);

[1042] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (519);

[1043] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (520);

[1044] (R)-1-(3-(2-(6-(3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)ethan-1-one (521);

[1045] 1-(3-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)ethan-1-one (522);

[1046] (S)-1-(3-(2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)-2-methoxypropan-1-one (523);

[1047] (S)-1-(3-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)-2-methoxypropan-1-one (524);

[1048] (R)-1-(3-(2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)-2-methoxypropan-1-one (525);

[1049] (R)-1-(3-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)-2-methoxypropan-1-one (526);

[1050] 1-(3-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)-2-methoxyethan-1-one (527);

[1051] (R)-1-(3-(2-(6-(3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)-2-methoxyethan-1-one (528);

[1052] (R)-1-(3-(2-(6-(3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)-2-methoxyethan-1-one (529);

[1053] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1r,4r)-4-hydroxycyclohexane-1-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (530);

[1054] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1R,3S)-3-hydroxycyclohexane-1-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (531);

[1055] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1R,3S)-3-hydroxycyclohexane-1-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (532);

[1056] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1S,3R)-3-hydroxycyclohexane-1-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (533);

[1057] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1S,3R)-3-hydroxycyclohexane-1-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (534);

[1058] (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (535);

[1059] (R)-1-(3-(2-(6-(3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)-2-methoxy-2-methylpropan-1-one (536);

[1060] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1r,4r)-4-hydroxycyclohexane-1-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (537);

[1061] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (538);

[1062] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (539);

[1063] (R)-1-(3-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)-2-methoxypropan-1-one (540);

[1064] (R)-1-(3-(2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)-2-methoxypropan-1-one (541);

[1065] (S)-1-(3-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)-2-methoxypropan-1-one (542);

[1066] (S)-1-(3-(2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)-2-methoxypropan-1-one (543);

[1067] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(tetrahydro-2H-pyran-2-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (544);

[1068] ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(tetrahydro-2H-pyran-2-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (545);

[1069] (R)-1-(3-(2-(6-(3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)-2-methoxyethan-1-one (546);

[1070] 1-(3-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)-2-methoxyethan-1-one (547);

[1071] 1-(3-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)ethan-1-one (548);

[1072] 1-(3-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)ethan-1-one (549);

[1073] 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (550);

[1074] 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)-1-methylpyrrolidin-2-one (551);

[1075] 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)-1-methylpyrrolidin-2-one (552);

[1076] 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)-1-methylpyrrolidin-2-one (553);

[1077] 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)-1-methylpyrrolidin-2-one (554);

[1078] (R)-(2-(7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)(3-aminopiperidin-1-yl)methanone (555);

[1079] (2-(7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone (556);

[1080] (2-(7-(2-(4-amino-1H-pyrazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone (557);

[1081] (R)-(2-(7-(2-(4-amino-1H-pyrazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)(3-aminopiperidin-1-yl)methanone (558);

[1082] (S)-5-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (559);

[1083] (S)-5-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (560);

[1084] (R)-5-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (561);

[1085] 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (562);

[1086] 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (563);

[1087] 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (564);

[1088] 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (565);

[1089] 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (566);

[1090] 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (567);

[1091] (S)-5-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (568);

[1092] (S)-5-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (569);

[1093] (R)-5-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (570);

[1094] 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (571);

[1095] 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (572);

[1096] 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (573);

[1097] (2-(7-(2-(1H-imidazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone (574);

[1098] (R)-(2-(7-(2-(1H-imidazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)(3-aminopiperidin-1-yl)methanone (575);

[1099] 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)-1-methylpyrrolidin-2-one (576);

[1100] 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)-1-methylpyrrolidin-2-one (577);

[1101] 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)-1-methylpyrrolidin-2-one (578);

[1102] 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)-1-methylpyrrolidin-2-one (579);

[1103] (R)-(2-(7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)(3-aminopiperidin-1-yl)methanone (580);

[1104] (2-(7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone (581);

[1105] (R)-(2-(7-(2-(4-amino-1H-pyrazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)(3-aminopiperidin-1-yl)methanone (582);

[1106] (2-(7-(2-(4-amino-1H-pyrazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone (583);

[1107] (S)-5-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (584);

[1108] (S)-5-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (585);

[1109] (R)-5-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (586);

[1110] (R)-5-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (587);

[1111] 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (588);

[1112] 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (589);

[1113] 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (590);

[1114] 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one (591);

[1115] (2-(7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone (592);

[1116] (R)-(2-(7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)(3-aminopiperidin-1-yl)methanone (593);

[1117] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(2-(2-methyl-1H-imidazol-1-yl)ethoxy)-1H-pyrrolo[2,3-c]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (594);

[1118] (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(2-(2-methyl-1H-imidazol-1-yl)ethoxy)-1H-pyrrolo[2,3-c]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (595);

[1119] (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(oxetan-3-ylmethoxy)-1H-pyrrolo[2,3-c]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (596);

[1120] (2-(7-(2-(1H-imidazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone (597);

[1121] (R)-(2-(7-(2-(1H-imidazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)(3-aminopiperidin-1-yl)methanone (598);

[1122] (R)-(2-(7-(2-(4H-1,2,4-triazol-4-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)(3-aminopiperidin-1-yl)methanone (599);

[1123] (2-(7-(2-(4H-1,2,4-triazol-4-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone (600);

[1124] 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one (601);

[1125] 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one (602);

[1126] 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one (603);

[1127] (5R)-5-(((2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one (604);

[1128] 4-(((2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one (605);

[1129] 4-(((2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one (606);

[1130] (5R)-5-(((2-(6-((7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one (607);

[1131] 4-(((2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one (608);

[1132] (R)-(2-(7-(2-(4H-1,2,4-triazol-4-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)(3-aminopiperidin-1-yl)methanone (609);

[1133] (2-(7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone (610);

[1134] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(2-(2-methyl-1H-imidazol-1-yl)ethoxy)-1H-pyrrolo[2,3-c]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (611);

[1135] (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(2-(2-methyl-1H-imidazol-1-yl)ethoxy)-1H-pyrrolo[2,3-c]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (612);

[1136] (2-(7-(2-(4H-1,2,4-triazol-4-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone (613);

[1137] 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one (614);

[1138] 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one (615);

[1139] (2-(7-(2-(1H-imidazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone (616);

[1140] (R)-(2-(7-(2-(1H-imidazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)(3-aminopiperidin-1-yl)methanone (617);

[1141] 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one (618);

[1142] 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one (619);

[1143] (2-(7-(2-(4H-1,2,4-triazol-4-yl)ethoxy)-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone (620); and

[1144] ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(3-(cyclopropylmethyl)-4-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)benzo[b]thiophen-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (621);

[1145] or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof.

[1146] In one embodiment, the present invention provides compounds using the RFMS PAD4 functional assay disclosed herein: 50 Value ≤ 4.000 μM, preferably IC 50 Value ≤ 1.000 μM, preferably IC 50 Value ≤ 0.500 μM, preferably IC 50 Value ≤ 0.100 μM, more preferably IC50 value ≤ 0.050 μM, more preferably IC 50 Value ≤ 0.03 μM, more preferably IC 50 Value ≤ 0.02 μM, even more preferably IC 50 Value ≤ 0.01 μM.

[1147] As defined and described above, X2 is selected from N and CR4. In some embodiments, X2 is N. In some embodiments, X2 is CR4. In certain embodiments, X2 is a functional group selected from the following examples:

[1148] As defined above, R1 is selected from: and

[1149] In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is

[1150] In some embodiments, R1 is selected from

[1151] and In some embodiments, R1 is selected from and In some embodiments, R1 is selected from

[1152]

[1153] and In some embodiments, R1 is selected from

[1154] and

[1155] In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is

[1156] In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is

[1157] In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is

[1158] In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is

[1159] In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is

[1160] In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is

[1161] In certain embodiments, R1 is selected from the functional groups described in the following examples.

[1162] and

[1163] As defined and described above, R2 is selected from H, F, Cl, Br, -OR b , optionally through one or more R e Substituted C 1-3 In some embodiments, R2 is H. In some embodiments, R2 is F, Cl, Br. In some embodiments, R2 is F. In some embodiments, R2 is C 1-3 In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is propyl. In some embodiments, R2 is OR b In some embodiments, R2 is -OCH3. In some embodiments, R2 is -OCH2CH3. In some embodiments, R2 is -OCH2CH2CH3. In certain embodiments, R2 is -OCH(F)2. In certain embodiments, R2 is selected from the functional groups described in the following examples. R2 is preferably selected from H, F, Cl, CH3 and OCH3.

