HETEROCYCLICAL PAD4 HIBITORS

Description

FIELD OF THE INVENTION

[0001] The invention generally relates to substituted heterocyclic compounds, pharmaceutical compositions comprising these compounds, and these compounds for use in a method of the treatment of a disease or a disorder associated with PAD4 enzyme activity.BACKGROUND OF THE INVENTION

[0002] PAD4 is a member of the peptidylarginine deiminase (PAD) family of enzymes capable of catalysing the citrullination of arginine into citrulline within peptide sequences. PAD4 is responsible for the deimination or citrullination of a variety of proteins in vitro and in vivo, with consequences of diverse functional responses in a variety of diseases (Jones J.E. et al, Curr. Opin. Drug Discov. Devel., 12(5), (2009), 616-627). Examples of exemplar diseases or disorders include rheumatoid arthritis, diseases with neutrophilic contributions to pathogenesis (for example vasculitis, systemic lupus erythematosus, ulcerative colitis) in addition to oncology indications. PAD4 inhibitors also have wider applicability as tools and therapeutics for human diseases and disorders through epigenetic mechanisms.

[0003] Inhibitors of PAD4 have utility against Rheumatoid Arthritis (RA). RA is an autoimmune disease affecting approximately 1% of the population (Wegner N. et al, Immunol. Rev., 233(1), (2010), 34-54). It is characterized by inflammation of articular joints leading to debilitating destruction of bone and cartilage. A weak genetic association between PAD4 polymorphisms and susceptibility to RA has been suggested, albeit inconsistently, in a number of population studies (Kochi Y. et al, Ann. Rheum. Dis., 70, (2011), 512-515). PAD4 (along with family member PAD2) has been detected in synovial tissue where it is responsible for the deimination of a variety of joint proteins. This process is presumed to lead to a break of tolerance to, and initiation of immune responses to, citrullinated substrates such as fibrinogen, vimentin and collagen in RA joints. These anti-citrullinated protein antibodies (ACPA) contribute to disease pathogenesis and may also be used as a diagnostic test for RA (e.g. the commercially available CCP2 or cyclic citrullinated protein 2 test). In addition, increased citrullination may also offer additional direct contributions to disease pathogenesis through its ability to affect directly the function of several joint and inflammatory mediators (e.g. fibrinogen, anti-thrombin, and multiple chemokines). In a smaller subset of RA patients, anti-PAD4 antibodies can be measured and may correlate with a more erosive form of the disease.

[0004] PAD4 inhibitors are also useful for the reduction of pathological neutrophil activity in a variety of diseases. Studies suggest that the process of Neutrophil Extracellular Trap (NET) formation, an innate defense mechanism by which neutrophils are able to immobilize and kill pathogens, is associated with histone citrullination and is deficient in a 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). PAD4 inhibitors may therefore have applicability for diseases where NET formation in tissues contributes to local injury and disease pathology. Such diseases include, but are not limited to, small vessel vasculitis (Kessenbrock K. et al, Nat. Med., 15(6), (2009), 623-625), systemic lupus erythematosus (Hakkim A. et al, Proc. Natl. Acad. Sci. USA, 107(21), (2010), 9813-9818, and Villanueva E. et al, J. Immunol., 187(1), (2011), 538-52), ulcerative colitis (Savchenko A. et al, Pathol. Int., 61(5), (2011), 290-7), cystic fibrosis, asthma (Dworski R. et al, J. Allergy Clin. Immunol., 127(5), (2011), 1260-6), deep vein thrombosis (Fuchs T. et al, Proc. Natl. Acad. Sci. USA, 107(36), (2010), 15880-5), periodontitis (Vitkov L. et al, Ultrastructural Pathol., 34(1), (2010), 25-30), sepsis (Clark S.R. et al, Nat. Med., 13(4), (2007), 463-9), appendicitis (Brinkmann V. et al, Science, 303, (2004), 1532-5), and stroke. In addition, there is evidence that NETs may contribute to pathology in diseases affecting the skin, e.g., in cutaneous lupus erythematosis (Villanueva E. et al, J. Immunol., 187(1), (2011), 538-52) and psoriasis (Lin A.M. et al., J. Immunol., 187(1), (2011), 490-500), so a PAD4 inhibitor may show benefit to tackle NET skin diseases, when administered by a systemic or cutaneous route. PAD4 inhibitors may affect additional functions within neutrophils and have wider applicability to neutrophilic diseases.

[0005] Studies have demonstrated efficacy of tool PAD inhibitors (for example, chloro-amidine) in a number of animal models of disease, including collagen-induced arthritis (Willis V C. et al, J. Immunol., 186(7), (2011), 4396-4404), dextran sulfate sodium (DSS)-induced experimental colitis (Chumanevich A.A. et al, Am. J. Physiol. Gastrointest. Liver Physiol., 300(6), (2011), G929-G938), spinal cord repair (Lange S. et al, Dev. Biol., 355(2), (2011), 205-14), and experimental autoimmune encephalomyelitis (EAE). The DSS colitis report also demonstrates that chloro-amidine drives apoptosis of inflammatory cells both in vitro and in vivo, suggesting that PAD4 inhibitors may be effective more generally in widespread inflammatory diseases.

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

[0007] The aforementioned role of PAD4 in deiminating arginine residues in histones may be indicative of a role for PAD4 in epigenetic regulation of gene expression. PAD4 is the primary PAD family member observed to be resident in the nucleus as well as the cytoplasm. Early evidence that PAD4 may act as a histone demethyliminase as well as a deiminase is inconsistent and unproven. However, it may reduce histone arginine methylation (and hence epigenetic regulation associated with this mark) indirectly via depletion of available arginine residues by conversion to citrulline. PAD4 inhibitors are useful as epigenetic tools or therapeutics for affecting expression of varied target genes in additional disease settings. Through such mechanisms, PAD4 inhibitors may also be effective in controlling citrullination levels in stem cells and may therefore therapeutically affect the pluripotency status and differentiation potential of diverse stem cells including, but not limited to, embryonic stem cells, neural stem cells, haematopoietic stem cells and cancer stem cells. Accordingly, there remains an unmet need to identify and develop PAD4 inhibitors for the treatment of PAD4-mediated diseases or disorders.

[0008] WO 2014 / 015905 discloses 2-(azaindole-2-yl)benzimidazoles as PAD4 inhibitors useful in the treatment of various disorders, for example rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, and psoriasis.SUMMARY OF THE INVENTION

[0009] Accordingly, there are provided compounds of Formula (Ia): or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0010] In another general aspect, there are provided pharmaceutical compositions comprising at least one compound of Formula (Ia), or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0011] In another general aspect, there is provided a compound for use in a method of treating a disease or a disorder associated with PAD4 enzyme activity, the method comprising administering to a subject in need of such treatment, a therapeutically effective amount of at least one compound of Formula (Ia), or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0012] 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 claims.DETAILED DESCRIPTION OF THE INVENTION1. Definitions

[0013] The following are definitions of terms used in this specification. The initial definition provided for a group or term herein applies to that group or term throughout the specification, individually or as part of another group, unless otherwise indicated. Although the invention is described with reference to exemplary embodiments, it should nevertheless be understood that no limitation of the scope of the invention is thereby intended. Numerous alterations and further modifications of the inventive features of the invention can be envisaged by one skilled in the relevant art, and having possession of this disclosure. All such alterations and modifications are to be considered within the scope of the invention as defined in the appended claims.

[0014] The term "C 1-6 alkyl" as used herein refers to and includes straight and branched chain hydrocarbon groups containing 1 to 6 carbon atoms. Typical, non-limiting examples of C 1-6 alkyl include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, and isohexyl.

[0015] The term "alkenyl" as used herein refers to and includes straight or branched chain hydrocarbon groups containing 2 to 20 carbons, which include 1 to 6 double bonds. Typical, non-limiting examples of alkenyl include vinyl, 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, and 4-dodecenyl.

[0016] The term "alkynyl" as used herein refers to and includes straight or branched chain hydrocarbon groups containing 2 to 12 carbon atoms, and at least one carbon to carbon triple bond. Typical, non-limiting examples of alkynyl 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, and 4-decynyl.

[0017] The term "cycloalkyl" as used herein refers to and includes a saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon group containing 1 to 3 rings (for example, monocyclic, bicyclic, or tricyclic), and containing a total of 3 to 20 carbon atoms forming the rings. The cycloalkyl may be optionally substituted. The rings of multi-ring cycloalkyls may exist as fused, bridged and / or joined through one or more spiro union to 1 or 2 aromatic cycloalkyl or heterocyclic rings. Typical, non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, and cycloheptadienyl.