[1164] As defined and described above, R3 is selected from CH3 and CD3. In some embodiments, R3 is CH3. In some embodiments, R3 is CD3. In certain embodiments, R3 is selected from the functional groups described in the following examples. R3 is preferably selected from H, F, Cl, CH3 and CH2OH.

[1165] As defined and described above, R4 is independently selected from H, F, Cl, Br, C 1-4 Alkyl, OC substituted with one or more R5 1-4 alkyl, and

[1166] In some embodiments, R4 is H. In some embodiments, R4 is selected from F, Cl, and Br.

[1167] In some embodiments, R4 is C 1-3 In some embodiments, R4 is CH3.

[1168] In some embodiments, R4 is selected from and

[1169] In some embodiments, R4 is In some embodiments, R4 is In some embodiments, R4 is In some embodiments, R4 is

[1170] In some embodiments, R4 is In some embodiments, R4 is Wherein R5 is selected from F, Cl, -OH, -C(=O)NH2. In some embodiments, R4 is In some embodiments, R4 is

[1171] In some embodiments, R4 is selected from and In some embodiments, R4 is In some embodiments, R4 is In some embodiments, R4 is

[1172] In some embodiments, R4 is selected from and In some embodiments, R4 is

[1173] In some embodiments, R4 is selected from and In some embodiments, R4 is Wherein R5 is selected from F, Cl and CH2OH. In some embodiments, R4 is wherein R5 is selected from F, Cl, -OH, -OCH3-OCH2CH3 and NH2. In certain embodiments, R4 is selected from the functional groups described in the following examples.

[1174] R4, independently or together with R5 and R6, is preferably selected from H, F, Cl, C optionally substituted with one or more substituents selected from F, Cl and OH 1-5 Alkyl, C 3-6 Cycloalkyl,

[1175]

[1176]

[1177]

[1178] and

[1179] As defined and described above, R5 is independently selected from H, F, Cl, Br, CN, =O, optionally substituted with one or more R e Substituted C 1-4 Alkyl, optionally substituted with one or more R e Substituted C 2-4 Alkenyl, optionally substituted with one or more R e Substituted C 2-4 Alkynyl, -(CR d R d ) r OR b 、-(CR d R d ) r S(O) p R c 、-(CR d R d ) r S(O) p NR a R a 、-(CR d R d ) r NR a S(O) p R c 、-(CR d R d ) r NR a R a 、-(CR d R d ) r NR a C(=O)R b 、-(CR d R d ) r NR a C(=O)OR b 、-(CR d R d ) r NR a C(=O)NR a R a 、-(CR d R d ) r C(=O)R b 、-(CR d R d ) r C(=O)OR b 、-(CR d Rd ) r C(=O)NR a R a 、-(CR d R d ) r OC(=O)R b 、-(CR d R d ) r OC(=O)OR b 、-(CR d R d ) r O(CH2) r C(=O)NR a R a , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e substituted heterocyclic group.

[1180] In some embodiments, R5 is independently selected from H, F, Cl, CN, C 1-4 Alkyl (optionally 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, -NR a S(O)2C 2-4 Alkenyl, -(CH2) 0-1 OH, OC 1-4 Alkyl, -(CH2) 0-1 NH2, -(CH2) 0-1 NHC(=O)C 1-4 Alkyl, -NRaC(=O)C 2- 4alkenyl, -NHC(=O)C 2-4 Alkynyl, -(CH2) 0-1 C(=O)OH, -C(=O)OC 1-4 Alkyl, -NHC(=O)OC 1-4 Alkyl, -NHC(=O)O(CH2)2OC 1-4 Alkyl, -NHC(=O)OCH2-cyclopropyl, -NHC(=O)NH2, C(=O)NHC 1-4 Alkyl, CONH(CH2) 1-2 C(=O)OH、-(CH2) 0-1C(=O)NH2、-(CH2) 0-1 C(=O)NHC 1-4 Alkyl, C(=O)NH-pyridine, -C(=O)NH(CH2)2N(C 1-4 alkyl)2, -C(=O)NH(CH2)2OH, -C(=O)NH(CH2)2S(O)2C 1-4 Alkyl and -OC(=O)C 1-4 alkyl.

[1181] In some embodiments, R5 is F. In some embodiments, R5 is C 1-4 In some embodiments, R5 is -OH or -OC 1-3 In some embodiments, R5 is -NHS(O)2C 1-4 In some embodiments, R5 is selected from the functional groups described in the following examples.

[1182] In some embodiments, R4 is OC substituted with one or more R5 1-3 Alkyl; R5 is

[1183] and

[1184] As defined and described above, R6 is independently selected from H, optionally substituted by one or more R e Substituted C 1-3 Alkyl, -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 , optionally through one or more R e substituted aryl, or optionally substituted by one or more R e In some embodiments, R6 is H. In some embodiments, R6 is methyl or isopropyl. In some embodiments, R6 is -(CH2)2OH. In some embodiments, R6 is selected from the functional groups described in the following examples. R6 is preferably selected from H, optionally substituted by one or more R e Substituted C 1-6 Alkyl, -S(O)p R c 、-S(O) p NR a R a 、-C(=O)R b 、-C(=O)OR b 、-C(=O)NR a R a , optionally through one or more R e Substituted C 3-6 Cycloalkyl, optionally substituted with one or more R e substituted aryl, and optionally substituted by one or more R e In some embodiments, R4, R5 and R6 are collectively selected from

[1185] and

[1186] In some embodiments, R7 is selected from H, F, Cl, Br and C 1-4 In some embodiments, R7 is H. In some embodiments, R7 is C 1-3 In some embodiments, R7 is selected from the functional groups described in the following examples. R7 is preferably selected from H, F and Cl.

[1187] As defined and described above, R8 is independently selected from H and optionally substituted by one or more selected from F, Cl and C 3-6 Substituents of cycloalkyl substituted C 1-6 In some embodiments, R8 is H. In some embodiments, R8 is C 3-6 Cycloalkyl substituted C 1-2 In some embodiments, R8 is methyl. In some embodiments, R8 is ethyl. In some embodiments, R8 is cyclopropyl. Preferably, R8 is CH2-cyclopropyl or CH2-cyclobutyl. In some embodiments, R8 is CH2-cyclobutyl optionally substituted with methyl and –OH. In certain embodiments, R8 is selected from the functional groups described in the following examples.

[1188] As defined and described above, R a Independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R eSubstituted -(CH2) r -C 3-10 Carbocyclic group and optionally one or more R e Substituted -(CH2) r -heterocyclyl; or R a and R a Together with the nitrogen atom to which they are attached, they form a e Substituted heterocycle.

[1189] As defined and described above, R b Independently selected from H, optionally through one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclic group.

[1190] As defined and described above, R c Independently selected from optionally one or more R e Substituted C 1-6 Alkyl, optionally substituted with one or more R e Substituted C 2-6 Alkenyl, optionally substituted with one or more R e Substituted C 2-6 Alkynyl, optionally substituted with one or more R e Substituted -(CH2) r -C 3-10 Carbocyclic group, and optionally one or more R e Substituted -(CH2) r -heterocyclic group.

[1191] As defined and described above, R d independently selected from H and optionally substituted with one or more R e Substituted C 1-6 alkyl.

[1192] As defined and described above, R e Independently selected from F, Cl, Br, CN, NH2, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, =O, OH, -OC 1-6 Alkyl, -CO2H, optionally with one or more Rf Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted with one or more R f Substituted -(CH2) r -C 3-6 Cycloalkyl, optionally substituted with one or more R f Substituted -(CH2) r -aryl, and optionally one or more R f Substituted -(CH2) r -heterocyclic group.

[1193] As defined and described above, R f independently selected from F, Cl, Br, CN, OH, C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl, and phenyl.

[1194] As defined and described above, p is independently selected from 0, 1 and 2 at each occurrence.

[1195] As defined and described above, r is 0-4. In some embodiments, r is 0. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4.

[1196] In some embodiments, the compound of formula (Ia) is selected from the following examples. In certain embodiments, the present invention provides any compound described above and herein, or a pharmaceutically acceptable salt thereof, or a composition for use in treatment. In some embodiments, the present invention provides an isolated form of any compound described above and herein. In some embodiments, the present invention provides a compound according to any of the following claims.

[1197] 3. Pharmaceutical Compositions

[1198] In another aspect, the present invention provides a composition comprising a compound of the invention or a stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of the compound in the composition of the present invention is such that PAD4 can be effectively and measurably inhibited in a biological sample or patient. In certain embodiments, the amount of the compound in the composition of the present invention is such that PAD4 can be effectively and measurably inhibited in a biological sample or patient. In certain embodiments, the composition of the present invention is formulated to administer to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated to be orally administered to a patient.

[1199] As used herein, the term "subject" is used interchangeably with the term "patient" and means an animal, preferably a mammal. In some embodiments, the subject or patient is a human. In other embodiments, the subject (or patient) is a veterinary subject (or patient). In some embodiments, the veterinary subject (or patient) is a canine, feline, or equine subject.

[1200] The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[1201] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution, and isotonic sodium chloride solution may be used. In addition, sterile fixed oils are conventionally used as solvents or suspending media.

[1202] For this purpose, any bland, fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are suitable for the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated forms. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as carboxymethylcellulose 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.

[1203] The pharmaceutically acceptable compositions of the present invention can be orally administered in any acceptable oral dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, common 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 dry corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavorings, or coloring agents may also be added.

[1204] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration. These suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[1205] The pharmaceutically acceptable compositions of the present invention can also be applied topically, especially when the therapeutic target includes areas or organs (including diseases of the eyes, skin, or lower intestinal tract) that are easily accessible by topical application. Suitable topical formulations for each of these areas or organs are easy to prepare. Topical application of the lower intestinal tract can be achieved with rectal suppository formulations (see above) or with suitable enema formulations. A topical transdermal patch can also be used. For topical application, the pharmaceutically acceptable compositions provided can be formulated into a suitable ointment form containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.

[1206] Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[1207] For ophthalmic use, provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic pH-adjusted sterile saline with or without preservatives such as benzalkonium chloride, or preferably as solutions in isotonic pH-adjusted sterile saline. Alternatively, for ophthalmic use, pharmaceutically acceptable compositions can be formulated in the form of an ointment such as paraffin.

[1208] The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. These compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in normal saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[1209] The pharmaceutically acceptable compositions of the present invention are preferably formulated for oral administration. The formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[1210] The pharmaceutically acceptable compositions of the present invention can be administered orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (e.g., via powders, ointments, or drops), buccally, as an oral or nasal spray, or the like to humans and other animals. In certain embodiments, the compounds of the present invention can be administered orally or parenterally one or more times a day at a dosage level of about 0.01 mg / kg to about 50 mg / kg, and preferably about 1 mg / kg to about 25 mg / kg, of the subject's body weight per day to achieve the desired therapeutic effect.

[1211] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain: inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan; and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and aromatics.

[1212] Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any mild fixed oil including synthetic monoglycerides or diglycerides can be used. In addition, fatty acids such as oleic acid can be used to prepare injectables.

[1213] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[1214] In order to prolong the effect of the compounds of the present invention, it is often necessary to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension 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 the crystal size and crystal form. Alternatively, delayed absorption of the compound administered parenterally can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming a microencapsulation matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the properties of the specific polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations can also be prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

[1215] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol; or suppository waxes which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[1216] 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 pharmaceutically acceptable inert excipient or carrier (such as sodium citrate or dicalcium phosphate) and / or the following: (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants such as glycerol; (d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (e) disintegrating agents such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) absorbents such as kaolin and bentonite; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[1217] Solid compositions of similar types can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (lactose or milk sugar) and high molecular weight polyethylene glycol and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in pharmaceutical formulation technology. They may optionally contain an emulsifier and may also have a composition that releases the active ingredient only or preferably in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of similar types can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (lactose or milk sugar) and high molecular weight polyethylene glycol and the like.

[1218] The active compound may also be present in a microencapsulated form together with one or more excipients as mentioned above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, release-controlled coatings and other coatings well known in pharmaceutical formulation technology. In the solid dosage form, the active compound may be mixed with at least one inert diluent (such as sucrose, lactose or starch). As commonly practiced, the dosage form may also include additional substances other than the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also include a buffer.

[1219] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed with a pharmaceutically acceptable carrier and any desired preservatives or buffers that may be needed under sterile conditions. Ophthalmic formulations, ear drops, and eye drops are also encompassed within the scope of the present invention. In addition, the present invention encompasses the use of transdermal patches, which have the added advantage of controlled delivery of the compound to the body. Such dosage forms are prepared by dissolving or distributing the compound in an appropriate medium. Absorption enhancers can also be used to increase the transdermal amount of the compound. Rate can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[1220] The amount of the compound of the invention that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending on the host being treated, the particular mode of administration, etc. Preferably, provided compositions should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[1221] The compounds of the present invention may be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies are in the form of fixed combinations of the compounds of the present invention and one or more other therapeutic compounds or of staggered or independent administration of the compounds of the present invention and one or more other therapeutic compounds, or of fixed combinations in combination with one or more other therapeutic compounds. Exemplary such other therapeutic agents include corticosteroids, rolipram, calciphosphatase, cytokine-suppressing anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide and other immunosuppressants; nuclear translocation inhibitors such as deoxyspiracil (DSG); nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as Such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf); cytotoxic drugs such as azathiprine and cyclophosphamide; TNF-α inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptors and rapamycin (sirolimus or Rapamune) or its derivatives. In addition or in addition, the compounds of the present invention can be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention or a combination thereof, especially for tumor therapy. As described above, in the context of other treatment strategies, long-term therapy is also possible, as is adjuvant therapy. Other possible treatments are therapies that maintain the patient's status after tumor regression, or even chemopreventive therapy (for example, for patients at risk).

[1222] Those additional agents may be administered separately from the composition containing the compounds of the invention as part of a multiple-dose regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of the invention into a single composition. If administered as part of a multiple-dose regimen, the two active agents may be provided simultaneously, sequentially, or within a certain time period of each other (generally within 5 hours of each other).

[1223] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form. Thus, the present invention provides a single unit dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[1224] The amount of the compound of the invention and the additional therapeutic agent (in those compositions comprising additional therapeutic agents as described above) that can be combined with the carrier materials to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. Preferably, the compositions of the invention should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of the compound of the invention can be administered.

[1225] In those compositions that include an additional therapeutic agent, that additional therapeutic agent and the compounds of the invention may act synergistically. Thus, the amount of the additional therapeutic agent in these compositions will be less than the amount required in a monotherapy utilizing only that therapeutic agent.

[1226] The amount of the additional therapeutic agent present in the compositions of the present invention will not exceed the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of the additional therapeutic agent in the compositions disclosed herein will preferably be in the range of about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[1227] 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 employed, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, as well as the severity of the specific disease or condition being treated. The amount of the compound of the invention in the composition will also depend on the specific compound in the composition.

[1228] 4. Uses of the Compound

[1229] The compounds and compositions described herein are generally useful for inhibiting PAD4.

[1230] The activity of the compounds used as PAD4 inhibitors in the present invention can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that measure inhibition of PAD4. Detailed conditions for assaying the compounds used as PAD4 inhibitors in the present invention are described in the examples below. In some embodiments, provided compounds selectively inhibit PAD4 compared to PAD2.

[1231] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder as described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have appeared. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[1232] The provided compounds are inhibitors of PAD4 and are therefore useful in treating one or more diseases or conditions associated with PAD4 enzyme activity. Thus, in certain embodiments, the present invention provides methods for treating a disease or condition associated with PAD4 enzyme activity, comprising the step of administering a compound of the invention or a pharmaceutically acceptable composition thereof to a patient in need thereof.

[1233] In one embodiment, the disease or condition associated with PAD4 enzyme activity is a disease, condition, or disorder mediated by inappropriate PAD4 activity. In some embodiments, the disease or condition associated with PAD4 enzyme activity is selected from the group consisting of: rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, and psoriasis. In another embodiment, the disease or condition associated with PAD4 enzyme activity is rheumatoid arthritis. In another embodiment, the disease or condition associated with PAD4 enzyme activity is systemic lupus. In another embodiment, the disease or condition associated with PAD4 enzyme activity is vasculitis. In another embodiment, the disease or condition associated with PAD4 enzyme activity is cutaneous lupus erythematosus. In another embodiment, the disease or condition associated with PAD4 enzyme activity is psoriasis.

[1234] In one embodiment, a method of treating rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis is provided, comprising administering to a human subject in need thereof a therapeutically effective amount of a provided compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.

[1235] In one embodiment, a method of treating rheumatoid arthritis is provided, comprising administering to a human subject in need thereof a therapeutically effective amount of a provided compound, its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts. In one embodiment, a method of treating systemic lupus is provided, comprising administering to a human subject in need thereof a therapeutically effective amount of a provided compound, its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts. In one embodiment, a method of treating vasculitis is provided, comprising administering to a human subject in need thereof a therapeutically effective amount of a provided compound, its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts. In one embodiment, a method of treating cutaneous lupus erythematosus is provided, comprising administering to a human subject in need thereof a therapeutically effective amount of a provided compound, its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts. In one embodiment, provided is a method of treating psoriasis, comprising administering to a human subject in need thereof a therapeutically effective amount of a provided compound, a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.