[0018] The terms "heterocyclic", "heterocyclyl" or "heterocyclo" as used herein refers to and includes optionally substituted, saturated, unsaturated or partially unsaturated 3 to 20 member cyclic groups (for example, 3 to 13 member monocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ring systems), which have at least one heteroatom in at least one carbon atom-containing ring. The heteroatom is selected from nitrogen, oxygen and / or sulfur atoms. Each ring of the heterocyclic group may have 1, 2, 3, 4 or 5 heteroatoms, subject to a condition that that at least one ring contains at least one heteroatom. The nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The rings of multi-ring heterocycles may be fused, bridged and / or joined through one or more spiro unions. Typical, non-limiting examples of heterocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl.

[0019] The term "aryl" as used herein refers to and includes aromatic homocyclic (i.e., hydrocarbon) monocyclic, bicyclic or tricyclic aromatic groups containing 6 to 14 carbons in the ring portion, and may optionally include one to three additional rings (either cycloalkyl, heterocyclo or heteroaryl) fused thereto. Typical, non-limiting examples of aryl groups includes phenyl, biphenyl, naphthyl (including 1-naphthyl, and 2-naphthyl), and anthracenyl.

[0020] The above-defined groups may optionally have one or more hydrogen atoms that are attached to a carbon atom substituted with any group known to one of skill in the art. Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.

[0021] The term "subject" as used herein refers to and includes any human or non-human organism that could potentially benefit from treatment with a PAD4 inhibitor. Exemplary subjects include humans and animals.

[0022] The terms "treating" or "treatment" as used herein refer to and include treatment of a disease-state in a subject, for example in a human or animal, and include: (a) inhibiting the disease-state, i.e., arresting it's development; (b) relieving the disease-state, i.e., causing regression of the disease state; and / or (c) preventing the disease-state from occurring in a subject.

[0023] The terms "preventing" or "prevention" as used herein refer to and include preventive treatment (i.e. prophylaxis and / or risk reduction) of a subclinical disease-state in a subject, for example in a human or animal, aimed at reducing the probability of the occurrence of a clinical disease-state. Subjects may be selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population. "Prophylaxis" therapies can be divided into (a) primary prevention, and (b) secondary prevention. Primary prevention is defined as treatment in a subject that has not yet presented with a clinical disease state, whereas secondary prevention is defined as preventing a second occurrence of the same or similar clinical disease state.

[0024] The term "therapeutically effective amount" refers to and includes an amount of a compound or a composition according to the invention that is effective when administered alone or in combination to prevent or treat the disease or disorder associated with PAD4 enzyme activity. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the preventive or therapeutic effect, whether administered in combination, serially, or simultaneously.

[0025] A "pharmaceutically acceptable carrier" refers to media generally accepted in the art for the delivery of biologically active agents to humans and / or animals. Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation, the type and nature of the active agent being formulated, the subject to which the agent-containing composition is to be administered, the intended route of administration of the compound or composition, and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Typical, non-limiting examples of such carriers include diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents, anti-bacterial agents, anti-fungal agents, lubricating agents, dispensing agents, and coating agents. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Allen, L. V., Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0026] Any tautomer, which may exist, is also contemplated herein as a part of the present invention. All stereoisomers of the compound of Formula (Ia), such as those, which may exist due to asymmetric carbons, including enantiomeric forms (which may exist even in the absence of asymmetric carbons, e.g., atropisomers) and diastereomeric forms are contemplated within the scope of this invention. Individual stereoisomers of the compound of Formula (Ia) may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centres in these compounds may have the S or R configuration as defined by the IUPAC 1974 Recommendations. In general, the compounds according to the invention may be described herein without specific stereochemistry for convenience, however all stereoisomeric forms are included within the scope of the invention.

[0027] The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (symbol D or 2< H) and tritium (symbol T or 3< H). For example, a methyl group may be represented by CH 3 or CD 3 . Isotopes of carbon include 13< C and 14< C. Isotopically-labeled compounds of the 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.

[0028] The compound of Formula (Ia) forms salts which are also within the scope of this invention. Reference to a compound of the Formula (Ia) herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, when a compound of Formula (Ia) contains both a basic moiety and an acidic moiety, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable salts include those generally acceptable in the art of pharmaceutical sciences for administration in a subject, including humans and animals. In general, the pharmaceutically acceptable salts are non-toxic and physiologically acceptable salts. Salts of the compounds according to the invention may be formed, for example, by reacting the compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0029] The compounds of Formula (Ia) which contain a basic moiety may 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 acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 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 tosylates, and undecanoates.

[0030] The compounds of Formula (Ia) which contain an acidic moiety may 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 (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)-ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, and lysine. Basic nitrogen-containing groups may be quaternized with agents 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 others.

[0031] The invention encompasses compounds of Formula (Ia), including their stereoisomers, enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts, pharmaceutical compositions comprising these compounds, and these compounds for use in a method of the treatment of diseases or disorders associated with PAD4 enzyme activity.2. Description of Certain Aspects of the Invention

[0032] In one aspect, the invention provides a compound of Formula (Ia): or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: is is selected from X 1 is independently selected from CR 2 and N; X 2 is independently selected from CR 4 and N; X 4 is independently selected from CR 2 and N; provided X 1 and X 4 are not both N; X 5 is independently selected from O and S; X 6 is independently selected from CR 4 , and N; provided 1) X 2 and X 6 are not both N; 2) when X 2 and X 6 are both CR 4 , one of R 4 is H; R 1 is independently selected from and R 2 is independently selected from H, F, Cl, C 1-4 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH, and -OC 1-4 alkyl; R 3 is independently selected from H, F, Cl, CN, -C(=O)OR b , and C 1-3 alkyl optionally substituted with one or more substituents selected from F, Cl, OH, NH 2 , and N 3 ; R 4 is independently selected from H, F, Cl, C 1-5 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH, C 3-6 cycloalkyl, R 7 is independently selected from H, F, and Cl; R 8 is independently selected from H, and C 1-6 alkyl optionally substituted with one or more substituents selected from F, Cl, and C 3-6 cycloalkyl; R b is independently selected from H, C 1-6 alkyl optionally substituted with one or more R e , C 2-6 alkenyl optionally substituted with one or more R e , C 2-6 alkynyl optionally substituted with one or more R e , -(CH 2 ) r -C 3-10 carbocyclyl optionally substituted with one or more R e , and -(CH 2 ) r -heterocyclyl optionally substituted with one or more R e ; R e is independently selected from F, Cl, Br, CN, NH 2 , -NH-C 1-4 alkyl, -N(C 1-4 alkyl) 2 , =O, OH, -OC 1-6 alkyl, -CO 2 H, C 1-6 alkyl optionally substituted with one or more R f , C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) r -C 3-6 cycloalkyl optionally substituted with one or more R f , -(CH 2 ) r -aryl optionally substituted with one or more R f , and -(CH 2 ) r -heterocyclyl optionally substituted with one or more R f ; R f is independently selected from F, Cl, Br, CN, OH, OC 1-5 alkyl, C 1-5 alkyl optionally substituted with OH, C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl, and phenyl; and r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.

[0033] In another aspect, the invention provides a compound of Formulae (IIa)-(XIII): or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are as defined in Formula (Ia).

[0034] In another aspect, the invention provides a compound having Formula (IIa): or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is independently selected from R 2 is independently selected from H, F, Cl, C 1-3 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH, and OC 1-3 alkyl; R 3 is independently selected from H, F, Cl, CH 3 , and CH 2 OH; R 4 is as defined above for Formula (Ia); R 7 is independently selected from H, F, and Cl; and R 8 is independently selected from H, and C 1-6 alkyl optionally substituted with one or more substituents selected from F, Cl, and C 3-6 cycloalkyl.

[0035] In another aspect, the invention provides a compound having Formula (IIIa): or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is independently selected from R 2 is independently selected from H, F, Cl, C 1-3 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH, and OC 1-3 alkyl; R 3 is independently selected from H, F, Cl, and C 1-3 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH; R 4 is as defined above for Formula (Ia); R 7 is independently selected from H, F, and Cl; and R 8 is independently selected from H, and C 1-6 alkyl optionally substituted with one or more substituents selected from F, Cl, and C 3-6 cycloalkyl.