[1236] In some embodiments, the disease or condition associated with PAD4 enzyme activity is selected from the group consisting of: acid-induced lung injury, acne (PAPA), acute lymphocytic leukemia, acute respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenocortical insufficiency, aging, AIDS, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary, aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, weight loss, angina, angioedema, anhidrotic ectodermal dysplasia-ID, ankylosing spondylitis, anterior segment, inflammation, antiphospholipid antibody syndrome, aphthous stomatitis, appendicitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune disease, autoimmune hepatitis, bee sting-induced inflammation, Behcet's disease disease), Behçet's syndrome, Bell's palsy, berylliosis, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiomegaly, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysms, chemically induced inflammation, chorioretinitis, chronic heart failure, chronic lung disease of prematurity, chronic lymphocytic leukemia, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue diseases, corneal ulcers, Crohn's disease disease), cryptopyrin-associated periodic syndromes, cryptococcosis, cystic fibrosis, interleukin-1 receptor antagonist deficiency (DIRA), dermatitis, dermatitis endotoxemia, dermatomyositis, diffuse endogenous pontine glioma, endometriosis, endotoxemia, epicondylitis, erythroblastopenia, familial amyloidosis polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, glomerulonephritis, gout, gouty arthritis, graft-versus-host disease, intestinal disease, head injury, headache, hearing loss, heart disease, hemolytic anemia, Henrietta-Schonlein purpura, hepatitis, hereditary periodic fever syndromes, herpes zoster and herpes simplex, HIV-1, Hodgkin's disease, Huntington's diseasedisease), drusen membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulin D syndrome with recurrent fever (HIDS), aplasia and other anemias, aplastic anemia, idiopathic thrombocytopenic purpura, incontinence pigmenti, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect sting-induced inflammation, iritis, irritation-induced inflammation, ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, kidney damage caused by parasitic infection, prevention and treatment of kidney transplant rejection, leptospirosis, leukemia, Loeffler's syndrome, lung damage, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria), deafness amyloidosis deafnessamyloidosis), multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis, myocarditis, mycosis fungoide, myelodysplastic syndrome, myositis, sinusitis, necrotizing enterocolitis, neonatal-onset multisystem inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological disorders, non-allergenic asthma, obesity, ocular allergies, optic neuritis, organ transplantation, osteoarthritis, otitis media, Paget's disease, pain, pancreatitis, Parkinson's disease disease), pemphigus, pericarditis, periodic fevers, periodontitis, peritoneal endometriosis, pertussis, pharyngitis and adenitis (PFAPA syndrome), plant-induced inflammation, pneumonia, pneumonitis, pneumocystis infection, kudzu / urushiol oil-induced inflammation, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyositis, psoriasis, psychosocial stress disorders, lung disease, pulmonary hypertension, pulmonary fibrosis, pyoderma gangrenosum, suppurative sterile arthritis, renal disease, retinal disease, rheumatic carditis, rheumatic disease, rheumatic arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell, sickle cell anemia, silica-induced disease, Sjogren's syndromesyndrome), skin diseases, sleep apnea, solid tumors, spinal cord injury, Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, solar dermatitis, temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplantation, TNF receptor-associated periodic syndrome (TRAPS), toxoplasmosis, transplantation, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticaria, uveitis, Wegener's granulomatosis, interstitial lung disease, psoriatic arthritis, juvenile idiopathic arthritis, Sjögren's syndrome syndrome), antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, antiphospholipid antibody syndrome, sepsis, deep vein thrombosis, fibrosis, Alzheimer's disease, scleroderma, and CREST syndrome.

[1237] In one embodiment, the present invention provides a provided compound or a pharmaceutically acceptable salt thereof for use in therapy. In another embodiment, the present invention provides a provided compound or a pharmaceutically acceptable salt thereof for use in treating a disease or condition mediated by inappropriate PAD4 activity. In another embodiment, the present invention provides a provided compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, for use in 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 stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, for use in treating rheumatoid arthritis. In another embodiment, the present invention provides a provided compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, for use in treating systemic lupus. In another embodiment, the present invention provides a provided compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, for use in treating vasculitis. In another embodiment, the present invention provides a provided compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, for use in treating cutaneous lupus erythematosus. In another embodiment, the present invention provides a provided compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, for use in treating psoriasis. In another embodiment, the present invention provides the use of a provided compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating a condition mediated by inappropriate PAD4 activity. In another embodiment, the present invention provides the use of a provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof for the manufacture of a medicament 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 a provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating rheumatoid arthritis. In another embodiment, the present invention provides the use of a provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating systemic lupus. In another embodiment, the present invention provides the use of a provided compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating vasculitis.In another embodiment, the present invention provides the use of a provided compound or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts for the manufacture of a medicament for treating cutaneous lupus erythematosus. In another embodiment, the present invention provides the use of a provided compound or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts for the manufacture of a medicament for treating psoriasis. In another embodiment, the present invention provides a pharmaceutical composition for treating or preventing a disease or condition mediated by inappropriate PAD4 activity, comprising a provided compound or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts. 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 a provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a pharmaceutical composition for treating or preventing rheumatoid arthritis, comprising a provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a pharmaceutical composition for treating or preventing systemic lupus, comprising a provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a pharmaceutical composition for treating or preventing vasculitis, comprising a provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a pharmaceutical composition for treating or preventing cutaneous lupus erythematosus, comprising a provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a pharmaceutical composition for treating or preventing psoriasis, comprising a provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.

[1238] All features of each of the aspects of the present invention apply mutatis mutandis to all other aspects. In order to more fully understand the invention described herein, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the present invention in any way.

[1239] 5. Examples

[1240] The following examples have been prepared, isolated and characterized using the methods disclosed herein. The following examples illustrate part of the scope of the present invention and are not intended to limit the scope of the present invention.

[1241] Details of the various HPLC / LC-MS methods used in the analysis of compounds and intermediates are provided below.

[1242] Method A: SUNFIRE C18 (4.6×150) mm, 3.5 μm column; flow rate 1 ml / min; gradient time 15 minutes; 10-100% solvent B; monitoring at 254 nm and 220 nm (solvent A: 5% acetonitrile (ACN), 95% water, 0.05% trifluoroacetic acid (TFA); solvent B: 95% ACN, 5% water, 0.05% TFA).

[1243] Method B: X-type electro-bridged phenyl (4.6×150) mm, 3.5 μm column; flow rate 1 ml / min; gradient time 15 minutes; 10-100% solvent B; monitoring at 254 nm and 220 nm (solvent A: 5% ACN, 95% water, 0.05% TFA; solvent B: 95% ACN, 5% water, 0.05% TFA).

[1244] Method C: Kinetex EVO C18 (4.6×100) mm, 2.6 μm, buffer: 0.05% TFA / water, mobile phase C: buffer:ACN (95:5), mobile phase D: ACN:buffer (95:5).

[1245] Method D: Kinetex biphenyl (4.6×100) mm, 2.6 μm, buffer: 0.05% TFA / water, mobile phase C: buffer:ACN (95:5), mobile phase D: ACN:buffer (95:5).

[1246] Method E: X-bridge BEH XP C18 (50×2.1) mm, 2.5 μm, time (min): 0-3% B: 0-100 Buffer A: 95% water: 5% ACN; 10 mM ammonium acetate (NH4OAc) B: 5% water: 95% ACN; 10 mM NH4OAc, flow rate: 1.1 ml / min, temperature: 50°C.

[1247] Method F: X-bridge BEH XP C18 (50×2.1) mm, 2.5 μm, time (min): 0-3%, B: 0-100, A: 95% water: 5% ACN; 0.1% TFA, B: 5% water: 95% ACN; 0.1% TFA, flow rate: 1.1 ml / min, temperature: 50°C.

[1248] Method G: ACQUITY BEH C18 (3×50) mm, 1.7 μm, buffer: 10 mM NH4OAc, mobile phase A: buffer: ACN (95:5), mobile phase B: buffer: ACN (5:95), flow rate: 0.7 ml / min, method: 0 min - 20% B, 20% to 100% B 2 min, 2 to 2.3 min - 100%.