[0036] In another aspect, the invention provides a compound having Formulae (IIa)-(IIIa), or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is independently selected from R 2 is independently selected from H, F, Cl, CH 3 , and OCH 3 ; R 3 is independently selected from H, F, Cl, CH 3 , and CH 2 OH; R 4 is as defined above for Formula (Ia); R 7 is H; and R 8 is C 1-3 alkyl substituted with one C 3-6 cycloalkyl.

[0037] In another aspect, the invention provides a compound having Formula (IVa): or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is independently selected from R 2 is independently selected from H, F, Cl, C 1-3 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH, and OC 1-3 alkyl; R 3 is independently selected from H, F, Cl, and C 1-3 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH; R 4 is as defined above for Formula (Ia); R 7 is independently selected from H, F, and Cl; and R 8 is independently selected from H, and C 1-6 alkyl optionally substituted with one or more substituents selected from F, Cl, and C 3-6 cycloalkyl.

[0038] In another aspect, the invention provides a compound having Formulae (IIa)-(IIIa), or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R 4 is independently selected from and and other variables are as defined in Formulae (IIa)-(IIIa).

[0039] In another aspect, the invention provides a compound having Formula (Va): or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is independently selected from R 2 is independently selected from H, F, Cl, CH 3 , and OCH 3 ; R 3 is independently selected from H, F, Cl, CN, CH 3 , and CH 2 OH; R 4 is as defined above for Formula (Ia); R 7 is independently selected from H, F, and Cl; and R 8 is independently selected from H, and C 1-6 alkyl optionally substituted with one or more substituents selected from F, Cl, and C 3-6 cycloalkyl.

[0040] In another aspect, the invention provides a compound having Formula (Va), or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is independently selected from R 2 is CH 3 ; R 3 is CH 3 ; and R 4 is independently selected from, R 7 is H; and R 8 is C 1-2 alkyl optionally substituted with cyclopropyl.

[0041] In another aspect, the invention provides a compound having Formula (VIa): or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is independently selected from R 3 is independently selected from H, F, and CH 3 ; R 4 is as defined above for Formula (Ia); R 7 is independently selected from H, F, and Cl; and R 8 is independently selected from H, and C 1-6 alkyl optionally substituted with one or more substituents selected from F, Cl, and C 3-6 cycloalkyl.

[0042] In another aspect, the invention provides a compound having Formula (VIa), or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is independently selected from R 3 is CH 3 ; R 4 is independently selected from F, Cl, R 7 is H; and R 8 is C 1-2 alkyl optionally substituted with cyclopropyl.

[0043] In another aspect, the invention provides a compound having Formula (VII): or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is independently selected from R 2 is independently selected from H, F, Cl, CH 3 , and OCH 3 ; R 3 is independently selected from H, F, and CH 3 ;R 4 is as defined above for Formula (Ia); R 7 is independently selected from H, F, and Cl; and R 8 is independently selected from H, and C 1-6 alkyl optionally substituted with one or more substituents selected from F, Cl, and C 3-6 cycloalkyl.

[0044] In another aspect, the invention provides a compound having Formula (VIII): or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is independently selected from R 2 is independently selected from H, F, and OCH 3 ; R 3 is independently selected from H, F, and CH 3 ; R 4 is as defined above for Formula (Ia); R 7 is independently selected from H, F, and Cl; and R 8 is independently selected from H, and C 1-6 alkyl optionally substituted with one or more substituents selected from F, Cl, and C 3-6 cycloalkyl.

[0045] In another aspect, the invention provides a compound having Formula (XIII): or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is independently selected from R 2 is independently selected from H, F, CH 3 , and OCH 3 ; R 3 is independently selected from H, F, and CH 3 ;R 4 is as defined above for Formula (Ia); R 8 is independently selected from H, and C 1-6 alkyl optionally substituted with one or more substituents selected from F, Cl, and C 3-6 cycloalkyl.

[0046] Typical, non-limiting examples of the compounds according to the invention include: ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); 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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); 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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((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); ((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); 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); ((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); ((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); ((3R, SR)-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); 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); ((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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (22); 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); 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); ((7R)-7-Amino-2-azabicyclo[2.2. 1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(cyclopropylmethyl)-6-methyl-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (27); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(6-cyclopropyl-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (28); 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); 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); ((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); ((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); ((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); ((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); ((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); ((3R, SR)-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); ((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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); 3((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); 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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); 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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((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); ((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); ((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); ((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); 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); ((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); 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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (63); 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); 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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); 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); ((7R)-7-Amino-2-azabicyclo[2.2. 1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((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); 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); ((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); 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); 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); 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); ((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); ((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); ((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); 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); 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); ((7R)-7-Amino-2-azabicyclo[2.2. 1]heptan-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); ((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); 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); ((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); 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); 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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((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); ((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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (100); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); ((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); ((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); ((7R)-7-Amino-2-azabicyclo [2.2.1 ]heptan-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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); 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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); 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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyrazin-6-yl)methanone (113); ((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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); (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]heptan-2-yl)methanone (116); (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); 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); 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); 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); 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); [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); [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); 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); (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); 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); 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); 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); 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); 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); (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); (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); (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); 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); (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); 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); 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); 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); 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); [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); 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); 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); 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); 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); 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); [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); 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); 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); [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); 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); (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); 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); 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); (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); 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); 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); 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); 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); 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); 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); (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); (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); 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); (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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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); (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]heptan-7-amine (266); 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); (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]heptan-7-amine (268); 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); (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); 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); 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); 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); (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); 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); (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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); (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); (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); (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); (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); (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); 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); 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); (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]heptan-7-amine (295); (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]heptan-7-amine (296); (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]heptan-7-amine (297); (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]heptan-7-amine (298); (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]heptan-7-amine (299); (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]heptan-7-amine (300); 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); 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); 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); 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); 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); (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]heptan-7-amine (306); 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); 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); (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); (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); (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); 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); 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); 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); 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); 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); 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); (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]heptan-7-amine (318); 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); (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]heptan-7-amine (320); (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); (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); (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); 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); 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); (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]heptan-7-amine (326); (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]heptan-7-amine (327); 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); 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); (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]heptan-7-amine (330); 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); (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]heptan-7-amine (332); (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]heptan-7-amine (333); 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); 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); (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]heptan-7-amine (336); 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); 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); 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); 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); (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]heptan-7-amine (341); 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); 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); [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); (3R)-1-{2-[1'-(Cyclopropylmethyl)-1H,1'H-[5,6'-biindole]-2'-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}piperidin-3-amine (345); 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); 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); 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); (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); (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]heptan-7-amine (350); (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]heptan-7-amine (351); 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); 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); 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); (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); 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); 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); 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); 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); 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); (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); 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); 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); 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); (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); 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); 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); (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); N-[4-(2-{ 6-[(3R, SR)-3-Amino-5-fluoropiperidine-1-carbonyl]-3-methylpyrazolo[1,5-a]pyridin-2-yl}-1-(cyclopropylmethyl)-1H-indol-6-yl)phenyl]methanesulfonamide (369); 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); [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); 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); 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); (3R,5R)-1-{2-[1'-(Cyclopropylmethyl)-1H,1'H-[5,6'-biindole]-2'-yl]-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl} -5-fluoropiperidin-3-amine (374); [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); 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); 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); 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); (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); 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); 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 (Diastereomeric mixture) (381); 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 (Diastereomeric mixture) (382); 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); 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); 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 (Diastereomeric mixture) (385); ((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); ((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); ((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); ((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); ((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); ((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); (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); ((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); ((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); (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); (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); ((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); (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); ((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); ((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); (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); (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); (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); (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); 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); ((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); ((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); ((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); ((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); (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); 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); 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); (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); ((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); ((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); ((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); 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); (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); ((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); (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); ((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); (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); (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); (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); (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); (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); 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); 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); (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); Ethyl 2-(7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridine-6-carboxylate (430); 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); 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); (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); 1-(4-(2-(6-((3R,SR)-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); (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); 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); (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); (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); 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); (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); ((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); (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); 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); ((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); ((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); 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); (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); ((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); ((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); ((3R,5R)-3-amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1R,3 S)-3-hydroxycyclohexane-1-carbonyl)piperidin-4-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (449); ((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); ((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); 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); 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); (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); (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); (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); ((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); ((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); (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); (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); (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); ((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); ((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); (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); (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); ((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); (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); Methyl (R)-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); Methyl 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-carboxylate (469); Methyl 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-carboxylate (470); (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); (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); (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); ((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); (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); 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); 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); 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); (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); (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); 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); 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); (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); ((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); ((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); ((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); ((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); ((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); ((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); ((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); ((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); (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); (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); 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); 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); ((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); (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); (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); (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); (S)-1-(4-(2-(6-((3R,5R)-3-Amino-5-fluoropiperidine-1-carb onyl)-3-methylpyrazolo[1,5-a]pyridin-2-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-7-yl)piperidin-1-yl)-2-methoxypropan-1-one (500); 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); (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); 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); (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); ((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); (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); 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); ((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); ((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); (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); 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); (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); 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); ((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); (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); (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); ((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); 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); ((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); ((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); (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); 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); (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); (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); (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); (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); 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); (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); (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); ((R)-3-Aminopiperidin-1-yl)(2-(1-(cyclopropylmethyl)-7-(1-((1r,4r)-4-hydroxycyc1ohexane-1-carbonyl)azetidin-3-yl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone (530); ((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); ((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); ((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); ((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); (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); (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); ((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); ((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); ((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); (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); (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); (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); (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); ((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); ((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); (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); 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); 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); 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); 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); 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); 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); 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); 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); (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); (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); (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); (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); (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); (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); (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); 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); 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); 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); 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); 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); 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); (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); (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); (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); 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); 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); 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); (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); (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); 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); 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); 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); 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); (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); (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); (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); (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); (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); (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); (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); (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); 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); 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); 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); 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); (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); (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); ((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); (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); (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); (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); (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); (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); (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); 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); 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); 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); (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); 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); 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); (SR)-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); 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); (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); (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); ((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); (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); (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); 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); 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); (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); (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); 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); 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); (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 ((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); or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0047] In one embodiment, the present invention may provide compounds with IC 50 values ≤ 4.000 µM, using the RFMS PAD4 functional assay disclosed herein, preferably, IC 50 values ≤ 1.000 µM, preferably, IC 50 values ≤ 0.500 µM, preferably, IC 50 values ≤ 0.100 µM, more preferably, IC 50 values ≤ 0.050 µM, more preferably, IC 50 values ≤ 0.03 µM, more preferably, IC 50 values ≤ 0.02 µM, even more preferably, IC 50 values ≤ 0.01 µM.

[0048] As defined above and described herein, X 2 is selected from N and CR 4 . In some embodiments, X 2 is N. In some embodiments, X 2 is CR 4 . In certain embodiments, X 2 is selected from those functional groups depicted in the examples below.

[0049] In some embodiments, R 1 is In some embodiments, R 1 is R 1 is selected from

[0050] In some embodiments, R 2 is H. In some embodiments, R 2 is F. In some embodiments, R 2 is C 1-3 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl. In some embodiments, R 2 is -OCH 3 . In some embodiments, R 2 is -OCH 2 CH 3 . In some embodiments, R 2 is -OCH 2 CH 2 CH 3 . In certain embodiments, R 2 is selected from those functional groups depicted in the examples below. R 2 is preferably selected from H, F, Cl, CH 3 , and OCH 3 .

[0051] In some embodiments, R 3 is CH 3 .R 3 is preferably selected from H, F, Cl, CH 3 , and CH 2 OH. In some embodiments, R 4 is H. In some embodiments, R 4 is C 1-3 alkyl. In some embodiments, R 4 is CH 3 . In some embodiments, R 4 is selected from In some embodiments, R 4 is In some embodiments, R 4 is

[0052] R 4 is selected from H, F, Cl, C 1-5 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH, C 3-6 cycloalkyl,

[0053] In some embodiments, R 7 is H. R 7 is selected from H, F, and Cl.

[0054] As defined above and described herein, R 8 is selected from H and C 1-6 alkyl optionally substituted with one or more substitutents selected from F, Cl, and C 3-6 cycloalkyl. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is C 1-2 alkyl substituted with C 3-6 cycloalkyl. In some embodiments, R 8 is methyl. In some embodiments, R 8 is ethyl. In some embodiments, R 8 is cyclopropyl. Preferably, R 8 is - CH 2 -cyclopropyl or -CH 2 -cyclobutyl. In certain embodiments, R 8 is selected from those functional groups depicted in the examples below.

[0055] As defined above and described herein, R b is independently selected from H, C 1-6 alkyl optionally substituted with one or more R e , C 2-6 alkenyl optionally substituted with one or more R e , C 2-6 alkynyl optionally substituted with one or more R e , -(CH 2 ) r -C 3-10 carbocyclyl optionally substituted with one or more R e , and -(CH 2 ) r -heterocyclyl optionally substituted with one or more R e .

[0056] As defined above and described herein, R e is independently selected from F, Cl, Br, CN, NH 2 , -NH-C 1-4 alkyl, -N(C 1-4 alkyl) 2 , =O, OH, -OC 1-6 alkyl, -CO 2 H, C 1-6 alkyl optionally substituted with one or more R f , C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) r -C 3-6 cycloalkyl optionally substituted with one or more R f , -(CH 2 ) r -aryl optionally substituted with one or more R f , and -(CH 2 ) r -heterocyclyl optionally substituted with one or more R f .

[0057] As defined above and described herein, R f is independently selected from F, Cl, Br, CN, OH, C 1-5 alkyl optionally substituted with OH, C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl, and phenyl.

[0058] As defined above and described herein, r is 0-4. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4.

[0059] In some embodiments, the compound of Formula (Ia) is selected from examples depicted below. 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 therapy. In some embodiments, the present invention provides any compound described above and herein in isolated form. In some embodiments, the present invention provides the compounds according to any one of claims presented below.3. Pharmaceutical Compositions

[0060] In another aspect, the invention provides a composition comprising a compound of this invention or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of a compound in the compositions of this invention is such that it is effective to measurably inhibit PAD4 in a biological sample or in a patient. A composition of this invention may be formulated for administration to a patient in need of such composition. A composition of this invention may be formulated for oral administration to a patient.

[0061] The term "subject," as used herein, is used interchangeably with the term "patient" and means an animal, preferably a mammal.A subject or patient may be a human. A subject (or patient) may be a veterinary subject (or patient).A veterinary subject (or patient) may be a canine, a feline, or an equine subject.

[0062] 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 with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, 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 carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0063] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. The compositions may be administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0064] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0065] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0066] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These 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 therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0067] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.

[0068] Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components 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.

[0069] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0070] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0071] Preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. Pharmaceutically acceptable compositions of this invention may be administered without food.Pharmaceutically acceptable compositions of this invention can also be administered with food.

[0072] Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, as required. The compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0073] 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 compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0074] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0075] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0076] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0077] 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 a suppository wax 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.

[0078] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, 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.

[0079] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols. The 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 the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols.

[0080] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0081] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0082] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. 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.

[0083] A compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. Exemplary of such other therapeutic agents include corticosteroids, rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs (CSAIDs), Interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyspergualin (DSG); non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf); cytotoxic drugs such as azathiprine and cyclophosphamide; TNF-α inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof. A compound of the current invention can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.

[0084] Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

[0085] As used herein, the term "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention may provide a single unit dosage form comprising a compound of the current invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0086] The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of an inventive compound can be administered.

[0087] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent.

[0088] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0089] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease or disorder being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.4. Uses of Compounds

[0090] Compounds and compositions described herein are generally useful for the inhibition of PAD4.

[0091] The activity of a compound utilized in this invention as an inhibitor of PAD4, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine the inhibition of PAD4. Detailed conditions for assaying a compound utilized in this invention as an inhibitor of PAD4 are set forth in the Examples below. A provided compound may inhibit PAD4 selectively as compared to PAD2.

[0092] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0093] Provided compounds are inhibitors of PAD4 and are therefore useful for treating one or more diseases or disorders associated with PAD4 enzyme activity. Thus, the compounds of the present invention may be used in a method for treating a disease or a disorder associated with PAD4 enzyme activity, comprising the step of administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof.

[0094] A disease or a disorder associated with PAD4 enzyme activity may be a disease, condition, or disorder mediated by inappropriate PAD4 activity. A disease or a disorder associated with PAD4 enzyme activity may be selected from the group consisting of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, and psoriasis. The disease or a disorder associated with PAD4 enzyme activity may be rheumatoid arthritis. The disease or a disorder associated with PAD4 enzyme activity may be systemic lupus.The disease or a disorder associated with PAD4 enzyme activity may be vasculitis. The disease or a disorder associated with PAD4 enzyme activity may be cutaneous lupus erythematosus. The disease or a disorder associated with PAD4 enzyme activity may be psoriasis.