[1249] Method H: Kinetex XB C18 (75×3) mm, 2.6 μm, mobile phase A: 10 mM NH 4 OAc / water, water:ACN (98:02), mobile phase B: 10 mM NH 4 OAc / water:ACN (02:98), gradient: 20-100% B over 4 minutes, flow rate: 1.0 ml / minute.

[1250] Method I: ACQUITY BEH C18 (3×50) mm, 1.7 μm, buffer: 0.05% TFA / water, mobile phase A: buffer: ACN (95:5), mobile phase B: ACN: buffer (95:5).

[1251] Method J: Column: HALO C18, 3×30 mm, 2.7 μm; Mobile phase A: water + 0.05% TFA, Mobile phase B: acetonitrile + 0.05% TFA; Flow rate: 1.5 mL / min; Gradient: 5% B to 95% B in 2.5 min, hold at 95% for 1 min, 95% B to 5% B in 0.05 min; Detection: MS and UV (254 nm).

[1252] Method K: Column: Shim-pack XR-ODS, 3×50 mm, 2.2 μm; Mobile phase A: water / 0.05% TFA, Mobile phase B: acetonitrile / 0.05% TFA; Flow rate: 1.2000 mL / min; Gradient: 5% B to 95% B in 3.3 min, hold at 95% for 0.7 min, 95% B to 5% B for 0.1 min; Detection: MS and UV (254 nm).

[1253] The general procedure for purification using reverse phase HPLC (RP-HPLC) is as follows. Typically, the sample to be purified was dissolved in DCM:MeOH (2:1), 20 wt% poly(4-vinylpyridine) (Aldrich #226963) was added to this solution, and the container containing the solution was placed on a shaker for 2 hours. Thereafter, the contents were filtered through a 25 mm syringe filter equipped with a 0.45 μm nylon membrane (VWR #28145-489) into a clean vial and dried using centrifugal evaporation to obtain the purified sample.

[1254] General synthesis procedure:

[1255] Intermediate 1

[1256] 1-Amino-3-methoxy-5-(methoxycarbonyl)pyridin-1-ium 2,4-dinitrophenolate

[1257]

[1258] O-(2,4-dinitrophenyl)hydroxylamine (10.01 g, 50.3 mmol) was added to a stirred solution of methyl 5-methoxynicotinate (7 g, 41.9 mmol) in tetrahydrofuran (THF, 50 ml) and water (50 ml). The reaction mixture was heated to 40° C., stirred for 12 hours, and filtered to give 1-amino-3-methoxy-5-(methoxycarbonyl)pyridin-1-ium (10 g, 130%) as a yellow-brown solid, which was used in the next step without further purification. Liquid chromatography mass spectrometry analysis (LC-MS) m / z: 183.1 [M+H] + .

[1259] Intermediate 2

[1260] tert-Butyl-3-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)propiolate

[1261]

[1262] Tert-butyl propiolate (0.605 g, 4.80 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.153 g, 0.218 mmol) were added to a stirred solution of 1-(cyclopropylmethyl)-2-iodo-1H-pyrrolo[2,3-b]pyridine (1.3 g, 4.36 mmol) in a mixture of triethylamine (TEA, 5 ml) and THF (5 ml). The reaction mixture was heated to 65° C., stirred for 1 hour, and filtered through a bed of celite. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by chromatography on a silica gel column (40 g, Purification by SiO2 column (eluted with 20% ethyl acetate (EtOAc) / hexane) gave the title compound (1.2 g, 93%) as a brown liquid. LC-MS m / z: 297.1 [M+H] + . 1H NMR (300MHz, chloroform-d) δppm:8.55-8.38(m,1H),7.99-7.87(m,1H),7.26-6.99(m,1H),7.04-6.99(m,1H) ),4.43-4.06(m,2H),3.26-3.16(m,1H),1.65-1.38(m,10H),1.34-1.07(m,1H),0.59-0.39(m,4H).

[1263] Intermediate 3

[1264] 6-Chloro-1-(cyclopropylmethyl)-2-iodo-1H-pyrrolo[2,3-b]pyridine

[1265]

[1266] Sodium hydride (2.87 g, 71.8 mmol) was added to a stirred solution of 6-chloro-2-iodo-1H-pyrrolo[2,3-b]pyridine (10 g, 35.9 mmol) in dimethylformamide (DMF, 200 ml) at 0° C., and the reaction mixture was stirred for 0.5 hours before the addition of (bromomethyl)cyclopropane (4.50 ml, 46.7 mmol). The reaction mixture was stirred for 1 hour, poured into ice water (200 ml), and extracted with ethyl acetate (3×200 ml). The combined organic fractions were washed with water (2×300 ml) and brine (2×200 ml), dried over sodium sulfate (Na 2 SO 4 ), filtered, and concentrated to give the crude product, which was purified by chromatography on a silica gel column (80 g, Purification by silica column with 0-50% EtOAc / hexanes as eluent gave the title compound as a yellow solid (8 g, 67%). LC-MS m / z: 332.9 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ ppm: 7.75 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.79 (s, 1H), 1.46-1.26 (m, 1H), 0.61-0.44 (m, 4H).

[1267] Intermediate 4

[1268] tert-Butyl-3-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)propiolate

[1269]

[1270] To a stirred solution of 6-chloro-1-(cyclopropyl-methyl)-2-iodo-1H-pyrrolo[2,3-b]pyridine (Intermediate 3, 4 g, 12.03 mmol) in a mixture of TEA (10 ml) and THF (10 ml) was added tert-butyl propiolate (1.669 g, 13.23 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.422 g, 0.601 mmol). The reaction mixture was stirred at 50° C. for 1 hour and filtered through a bed of celite. The filtrate was concentrated under reduced pressure to obtain the crude compound, which was purified by chromatography on a silica gel column (40 g, 10 ml). Purification by SiO2 column (eluted with 20% EtOAc / hexanes) gave the title compound (2.5 g, 63%) as a yellow liquid. LC-MS m / z: 331.1 [M+H] + .

[1271] Intermediate 5

[1272] 6-Bromo-1-(cyclopropylmethyl)-2-ethynyl-1H-indole

[1273]

[1274] Potassium carbonate (K2CO3, 11.18 g, 81 mmol) was added to a stirred solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (51.8 g, 27.0 mmol, 10% acetonitrile solution) in methanol (MeOH, 50 ml), followed by the addition of 6-bromo-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (7.5 g, 27.0 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature, stirred for 6 hours, and concentrated under vacuum to give a crude residue, which was diluted with water and extracted with EtOAc (2×100 ml). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by chromatography on a silica gel column (40 g, HPLC elution). Purification by SiO2 column (eluting with 0-5% EtOAc / hexanes) gave the title compound (6.3 g, 85%) as a brown liquid. LC-MS m / z: 276.1 [M+2H] + .

[1275] Intermediate 6

[1276] tert-Butyl-3-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)propiolate

[1277]

[1278] Lithium diisopropylamide (LDA, 17.23 ml, 34.5 mmol) was added to a stirred solution of 6-bromo-1-(cyclopropylmethyl)-2-ethynyl-1H-indole (Intermediate 5, 6.3 g, 22.98 mmol) in THF (10 ml) at 0° C. and the reaction mixture was stirred for 30 minutes before Boc2O (5.34 ml, 22.98 mmol) was slowly added. The reaction mixture was stirred for 1 hour, quenched with water, and extracted with EtOAc (2×100 ml). The combined organic layers were washed with water (2×300 ml) and brine (2×200 ml), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by chromatography on a silica gel column (80 g, The crude product was purified by silica column with 0-5% EtOAc / hexane as eluent to give the title compound (6.2 g, 72%). LC-MS m / z: 318.0 [M-isobutylene + H] + . 1 H NMR (400MHz, DMSO-d6) δppm: 7.94 (s, 1H), 7.58 (d, J = 8.5Hz, 1H), 7.26 (dd, J = 1.5, 8.5Hz, 1 H),7.21(s,1H),4.17(d,J=7.0Hz,2H),1.51(s,9H),1.27-1.18(m,1H),0.52-0.40(m,4H).

[1279] Intermediate 7

[1280] 1-(Cyclopropylmethyl)-2-(trimethylstannyl)-1H-pyrrolo[2,3-b]pyridine

[1281]

[1282] Hexamethylditin (0.278 ml, 1.342 mmol) was added to a stirred solution of 1-(cyclopropyl-methyl)-2-iodo-1H-pyrrolo[2,3-b]pyridine (0.2 g, 0.671 mmol) in 1,4-dioxane (1.5 ml), and the reaction mixture was degassed with argon for 5 minutes, followed by the addition of [1,1'-bis(di-tert-butylphosphino)-ferrocene]-dichloropalladium(II) (0.031 g, 0.047 mmol). The reaction mixture was stirred at 70 ° C. for 2 hours, filtered through a bed of celite, and the filtrate was concentrated to give the crude product (250 mg), which was used in the next step without further purification. LC-MS m / z: 337 [M + H] + .