[0095] Compounds of the present invention may be used in a method of treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis, which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0096] A compound of the present invention may be used in a method of treatment of rheumatoid arthritis, which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. A compound of the present invention may be used in a method of treatment of systemic lupus, which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. A compound of the present invention may be used in a method of treatment of vasculitis, which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. A compound of the present invention may be used in a method of treatment of cutaneous lupus erythematosus, which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. A compound of the present inventoion may be used in a method of treatment of psoriasis, which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0097] A disease or a disorder associated with PAD4 enzyme activity may be 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, ageing, AIDS, alcoholic hepatitis, alcoholic liver disease, allergen induced asthma, allergic bronchopulmonary, aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotropic lateral sclerosis, weight loss, angina pectoris, angioedema, anhidrotic ecodermal dysplasia-ID, ankylosing spondylitis, anterior segment, inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, Bechet's disease, Bechet's syndrome, Bells Palsey, berylliosis, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysm, chemical irritant-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 disease, corneal ulcer, crohn's disease, cryopyrin-associated periodic syndromes, cyrptococcosis, cystic fibrosis, deficiency of the interleukin-1-receptor antagonist (DIRA), dermatitis, dermatitis endotoxemia, dermatomyositis, diffuse intrinsic pontine glioma, endometriosis, endotoxemia, epicondylitis, erythroblastopenia, familial amyloidotic polyneuropathy, familial cold urticarial, familial Mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, glomerular nephritis, gout, gouty arthritis, graft-versus-host disease, gut diseases, head injury, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Scholein purpura, hepatitis, hereditary periodic fever syndrome, herpes zoster and simplex, HIV-1, Hodgkin's disease, Huntington's disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulinemia D with recurrent fever (HIDS), hypoplastic and other anemias, hypoplastic anemia, idiopathic thrombocytopenic purpura, incontinentia pigmenti, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, iritis, irritant-induced inflammation, ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, kidney injury caused by parasitic infections, kidney injury caused by parasitic infections, kidney transplant rejection prophylaxis, leptospiriosis, leukemia, Loeffler's syndrome, lung injury, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria deafness amyloidosis), multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis, myocarditis, mycosis fungoides, myelodysplastic syndrome, myositis, nasal sinusitis, necrotizing enterocolitis, neonatal onset multisystem inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological diseases, non-allergen induced asthma, obesity, ocular allergy, optic neuritis, organ transplant, osteoarthritis, otitis media, Paget's disease, pain, pancreatitis, Parkinson's disease, pemphigus, pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pertussis, pharyngitis and adenitis (PFAPA syndrome), plant irritant-induced inflammation, pneumonia, pneumonitis, pneumosysts infection, poison ivy / urushiol oil-induced inflammation, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyositis, psoriasis, psychosocial stress diseases, pulmonary disease, pulmonary hypertension, pulmonary fibrosis, pyoderma gangrenosum, pyogenic sterile arthritis, renal disease, retinal disease, rheumatic carditis, rheumatic disease, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell, sickle cell anemia, silica-induced disease, Sjogren's syndrome, skin diseases, sleep apnea, solid tumors, spinal cord injury, Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplant, TNF receptor associated periodic syndrome (TRAPS), toxoplasmosis, transplant, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticarial, uveitis, Wegener's granulomatosis, interstitial lung disease, psoriatic arthritis, juvenile idiopathic arthritis, Sjögren's syndrome, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, antiphospholipid antibody syndrome, sepsis, deep vein thrombosis, fibrosis, Alzheimer's, scleroderma and CREST syndrome.

[0098] In one embodiment, the invention provides a compound, or a pharmaceutically acceptable salt thereof, for use in therapy.A compound of the present invention, or a pharmaceutically acceptable salt thereof, may be used in a method of treatment of a disease or a disorder mediated by inappropriate PAD4 activity. A compound of the present invention, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, may be used in a method of treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis. A compound of the present invention, the invention provides a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, may be used in a method of treatment of rheumatoid arthritis. A compound of the present invention, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, may be used in a method of treatment of systemic lupus.A compound of the present invention, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, may be used in a method of treatment of vasculitis. A compound of the present invention, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, may be used in a method of treatment of cutaneous lupus erythematosus.A compound of the present invention, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, may be used in a method of treatment of psoriasis. A compound of the present invention, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, may be used in the manufacture of a medicament for use in the treatment of a disorder mediated by inappropriate PAD4 activity.A compound of the present invention, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, may be used in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis. A compound of the present invention, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, may be used in the manufacture of a medicament for use in the treatment of rheumatoid arthritis. A compound of the present invention, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, may be used in the manufacture of a medicament for use in the treatment of systemic lupus.A compound of the present invention, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, may be used in the manufacture of a medicament for use in the treatment of vasculitis. A compound of the present invention, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, may be used in the manufacture of a medicament for use in the treatment of cutaneous lupus erythematosus.A compound of the present invention, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, may be used in the manufacture of a medicament for use in the treatment of psoriasis. A pharmaceutical composition of the pesent invention may be used for the treatment or prophylaxis of a disease or a disorder mediated by inappropriate PAD4 activity comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition of the pesent invention may be used for the treatment or prophylaxis of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis, comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition of the pesent invention may be used for the treatment or prophylaxis of rheumatoid arthritis comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition of the pesent invention may be used for the treatment or prophylaxis of systemic lupus comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition of the pesent invention may be used for the treatment or prophylaxis of vasculitis comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. or the treatment or prophylaxis of cutaneous lupus erythematosus comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition of the pesent invention may be used for the treatment or prophylaxis of psoriasis comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0099] All features of each of the aspects of the invention apply to all other aspects mutatis mutandis. In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.5. Examples

[0100] The following Examples have been prepared, isolated and characterized using the methods disclosed herein. The following examples demonstrate a partial scope of the invention and are not meant to be limiting of the scope of the invention.

[0101] Details of various HPLC / LC-MS methods used in the analysis of compounds and intermediates is provided below.

[0102] Method A: SUNFIRE C18 (4.6×150) mm, 3.5 µm column; flow rate 1 ml / min; gradient time 15 min; 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).

[0103] Method B: X-Bridge Phenyl (4.6×150) mm, 3.5 µm column; flow rate 1 ml / min; gradient time 15 min;% 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).

[0104] Method C: Kinetex EVO C18 (4.6×100) mm, 2.6 µm, buffer: 0.05% TFA in water, mobile phase C: buffer: ACN (95:5), mobile phase D: ACN: buffer (95:5).

[0105] Method D: Kinetex Biphenyl (4.6× 100) mm, 2.6 µm, buffer: 0.05% TFA in water, mobile phase C: buffer: ACN (95:5), mobile phase D: ACN: buffer (95:5).

[0106] Method E: XBridge BEH XP C18 (50×2.1) mm, 2.5µm, Time (min): 0-3% B: 0-100 buffer A: 95% water: 5% ACN; 10 mM ammonium acetate (NH 4 OAc) B: 5% water: 95% ACN; 10 mM NH 4 OAc, flow: 1.1 ml / min, temperature: 50°C.

[0107] Method F: XBridge BEH XP C18 (50×2.1) mm, 2.5µm, time (min): 0-3%, B: 0-100, A: 95% water: 5% ACN; 0.1% TFA, B: 5% water: 95% ACN; 0.1%TFA, flow: 1.1 ml / min, temperature: 50°C.

[0108] Method G: ACQUITY UPLC ®< BEH C18 (3×50) mm, 1.7µm, buffer: 10 mM NH 4 OAc, mobile phase A: buffer: ACN (95:5), mobile phase B: buffer: ACN (5:95), flow:0.7ml / min, method: 0 min-20% B, 20% to 100% B 2 min, 2 to 2.3min-100%.

[0109] Method H: Kinetex XB C18 (75×3) mm, 2.6µm, mobile phase A: 10 mM NH 4 OAc in water, water: ACN (98:02), mobile phase B: 10 mM NH 4 OAc in water: ACN (02:98), gradient: 20-100%B over 4 min, flow: 1.0ml / min.

[0110] Method I: ACQUITY UPLC ®< BEH C18 (3×50) mm, 1.7µm, buffer: 0.05% TFA in water, mobile phase A: buffer: ACN (95:5), mobile phase B: ACN: buffer (95:5).

[0111] Method J: Column: HALO C18, 3x30 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).

[0112] 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 in 0.1 min; Detection: MS and UV (254 nm).

[0113] 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% by weight of 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 fitted with a 0.45 µm nylon membrane (VWR # 28145-489) into a clean vial, and dried using centrifugal evaporation to afford the purified sample.General synthetic procedures:Intermediate 11-Amino-3-methoxy-5-(methoxycarbonyl)pyridin-1-ium 2,4-dinitrophenolate

[0114]

[0115] 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 afford 1-amino-3-methoxy-5-(methoxycarbonyl)pyridin-1-ium (10 g, 130%) as yellowish brown solid, which was used in the next step without further purification. Liquid chromatography-mass spectrometry (LC-MS) m / z: 183.1 [M+H] +< .Intermediate 2tert-Butyl-3-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)propiolate

[0116]

[0117] 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 celite bed. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified using a silica gel column (40 g, Redisep ®< SiO 2 column, eluting with 20% ethyl acetate (EtOAc) in hexane) to afford the title compound (1.2 g, 93%) as a brown liquid. LC-MS m / z: 297.1 [M+H] +< . 1< H NMR (300 MHz, chloroform-d) δ ppm: 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).Intermediate 36-Chloro-1-(cyclopropylmethyl)-2-iodo-1H-pyrrolo[2,3-b]pyridine

[0118]

[0119] 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, followed by 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 obtain a crude product, which was purified using a silica gel column (80 g, Redisep ®< Silica column, 0-50% EtOAc in hexane as an eluent) to afford the title compound (8 g, 67%) as yellow solid. 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).Intermediate 4tert-Butyl-3-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)propiolate

[0120]

[0121] tert-Butyl propiolate (1.669 g, 13.23 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.422 g, 0.601 mmol) were added 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). The reaction mixture was stirred at 50°C for 1 hour, and filtered through a celite bed. The filtrate was concentrated under reduced pressure to obtain a crude compound, which was purified using a silica gel column (40 g, Redisep ®< SiO 2 column, eluting with 20% EtOAc in hexane) to afford the title compound (2.5 g, 63%) as yellow liquid. LC-MS m / z: 331.1 [M+H] +< .Intermediate 56-Bromo-1-(cyclopropylmethyl)-2-ethynyl-1H-indole

[0122]

[0123] Potassium carbonate (K 2 CO 3 , 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% solution in acetonitrile) in methanol (MeOH, 50 ml), followed by the addition of 6-bromo-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (7.5g, 27.0 mmol) at 0°C. The reaction mixture was allowed to warm to a room temperature, stirred for 6 hours, and concentrated under vacuum to afford a crude residue, which was diluted with water and extracted with EtOAc (2×100 ml). The combined organic layers were dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified using a silica gel column (40 g, Redisep ®< SiO 2 column, eluting with 0-5% EtOAc in hexane) to afford the title compound (6.3g, 85%) as a brown liquid. LC-MS m / z: 276.1 [M+2H] +< .Intermediate 6tert-Butyl-3-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)propiolate

[0124]

[0125] 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, 6.3g, 22.98 mmol) in THF (10 ml) at 0°C, and the reaction mixture was stirred for 30 min, followed by the addition of Boc 2 O (5.34 ml, 22.98 mmol) slowly. 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 Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified using a silica gel column (80 g, Redisep ®< Silica column, 0-5% EtOAc in hexane as an eluent) to afford the title compound (6.2 g, 72%). LC-MS m / z: 318.0 [M-isobutene+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 7.94 (s, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.26 (dd, J=1.5, 8.5 Hz, 1H), 7.21 (s, 1H), 4.17 (d, J=7.0 Hz, 2H), 1.51 (s, 9H), 1.27-1.18 (m, 1H), 0.52-0.40 (m, 4H).Intermediate 71-(Cyclopropylmethyl)-2-(trimethylstannyl)-1H-pyrrolo[2,3-b]pyridine

[0126]

[0127] 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 min, 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 celite bed, and the filtrate was concentrated to afford a crude product (250 mg), which was used in the next steps without further purification. LC-MS m / z: 337 [M+H] +< .Intermediate 81-Amino-3-(ethoxycarbonyl)pyridin-1-ium 2,4-dinitrophenolate

[0128]

[0129] Intermediate 8 was prepared following a procedure similar to the preparation of Intermediate 1 (10 g, 28.5mmol, 100%). LC-MS m / z: 168 [M+H] +< .Intermediate 91-Amino-3-fluoro-5-(methoxycarbonyl)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate

[0130]

[0131] O-(mesitylsulfonyl)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 afford 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] +< .Intermediate 101-(Cyclopropylmethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

[0132]

[0133] sec-Butyllithium (16.68 ml, 23.36 mmol) was added drop wise to a stirred solution of 1-(cyclopropylmethyl)-1H-indole (2 g, 11.68 mmol) in THF (20 ml) under argon atmosphere at -78°C. The reaction mixture was stirred further for 30 min, followed by 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 a room temperature for 2 hours, quenched with drop wise 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 column (EtOAc in hexane), and the purified product was isolated at 15% EtOAc in hexane. Required fractions were collected and volatiles were evaporated to dryness under reduced pressure to afford the title compound (2 g, 58%). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 0.32-0.44 (m, 4 H), 1.16-1.34 (m, 13 H), 4.32 (d, J=6.85 Hz, 2 H), 6.94-7.05 (m, 2 H), 7.16-7.25 (m, 1 H), 7.51-7.60 (m, 2 H).Intermediate 111-(Cyclopropylmethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine

[0134]

[0135] Intermediate 11 was prepared following a procedure similar to the preparation of Intermediate 10 (1.3 g, 31%). LC-MS (ESI) m / z: 300.3 [M+H] +< .Intermediate 126-Bromo-1-(cyclopropylmethyl)-2-iodo-1H-indole

[0136]

[0137] Sodium hydride (NaH, 1.372 g, 34.3 mmol) was added lot wise 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 drop wise the addition of (bromomethyl)-cyclopropane (2.498 ml, 25.7 mmol). The reaction mixture was stirred at a 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 sulphate, filtered, and the filtrate was evaporated under reduced pressure. The crude product thus obtained was purified using a silica gel column (24g, Redisep ®< SiO 2 column, eluting with 10% EtOAc in n-hexane) to afford the title compound (5g, 78%). LC-MS m / z: 377 [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 7.83 (s, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.14 (dd, J=1.8, 8.5 Hz, 1H), 6.82 (s, 1H), 4.13 (d, J=6.8 Hz, 2H), 1.31-1.13 (m, 1H), 0.51-0.41 (m, 4H).Intermediate 131-Amino-3-chloro-5-(methoxycarbonyl)pyridin-1-ium-2,4,6-trimethylbenzenesulfonate

[0138]

[0139] O-(mesitylsulfonyl)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 a room temperature for 2 hours, and evaporated under reduced pressure to afford 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] +< .Intermediate 14Ethyl 6-bromo-1-(cyclopropylmethyl)-1H-indole-2-carboxylate

[0140]

[0141] Potassium carbonate (10.3 g, 74.6 mmol) was added to a stirred solution of ethyl 6-bromo-1H-indole-2-carboxylate (10g, 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 afford 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] +< .Intermediate 15(6-Bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol

[0142]

[0143] LiBH 4 (15.52 ml, 62.1 mmol, 4 M in THF) was added to a stirred solution of Intermediate 14 (10g, 31 mmol) in THF (50 ml) at 0°C. The reaction mixture was allowed to warm to a room temperature over 1 hour, stirred for 16 hours, cooled to 0°C and additional amount of LiBH 4 (15.52 ml, 62.1 mmol, 4 M in THF) was added dropwise. The reaction mixture was stirred for 6 hours at a room temperature, cooled to 0°C, quenched by slow addition of saturated ammonium chloride solution (need to add carefully, sudden evolution of gas was noticed), stirred for ~ 45 minutes, and extracted with ethyl acetate (4×100 ml). The organic layers were separated, dried over Na 2 SO 4 , filtered and concentrated to obtain a crude product, which was further purified using a silica gel column (0-30% ethyl acetate / petether) to afford 6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol (8.5g, 98%). LC-MS m / z: 280.1 [M+H] +< .Intermediate 166-Bromo-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde

[0144]

[0145] Manganese dioxide (10.3 g, 119 mmol) was added to a stirred solution of Intermediate 15 (8.3g, 29.6 mmol) in THF (50 ml). The reaction mixture was stirred at 45°C for 2 hours, and filtered through a celite bed. The filtrate was concentrated in vacuo to obtain 6-bromo-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (7.6g, 92%) as a brown syrup, which was used further without purification. LC-MS m / z: 278.1 [M+H] +< .Intermediate 17(E)-6-Bromo-1-(cyclopropylmethyl)-2-(2-nitroprop-1-en-1-yl)-1H-indole