[1283] Intermediate 8

[1284] 1-Amino-3-(ethoxycarbonyl)pyridin-1-ium 2,4-dinitrophenolate

[1285]

[1286] Intermediate 8 (10 g, 28.5 mmol, 100%) was prepared following a similar preparation procedure to Intermediate 1. LC-MS m / z: 168 [M+H] + .

[1287] Intermediate 9

[1288] 1-Amino-3-fluoro-5-(methoxycarbonyl)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate

[1289]

[1290] O-(Sulfosulphonyl)hydroxylamine (8.33 g, 38.7 mmol) was added to a stirred solution of methyl 5-fluoronicotinate (5 g, 32.2 mmol) in dichloromethane (DCM, 20 ml) at 0°C. The reaction mixture was stirred for 2 hours and concentrated to give 1-amino-3-fluoro-5-(methoxycarbonyl)pyridin-1-ium (5 g, 91%) as a brown solid, which was used in the next step without further purification. LC-MS m / z: 171.0 [M+H] + .

[1291] Intermediate 10

[1292] 1-(Cyclopropylmethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

[1293]

[1294] Sec-BuLi (16.68 ml, 23.36 mmol) was added dropwise to a stirred solution of 1-(cyclopropylmethyl)-1H-indole (2 g, 11.68 mmol) in THF (20 ml) at -78 ° C under an argon atmosphere. The reaction mixture was further stirred for 30 minutes before the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.173 g, 11.68 mmol). The reaction mixture was stirred at room temperature for 2 hours, quenched by the dropwise addition of water (50 ml), and extracted with EtOAc (2×50 ml). The combined organic extracts were washed with water (100 ml) and brine (100 ml), dried over Na 2 SO 4 , filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude product thus obtained was purified using a silica gel column (EtOAc / hexane), and the purified product was isolated under 15% EtOAc / hexane. The desired fractions were collected and the volatiles were evaporated to dryness under reduced pressure to afford the title compound (2 g, 58%). 1 H NMR (400MHz, DMSO-d6) δppm: 0.32-0.44 (m, 4H), 1.16-1.34 (m, 13H), 4.32 (d, J = 6.85Hz, 2H), 6.94-7.05 (m, 2H), 7.16-7.25 (m, 1H), 7.51-7.60 (m, 2H).

[1295] Intermediate 11

[1296] 1-(Cyclopropylmethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine

[1297]

[1298] Intermediate 11 (1.3 g, 31%) was prepared following a similar preparation procedure to Intermediate 10. LC-MS (ESI) m / z: 300.3 [M+H] + .

[1299] Intermediate 12

[1300] 6-Bromo-1-(cyclopropylmethyl)-2-iodo-1H-indole

[1301]

[1302] Sodium hydride (NaH, 1.372 g, 34.3 mmol) was added portionwise to a stirred solution of 6-bromo-2-iodo-1H-indole (5.52 g, 17.15 mmol, Ref: Bioorg. Med. Chem. 22 (5), 2014, 1708) in DMF (20 ml) at 0 ° C., and the reaction mixture was stirred for 10 minutes, followed by dropwise addition of (bromomethyl)-cyclopropane (2.498 ml, 25.7 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with cold water (50 ml), and extracted with EtOAc (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The product was purified by chromatography on a silica gel column (24 g, The crude product thus obtained was purified by SiO2 column (eluted with 10% EtOAc / n-hexane) to give the title compound (5 g, 78%). LC-MS m / z: 377 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δppm: 7.83 (s, 1H), 7.43 (d, J = 8.3Hz, 1H), 7.14 (dd, J = 1.8, 8. 5Hz, 1H), 6.82 (s, 1H), 4.13 (d, J = 6.8Hz, 2H), 1.31-1.13 (m, 1H), 0.51-0.41 (m, 4H).

[1303] Intermediate 13

[1304] 1-Amino-3-chloro-5-(methoxycarbonyl)pyridin-1-ium-2,4,6-trimethylbenzenesulfonate

[1305]

[1306] O-(Sulfosulphonyl)hydroxylamine (2.6 g, 11.66 mmol) was added to a stirred solution of methyl 5-chloronicotinate (2 g, 11.66 mmol) in DCM (40 ml) at 0°C. The reaction mixture was stirred at room temperature for 2 hours and evaporated under reduced pressure to give crude 1-amino-3-chloro-5-(methoxycarbonyl)pyridin-1-ium (2.1 g, 96%) as a white solid, which was used in the next step without further purification. LC-MS m / z: 187.2 [M+H] + .

[1307] Intermediate 14

[1308] Ethyl 6-bromo-1-(cyclopropylmethyl)-1H-indole-2-carboxylate

[1309]

[1310] Potassium carbonate (10.3 g, 74.6 mmol) was added to a stirred solution of ethyl 6-bromo-1H-indole-2-carboxylate (10 g, 37.3 mmol) in DMF (60 ml), followed by the addition of (bromomethyl)cyclopropane (5.0 g, 37.3 mmol). The reaction mixture was stirred for 16 hours, and potassium carbonate (5 g) and (bromomethyl)cyclopropane (2.5 g) were added. The resulting reaction mixture was heated to 50° C. for 2 hours, diluted with water (150 ml), and extracted with ethyl acetate (3×150 ml). The combined organic layers were concentrated in vacuo to give ethyl 6-bromo-1-(cyclopropylmethyl)-1H-indole-2-carboxylate (10 g, 83%) as a brown solid, which was used further without purification. LC-MS m / z: 322.0 [M+H] + .

[1311] Intermediate 15

[1312] (6-Bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol

[1313]

[1314] LiBH4 (15.52 ml, 62.1 mmol, 4 M in THF) was added to a stirred solution of intermediate 14 (10 g, 31 mmol) in THF (50 ml) at 0°C. The reaction mixture was allowed to warm to room temperature over 1 hour, stirred for 16 hours, cooled to 0°C, and an additional amount of LiBH4 (15.52 ml, 62.1 mmol, 4 M in THF) was added dropwise. The reaction mixture was stirred at room temperature for 6 hours, cooled to 0°C, quenched by the slow addition of saturated ammonium chloride solution (careful addition is required, as sudden gas evolution is a concern), stirred for approximately 45 minutes, and extracted with ethyl acetate (4 x 100 ml). The organic layer was separated, dried over Na2SO4, filtered, and concentrated to afford the crude product, which was further purified using a silica gel column (0-30% ethyl acetate / petroleum ether) to afford 6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol (8.5 g, 98%). LC-MS m / z:280.1[M+H] + .

[1315] Intermediate 16

[1316] 6-Bromo-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde

[1317]

[1318] Manganese dioxide (10.3 g, 119 mmol) was added to a stirred solution of intermediate 15 (8.3 g, 29.6 mmol) in THF (50 ml). The reaction mixture was stirred at 45 ° C for 2 hours and filtered through a bed of celite. The filtrate was concentrated in vacuo to give 6-bromo-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (7.6 g, 92%) as a brown syrup, which was used further without purification. LC-MS m / z: 278.1 [M + H] + .

[1319] Intermediate 17

[1320] (E)-6-Bromo-1-(cyclopropylmethyl)-2-(2-nitroprop-1-en-1-yl)-1H-indole

[1321]

[1322] Ammonium acetate (122 mg, 1.582 mmol) was added to a stirred solution of intermediate 16 (400 mg, 1.438 mmol) in nitroethane (2 ml, 28.0 mmol). The reaction mixture was stirred at 90 ° C for 2 hours, diluted with water (5 ml), and extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give (E)-6-bromo-1-(cyclopropylmethyl)-2-(2-nitroprop-1-en-1-yl)-1H-indole (420 mg) as a yellow liquid, which was used in the next step without purification. LC-MS retention time: 1.26 min, m / z=335.1 [M+H] +

[1323] Intermediate 18

[1324] Ethyl 2-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridine-6-carboxylate

[1325]

[1326] Intermediate 8 (75 mg, 0.447 mmol) and copper (I) iodide (6 mg, 0.03 mmol) were added to a stirred solution of intermediate 17 (50 mg, 0.149 mmol) in DMF (1 ml). The reaction mixture was stirred at 80 ° C for 30 hours, concentrated to remove DMF, and water (10 ml) was added and the contents were extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified using a silica gel column (0-5% methanol / dichloromethane) to give ethyl 2-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridine-6-carboxylate (20 mg, 30%). LC-MS (ES): m / z=452.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δppm: 9.19 (s, 1H), 7.90 (s, 1H), 7.83 (d, J = 9.5Hz, 1H), 7.62-7.58 (m, 2H), 7.24-7.20 (m, 1H), 6.91 (s, 1H), 4 .50(d,J=7.0Hz,2H),4.36(q,J=7.0Hz,2H),2.42(s,3H),1.36(t,J=7.0Hz,3H),1.11(m,1H),0.32-0.26(m,2H),0.18-0.13(m,2H).