[0146]

[0147] 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 (5ml), and extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum to afford (E)-6-bromo-1-(cyclopropylmethyl)-2-(2-nitroprop-1-en-1-yl)-1H-indole as yellow liquid (420 mg), which was used in the next step without purification. LC-MS retention time: 1.26 min., m / z =335.1 [M+H] +< Intermediate 18Ethyl 2-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methylpyrazolo[1,5-a]pyridine-6-carboxylate

[0148]

[0149] 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 vacuum to obtain a crude product, which was purified using a silica gel column (0-5% methanol in dichloromethane) to afford 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 (400 MHz, DMSO-d 6 ) δ ppm: 9.19 (s, 1H), 7.90 (s, 1H), 7.83 (d, J=9.5 Hz, 1H), 7.62-7.58 (m, 2H), 7.24-7.20 (m, 1H), 6.91 (s, 1H), 4.50 (d, J=7.0 Hz, 2H), 4.36 (q, J=7.0 Hz, 2H), 2.42 (s, 3H), 1.36 (t, J=7.0 Hz, 3H), 1.11 (m, 1H), 0.32-0.26 (m, 2H), 0.18-0.13 (m, 2H).Intermediate 19Ethyl 2-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carboxylate

[0150]

[0151] Intermediate 19 was prepared following a procedure similar to the preparation of Intermediate 18 using appropriate reactants. LC-MS retention time: 1.76 min, m / z: 468.2 [M+H] (Method G). 1< H 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).Intermediate 206-Chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine

[0152]

[0153] Sodium hydride in mineral oil (60% w / w, 1.31 g, 32.8 mmol) was added portion wise to a stirred solution of 6-chloro-1H-pyrrolo[2,3-b]pyridine (5g, 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 a 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 obtain a crude product, which was purified using a silica gel column (0-5% ethyl acetate / pet ether) to afford 6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine (6.5g, 96%). LC-MS retention time: 1.85 min, m / z: 207.0 [M+H] (Method G).Intermediate 216-Chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde

[0154]

[0155] 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, followed by the addition of DMF (2 ml, 25.8 mmol). The reaction mixture was allowed to warm to -20°C, then to a room temperature, stirred for 12 hours, cooled to -10°C, and quenched by addition of saturated ammonium chloride solution. The reaction mixture was diluted with water (100 ml) and extracted with ethylacetate (3×100 ml). The combined organic layers were dried over sodium sulphate, filtered and the filtrate was concentrated in vacuo to obtain a crude product, which was purified using a silica gel column (0 to 15% ethyl acetate / pet ether) to afford 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).Intermediate 22(E)-6-Chloro-1-(cyclopropylmethyl)-2-(2-nitroprop-1-en-1-yl)-1H-pyrrolo[2,3-b]pyridine

[0156]

[0157] Intermediate 22 was prepared following a procedure similar to the preparation of Intermediate 17 using Intermediate 21. LC-MS retention time: 1.17 min, m / z: 292.2 [M+H] (Method G).Intermediate 23Ethyl 2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridine-6-carboxylate

[0158]

[0159] Intermediate 23 was prepared following a procedure similar to the preparation of Intermediate 18 using Intermediate 22 and Intermediate 8. LC-MS retention time: 1.66 min, m / z: 409.1 [M+H] (Method G).Intermediate 24Methyl 2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-chloro-3-methylpyrazolo[1,5-a]pyridine-6-carboxylate

[0160]

[0161] Intermediate 24 was prepared as a gummy liquid following a procedure similar to the preparation of Intermediate 18 using Intermediate 13 and Intermediate 22. LC-MS (ES): m / z : 429.1 [M+H] +< .Intermediate 25Ethyl 7-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-2-carboxylate

[0162]

[0163] K 2 CO 3 (15.46 g, 112 mmol) and PdCl 2 (dppf).CH 2 Cl 2 (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, stirred at 100°C for 3 hours thereafter, filtered through a celite bed, and the celite bed was thoroughly washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was purified using a silica gel column (0-30% ethyl acetate in pet ether) to afford the title compound (11.3 g, 82%) as a gummy liquid. LC-MS m / z: 369.4 [M-H] +< . 1H NMR (300 MHz, DMSO-d 6 ) δ ppm: 11.43 (s, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.21 (d, J=4.0 Hz, 1H), 7.24-7.04 (m, 2H), 5.96 (br, s, 1H), 4.34 (q, J=7.1 Hz, 2H), 4.08-3.99 (m, 2H), 3.62 (t, J=5.7 Hz, 2H), 1.51-1.45 (m, 2H), 1.46 (s, 9H), 1.34 (t, J=7.2 Hz, 3H).Intermediate 26Ethyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-indole-2-carboxylate

[0164]

[0165] 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 H 2 atmosphere for 4 hours. The reaction mixture was filtered through a celite bed, and the filtrate was concentrated under reduced pressure to obtain ethyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-indole-2-carboxylate (4.95 g, 98%). LC-MS m / z: 371.4 [M-H] +< . 1< H NMR (300 MHz, DMSO-d 6 ) δ ppm: 11.84 (s, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.21-7.01 (m, 3H), 4.36 (q, J=7.1 Hz, 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=7.2 Hz, 3H).Intermediate 27Ethyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate

[0166]

[0167] K 2 CO 3 (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 a 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 sulphate, and the volatiles were evaporated under reduced pressure to obtain a crude product, which was purified using a silica gel column (0-20% ethyl acetate in pet ether) to afford 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] +< .Intermediate 28tert-Butyl 4-(1-(cyclopropylmethyl)-2-(hydroxymethyl)-1H-indol-7-yl)piperidine-1-carboxylate

[0168]

[0169] LiBH 4 in tetrahydrofuran (10.08 ml, 40.3 mmol) 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 a room temperature, stirred for 48 hours, quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (4×50 ml). The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulphate, and evaporated under reduced pressure to obtain a crude product, which was purified using a silica gel column (0-70% ethyl acetate in pet ether) to afford tert-butyl 4-(1-(cyclopropylmethyl)-2-(hydroxymethyl)-1H-indol-7-yl)piperidine-1-carboxylate (3.7 g, 95%) as a gummy liquid. LC-MS m / z: 385.4 [M+H] +< . 1< H NMR (300 MHz, DMSO-d 6 ) δ ppm: 7.33 (d, J=6.8 Hz, 1H), 7.03-6.90 (m, 2H), 6.38 (s, 1H), 5.24 (br, t, 1H), 4.60 (s, 2H), 4.30 (d, J=5.3 Hz, 2H), 4.22-3.98 (m, 2H), 3.59-3.38 (m, 1H), 3.02-2.74 (m, 2H), 1.88-1.80 (m, 2H), 1.74-1.50 (m, 2H), 1.43 (s, 9 H), 1.19-1.01 (m, 1H), 0.55-0.37 (m, 2H), 0.36-0.19 (m, 2H).Intermediate 29tert-Butyl 4-(1-(cyclopropylmethyl)-2-formyl-1H-indol-7-yl)piperidine-1-carboxylate

[0170]

[0171] Manganese dioxide (9.04 g, 104 mmol) was added to a stirred solution of Intermediate 28 (4 g, 10.40 mmol) in tetrahydrofuran (60 ml). The reaction mixture was heated to 40°C, stirred for 2 hours, filtered through a celite bed, and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(1-(cyclopropylmethyl)-2-formyl-1H-indol-7-yl)piperidine-1-carboxylate (3.8 g, 96%). LC-MS m / z: 383.4 [M+H] +< . 1< H NMR (400 MHz, chloroform-d) δ ppm: 9.84 (s, 1H), 7.63 (dd, J=1.3, 7.8 Hz, 1H), 7.42-7.33 (m, 1H), 7.30 (s, 1H), 7.32 (s, 1H), 7.18 (t, J=7.6 Hz, 1H), 5.32 (s, 1H), 4.83 (d, J=6.0 Hz, 2H), 4.47-4.23 (m, 2H), 3.81-3.72 (m, 1H), 3.64-3.48 (m, 1H), 2.93 (br, t, J=12.3 Hz, 2H), 2.01-1.95 (m, 2H), 1.84-1.78 (m, 2H), 1.52 (s, 9H), 1.18-1.08 (m, 1H), 0.50-0.42 (m, 2H), 0.42-0.35 (m, 2H).Intermediate 30tert-Butyl (E)-4-(1-(cyclopropylmethyl)-2-(2-nitroprop-1-en-1-yl)-1H-indol-7-yl)piperidine-1-carboxylate