[1327] Intermediate 19

[1328] 2-(6-Bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carboxylic acid ethyl ester

[1329]

[1330] Intermediate 19 was prepared following similar preparation procedures to Intermediate 18 using appropriate reactants. LC-MS retention time: 1.76 min, m / z: 468.2 [M+H] (Method G). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.91 (s, 1H), 8.50 (s, 1H), 7.80 (dd, J = 3.01, 1.51 Hz, 1H), 7.43-7.60 (m, 1H), 6.85-6.91 (m, 1H), 6.75 (s, 1H), 4.37 (d, J = 6.5 Hz, 2H), 4.02 (s, 3H), 3.93 (s, 3H), 2.56-2.62 (m, 3H), 1.15-1.34 (m, 1H), 0.33-0.46 (m, 2H), 0.13-0.18 (m, 2H).

[1331] Intermediate 20

[1332] 6-Chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine

[1333]

[1334] Sodium hydride (60% w / w, 1.31 g, 32.8 mmol) in mineral oil was added portionwise to a stirred solution of 6-chloro-1H-pyrrolo[2,3-b]pyridine (5 g, 32.8 mmol) in DMF (25 ml) at 0 ° C. The reaction mixture was stirred for 15 minutes, followed by the slow addition of (bromomethyl)cyclopropane (4.42 g, 32.8 mmol) over 5 minutes. The reaction mixture was allowed to warm to room temperature, stirred for 16 hours, quenched with water (50 ml), and extracted with ethyl acetate (3×50 ml). The combined organic layers were concentrated in vacuo to give the crude product, which was purified using a silica gel column (0-5% ethyl acetate / petroleum ether) to give 6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine (6.5 g, 96%). LC-MS retention time: 1.85 minutes; m / z: 207.0 [M + H] (Method G).

[1335] Intermediate 21

[1336] 6-Chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde

[1337]

[1338] Sec-butyllithium (10.37 ml, 14.52 mmol, 1.4 M in cyclohexane) was added to a stirred solution of intermediate 20 (2 g, 9.68 mmol) in THF (20 ml) at -78 ° C. The contents were stirred for 30 minutes before the addition of DMF (2 ml, 25.8 mmol). The reaction mixture was allowed to warm to -20 ° C., then warmed to room temperature, stirred for 12 hours, cooled to -10 ° C., and quenched by the addition of saturated ammonium chloride solution. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (3 × 100 ml). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain the crude product, which was purified using a silica gel column (0 to 15% ethyl acetate / petroleum ether) to give 6-chloro-1- (cyclopropylmethyl) -1H- pyrrolo [2,3-b] pyridine -2- carbaldehyde (1.45 g, 64%) as an off-white crystalline solid. LC-MS retention time: 1.85 min, m / z: 235.0 [M+H] (Method G).

[1339] Intermediate 22

[1340] (E)-6-Chloro-1-(cyclopropylmethyl)-2-(2-nitroprop-1-en-1-yl)-1H-pyrrolo[2,3-b]pyridine

[1341]

[1342] Intermediate 22 was prepared using Intermediate 21 following a similar preparation procedure to Intermediate 17. LC-MS retention time: 1.17 min, m / z: 292.2 [M+H] (Method G).

[1343] Intermediate 23

[1344] 2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridine-6-carboxylic acid ethyl ester

[1345]

[1346] Intermediate 23 was prepared using Intermediate 22 and Intermediate 8 following a similar preparation procedure to Intermediate 18. LC-MS retention time: 1.66 min, m / z: 409.1 [M+H] (Method G).

[1347] Intermediate 24

[1348] 2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-chloro-3-methylpyrazolo[1,5-a]pyridine-6-carboxylic acid methyl ester

[1349]

[1350] Intermediate 24 was prepared as a colloidal liquid using Intermediate 13 and Intermediate 22 following a similar preparation procedure as Intermediate 18. LC-MS (ES): m / z: 429.1 [M+H] + .

[1351] Intermediate 25

[1352] 7-(1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-2-carboxylic acid ethyl ester

[1353]

[1354] KCO (15.46 g, 112 mmol) and PdCl(dppf).CHCl (3.05 g, 3.73 mmol) were added to a stirred solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (11.53 g, 37.3 mmol) and ethyl 7-bromo-1H-indole-2-carboxylate (10 g, 37.3 mmol) in dioxane (200 ml). The reaction mixture was purged with nitrogen for 2 minutes, then stirred at 100° C. for 3 hours, filtered through a celite bed, and the celite bed was washed thoroughly with ethyl acetate. The combined filtrates were concentrated under reduced pressure to give the crude product, which was purified using a silica gel column (0-30% ethyl acetate / petroleum ether) to give the title compound (11.3 g, 82%) as a gummy liquid. LC-MS m / z:369.4[MH] + . 1H NMR(300MHz, DMSO-d6)δppm:11.43(s,1H),7.57(d,J=7.2Hz,1H),7.21(d,J=4.0Hz,1H),7.24-7.04(m,2H),5.96(br,s,1H ), 4.34 (q, J = 7.1Hz, 2H), 4.08-3.99 (m, 2H), 3.62 (t, J = 5.7Hz, 2H), 1.51-1.45 (m, 2H), 1.46 (s, 9H), 1.34 (t, J = 7.2Hz, 3H).

[1355] Intermediate 26

[1356] 7-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-1H-indole-2-carboxylic acid ethyl ester

[1357]

[1358] Pd / C (7.18 g, 6.75 mmol, 50% wet) was added to a stirred solution of intermediate 25 (5.0 g, 13.50 mmol) in methanol (100 ml) purged with nitrogen, and the reaction mixture was stirred under an atmosphere of H for 4 hours. The reaction mixture was filtered through a bed of celite, and the filtrate was concentrated under reduced pressure to give ethyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-indole-2-carboxylate (4.95 g, 98%). LC-MS m / z: 371.4 [MH] + . 1 H NMR (300MHz, DMSO-d6) δppm: 11.84 (s, 1H), 7.49 (d, J = 7.6Hz, 1H), 7.21-7.01 (m, 3H), 4.36 (q, J = 7.1Hz, 2H), 4. 16-4.04(m,4H),3.61-3.42(m,1H),1.90-1.74(m,2H),1.59-1.47(m,2H),1.43(s,9H),1.35(t,J=7.2Hz,3H).

[1359] Intermediate 27

[1360] Ethyl 7-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate

[1361]

[1362] KCO (14.47 g, 105 mmol) and (bromomethyl)cyclopropane (14.14 g, 105 mmol) were added to a stirred solution of intermediate 26 (13 g, 34.9 mmol) in DMF (100 ml). The reaction mixture was stirred at 50° C. for 12 hours, allowed to cool to room temperature, diluted with water, and extracted with ethyl acetate (3×150 ml). The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and the volatiles were evaporated under reduced pressure to obtain the crude product, which was purified using a silica gel column (0-20% ethyl acetate / petroleum ether) to give ethyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate (4.8 g, 32%) as a gummy liquid. LC-MS m / z: 427.5 [M+H] + .

[1363] Intermediate 28

[1364] tert-Butyl 4-(1-(cyclopropylmethyl)-2-(hydroxymethyl)-1H-indol-7-yl)piperidine-1-carboxylate

[1365]

[1366] LiBH4 (10.08 ml, 40.3 mmol) in tetrahydrofuran was added to a stirred solution of intermediate 27 (4.3 g, 10.08 mmol) in tetrahydrofuran (80 ml) at 0°C. The reaction mixture was allowed to warm to room temperature, stirred for 48 hours, quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (4 x 50 ml). The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulfate, and ev...

Claims

1. A compound of formula (IIa): or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from and R2 is independently selected from H, F, Cl and OCH3; R3 is CH3; R4 is independently selected from H, F, Cl, C 1-5 alkyl, and R5 is H; R7 is H; and R8 is a C 3-6 Cycloalkyl substituted C 1-3 alkyl.

2. A compound of formula (IIIa): or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from and R2 is independently selected from H, F, Cl and OCH3; R3 is CH3; R4 is independently selected from H, F, Cl, C 1-5 alkyl, and R5 is H; R7 is H; and R8 is a C 3-6 Cycloalkyl substituted C 1-3 alkyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R4 is independently selected from H, Cl, C 1-5 alkyl, and 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein: R4 is independently selected from H, Cl, C 1-5 alkyl, and 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R4 is independently selected from and 6. A compound of formula (IVa): or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from and R2 is independently selected from H, F, Cl and OCH3; R3 is CH3; R4 is independently selected from H, F, Cl, and R7 is H; and R8 is C substituted by cyclopropyl 1-2 alkyl.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein: R2 is independently selected from H and OCH3; and R4 is independently selected from H, and 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein: R4 is independently selected from and 9. A compound of formula (Va): or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from and R2 is independently selected from H and OCH3; R3 is CH3; R4 is independently selected from H, F, Cl, and R7 is H; and R8 is C optionally substituted by cyclopropyl 1-2 alkyl.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein; R1 is independently selected from and R2 is OCH3; R4 is independently selected from and and R8 is C substituted by cyclopropyl 1-2 alkyl.

11. A compound of formula (VIa): or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from and R3 is CH3; R4 is independently selected from F, Cl, and R7 is H; and R8 is C substituted by cyclopropyl 1-2 alkyl.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein: R1 is and R4 is independently selected from F, Cl, and 13. A compound of formula (VII): or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from and R2 is OCH3; R3 is CH3; R4 is H; R7 is H; and R8 is a C 3-6 Cycloalkyl substituted C 1-6 alkyl.

14. A compound of formula (VIII): or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from and R2 is OCH3; R3 is CH3; R4 is H; R7 is H; and R8 is a C 3-6 Cycloalkyl substituted C 1-6 alkyl.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein: R8 is a C 3-6 Cycloalkyl substituted methyl.

16. A compound of formula (XIII): or a pharmaceutically acceptable salt thereof, the compound being:

17. A compound, or a pharmaceutically acceptable salt thereof, selected from: 5-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-cyclopropyl-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; 5-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-methyl-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; 3((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; 5-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one; 6-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; 6-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-fluoro-4-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; 4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-fluorobenzamide; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-cyclopropyl-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; 6-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one; 5-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(1-hydroxyethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-(4-aminopiperidin-1-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylbenzo[b]thiophen-6-yl)methanone; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-(4-aminopiperidin-1-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylbenzofuran-6-yl)methanone; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylbenzofuran-6-yl)methanone cyclopropylmethyl)-1H-indol-6-yl)isoindolin-1-one; 5-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-methyl-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone; 4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylbenzofuran-2-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)-2-fluorobenzamide; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-methoxypyridin-4-yl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(6-(4-aminopiperidin-1-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylbenzofuran-6-yl)methanone; ((7R)-7-amino-2-azabicyclo[2.2.1]hept-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-indol-2-yl)-3-methylbenzofuran-6-yl)methanone; N-[5-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)pyridin-2-yl]acetamide; (3R,5R)-1-{2-[1-(cyclopropylmethyl)-6-(4-methanesulfonylpiperidin-1-yl)-1H-indol-2-yl]-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-5-fluoropiperidin-3-amine; 3-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-methylphenol; 5-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-N-methylpyridine-2-carboxamide; 4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholin-3-one; (7R)-2-{2-[1-(cyclopropylmethyl)-6-(4-methanesulfonylpiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine; (7R)-2-{2-[1-(cyclopropylmethyl)-6-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl}-1H-indol-2-yl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine; (7R)-2-{2-[1-(Cyclopropylmethyl)-6-(1H-indazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine; 3-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-methylphenol; 1-[4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl]pyrrolidin-2-one; 4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-fluoro-5-methylbenzamide; (7R)-2-{2-[1-(Cyclopropylmethyl)-6-(7-fluoro-1H-indazol-6-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine; Methyl N-[5-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)pyridin-2-yl]carbamate; 4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholin-3-one; 1-[4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]pyrrolidin-2-one; (7R)-2-{2-[1-(cyclopropylmethyl)-6-(1H-indazol-6-yl)-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine; (7R)-2-{2-[1-(cyclopropylmethyl)-6-(1H-indazol-5-yl)-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine; N-[7-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-4-chloro-1-methyl-1H-indazol-3-yl]methanesulfonamide; 1-[2-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl-imidazolidin-2-one; 4-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)-2-chlorobenzamide; (7R)-2-{2-[1-(cyclopropylmethyl)-6-(1H-pyrazol-4-yl)-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine; (7R)-2-{2-[1-(cyclopropylmethyl)-6-(morpholin-4-yl)-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]hept-7-amine; (3R,5R)-1-{2-[1-(cyclopropylmethyl)-6-[4-(pyrrolidine-1-carbonyl)piperidin-1-yl]-1H-indol-2-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-5-fluoropiperidin-3-amine; 3-[1-(2-{6-[(3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)piperidin-4-yl]-1,3-oxazolidin-2-one; 2-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,1-difluoropropan-2-ol (diastereoisomer mixture); 2-(2-{6-[(7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,1,1-trifluoropropan-2-ol; ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(tetrahydro-2H-pyran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxycyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1r,4r)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxycyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(tetrahydrofuran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(tetrahydrofuran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxyethan-1-one; (S)-1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one; 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxyethan-1-one; ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1r,4r)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1r,4r)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; 1-(4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)ethan-1-one; (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)ethan-1-one; (R)-1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one; (R)-1-(4-(2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one; 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)ethan-1-one; 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxyethan-1-one; 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-hydroxyethan-1-one; (R)-1-(4-(2-(6-(3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-hydroxyethan-1-one; 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-ethoxyethan-1-one; ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1R,3S)-3-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1r,4r)-4-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)ethan-1-one; 1-(4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-methoxyethan-1-one; (R)-(3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(tetrahydro-2H-pyran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-(tetrahydrofuran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; (4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)(3-hydroxycyclobutyl)methanone; 4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidine-1-carboxylic acid methyl ester; (2R)-1-(4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)-2-hydroxypropan-1-one; (4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)(thiophen-2-yl)methanone; 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)ethan-1-one; 1-(4-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)piperidin-1-yl)ethan-1-one; 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)-3-methylbutan-1-one; ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-7-(1-(3-hydroxycyclobutane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; (R)-1-(4-(2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one; ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-5-fluoro-7-(1-(tetrahydro-2H-pyran-2-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; 1-(4-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperidin-1-yl)-2-methoxyethan-1-one; ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; 1-(3-(2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)-2-methoxyethan-1-one; ((R)-3-aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1r,4r)-4-hydroxycyclohexane-1-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone; 1-(3-(2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)azetidin-1-yl)ethan-1-one; 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one; (R)-(2-(7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)(3-aminopiperidin-1-yl)methanone; (2-(7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone; (2-(7-(2-(4-amino-1H-pyrazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone; 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one; 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one; 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one; 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one; (S)-5-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one; 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one; (2-(7-(2-(1H-imidazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone; (2-(7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone; (S)-5-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one; 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one; 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one; (2-(7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone; (2-(7-(2-(1H-imidazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone; (R)-(2-(7-(2-(1H-imidazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)(3-aminopiperidin-1-yl)methanone; (R)-(2-(7-(2-(4H-1,2,4-triazol-4-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)(3-aminopiperidin-1-yl)methanone; (2-(7-(2-(4H-1,2,4-triazol-4-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone; 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one; 4-(((2-(6-((3R,5R)-3-amino-5-fluoropiperidine-1-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one; (5R)-5-(((2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one; 4-(((2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one; (5R)-5-(((2-(6-((7S)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one; 4-(((2-(6-((7R)-7-amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one; (R)-(2-(7-(2-(4H-1,2,4-triazol-4-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)(3-aminopiperidin-1-yl)methanone; (2-(7-(2-(1H-imidazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)((3R,5R)-3-amino-5-fluoropiperidin-1-yl)methanone; (R)-(2-(7-(2-(1H-imidazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)(3-aminopiperidin-1-yl)methanone; 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one; 4-(((2-(6-((R)-3-aminopiperidine-1-carbonyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)oxy)methyl)pyrrolidin-2-one; or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

19. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or disorder associated with PAD4 enzyme activity.

20. Use of the composition of claim 18 in the preparation of a medicament for treating a disease or disorder associated with PAD4 enzyme activity.

21. The use according to claim 19 or 20, wherein the disease or the disorder associated with PAD4 enzyme activity is selected from rheumatoid arthritis, Alzheimer's disease, multiple sclerosis, lupus, Parkinson's disease and cancer.

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