[0172]

[0173] Ammonium acetate (0.937 g, 12.16 mmol) was added to a stirred solution of Intermediate 29 (3.1 g, 8.10 mmol) in nitroethane (20 ml, 280 mmol). The reaction mixture was heated to 80°C, stirred for 2 hours, diluted with water and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water and brine solution, dried over anhydrous sodium sulphate, and evaporated under reduced pressure to obtain tert-butyl (E)-4-(1-(cyclopropylmethyl)-2-(2-nitroprop-1-en-1-yl)-1H-indol-7-yl)piperidine-1-carboxylate (3.5 g, 98%). LC-MS m / z: 440.4 [M+H] +< . 1< H NMR (300 MHz, chloroform-d) δ ppm: 8.23 (s, 1H), 7.53 (d, J=6.80 Hz, 1H), 7.07-7.24 (m, 2H), 6.89 (s, 1H), 4.37 (br, s, 1H), 4.33 (br, d, J=5.3 Hz, 2H), 3.46-3.59 (m, 1H), 2.78-2.98 (m, 2H), 2.59 (s, 3H), 2.00-1.90 (m, 2H), 1.86-1.77 (m, 1H), 1.53-1.63 (m, 9H), 1.22-1.32 (m, 1H), 1.07-1.21 (m, 1H), 0.83 (br, d, J=2.27 Hz, 1H), 0.53-0.62 (m, 2H), 0.31 (q, J=5.16 Hz, 2H).Intermediate 31Ethyl 7-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1H-indole-2-carboxylate

[0174]

[0175] tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5.40 g, 17.48 mmol) and potassium carbonate (6.04 g, 43.7 mmol) were added to a stirred solution of ethyl 7-bromo-5-fluoro-1H-indole-2-carboxylate (5 g, 17.48 mmol) in 1,4-dioxane (45 ml) and water (5 ml). The reaction mixture was degassed with nitrogen for 2 min, followed by addition of PdCl 2 (dppf) (1.279 g, 1.748 mmol). The reaction mixture was degassed for additional 2 min, heated to 100°C for 3 hours, filtered through a celite bed, and the celite bed was washed with ethyl acetate (300 ml). The combined filtrates were concentrated under reduced pressure to obtain a crude product, which was purified using a silica gel column (0-30% ethyl acetate in hexane) to afford ethyl 7-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1H-indole-2-carboxylate (5.7 g, 84%). LC-MS m / z: 387.5 [M-H] +< . 1< H NMR (300 MHz, chloroform-d) δ ppm: 8.92 (br, s, 1H), 7.25-7.20 (m, 1H), 7.18 (d, J=2.2 Hz, 1H), 6.95 (dd, J=2.3, 10.2 Hz, 1H), 6.12 (br, s, 1H), 4.42 (q, J=7.2 Hz, 2H), 4.16 (br, d, J=3.0 Hz, 2H), 3.71 (t, J=5.5 Hz, 2H), 2.63-2.42 (m, 2H), 1.53 (s, 9H), 1.42 (t, J=7.2 Hz, 3H).Intermediate 32Ethyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-fluoro-1H-indole-2-carboxylate

[0176]

[0177] Pd / C (3.29 g, 15.45 mmol) was added to a solution of Intermediate 31 (6.0 g, 15.45 mmol) in methanol (60 ml) purged with nitrogen for 2 min. The reaction mixture was stirred under hydrogen atmosphere at 1 atmospheric pressure for 3 hours, filtered through a celite bed, and washed with ethyl acetate (300 ml). The combined organic layers were concentrated under reduced pressure to obtain ethyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-fluoro-1H-indole-2-carboxylate (5.5 g, 91%). LC-MS m / z: 389.2 [M-H] +< . 1< H NMR (300 MHz, DMSO-d 6 ) δ ppm: 12.00 (s, 1H), 7.25 (dd, J=2.3, 9.1 Hz, 1H), 7.15 (d, J=1.9 Hz, 1H), 7.00 (dd, J=2.5, 10.8 Hz, 1H), 4.36 (q, J=7.2 Hz, 2H), 4.11 (br d, J=12.5 Hz, 2H), 3.52 (br s, 1H), 3.34 (s, 1H), 3.07-2.74 (m, 2H), 1.81 (br d, J=11.7 Hz, 2H), 1.62-1.50 (m, 1H), 1.43 (s, 9H), 1.34 (t, J=7.0 Hz, 3H).Intermediate 33Ethyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indole-2-carboxylate

[0178]

[0179] Cesium carbonate (10.43 g, 32.0 mmol), TBAI (4.73 g, 12.81 mmol) and (bromomethyl)cyclopropane (3.46 g, 25.6 mmol) were added to a stirred solution of Intermediate 32 (5 g, 12.81 mmol) in DMF (50 ml). The reaction mixture was heated to 55°C for 16 hours, quenched with water (100 ml), and extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over sodium sulphate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified using a silica gel column (0-20% ethyl acetate in hexane) to afford ethyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(cyclopropylmethyl)-5-fluoro-1H-indole-2-carboxylate (4.8 g, 84%). LC-MS m / z: 389.3 [M+H] +< . 1< H NMR (400 MHz, chloroform-d) δ ppm: 7.32 (s, 1H), 7.18 (dd, J=2.5, 8.5 Hz, 1H), 6.99 (dd, J=2.8, 10.8 Hz, 1H), 4.79 (d, J=6.0 Hz, 2H), 4.44-4.34 (m, 2H), 3.55 (br, s, 1H), 2.92 (br, s, 2H), 2.00 (br, d, J=13.0 Hz, 2H), 1.76 (br, dd, J=4.0, 12.5 Hz, 2H), 1.52 (s, 9H), 1.45-1.40 (m, 3H), 1.05 (s, 1H), 0.48-0.39 (m, 2H), 0.38-0.30 (m, 2H).Intermediate 34tert-Butyl 4-(1-(cyclopropylmethyl)-5-fluoro-2-(hydroxymethyl)-1H-indol-7-yl)piperidine-1-carboxylate

[0180]

[0181] LiBH 4 (9.84 ml, 39.4 mmol) was added to a stirred solution of Intermediate 33 (3.5 g, 7.87 mmol) in THF (35 ml) at 0°C. The reaction mixture was stirred for 16 hours at a room temperature, filtered through a celite bed, and washed with ethyl acetate (70 ml). The combined organic layers were concentrated under reduced pressure to obtain crude tert-butyl 4-(1-(cyclopropylmethyl)-5-fluoro-2-(hydroxymethyl)-1H-indol-7-yl)piperidine-1-carboxylate (2.5 g, 79%). LC-MS m / z: 403.4 [M+H] +< . 1< H NMR (300 MHz, DMSO-d 6 ) δ ppm: 7.10 (dd, J=9.07, 2.64 Hz, 1H), 6.74-6.92 (m, 1H), 6.38 (s, 1H), 5.29 (t, J=5.48 Hz, 1H), 4.59 (d, J=5.67 Hz, 1H), 4.28 (br d, J=5.29 Hz, 2H), 4.13 (br d, J=12.46 Hz, 1H), 3.51 (br t, J=10.58 Hz, 1H), 3.13-3.32 (m, 1H), 2.35 (s, 2H), 2.27 (d, J=5.29 Hz, 1H), 1.84 (br d, J=12.84 Hz, 2H), 1.51-1.74 (m, 2H), 1.35-1.51 (m, 9H), 0.74-1.04 (m, 1H), 0.21-0.51 (m, 4H).Intermediate 35tert-Butyl 4-(1-(cyclopropylmethyl)-5-fluoro-2-formyl-1H-indol-7-yl)piperidine-1-carboxylate

[0182]

[0183] Manganese dioxide (0.691 g, 7.95 mmol) was added to a stirred solution of Intermediate 34 (3.2 g, 7.95 mmol) in tetrahydrofuran (32 ml). The reaction mixture was stirred for 16 hours, filtered through a celite bed, and washed with ethyl acetate (70 ml). The organic layers were concentrated under reduced pressure to obtain tert-butyl 4-(1-(cyclopropylmethyl)-5-fluoro-2-formyl-1H-indol-7-yl)piperidine-1-carboxylate (2.7 g, 85%). LC-MS m / z: 345.1 [M-tBu] +< . 1< H NMR (300 MHz, chloroform-d) δ ppm: 9.81 (s, 1H), 7.25-7.20 (m, 2H), 7.05 (dd, J=2.3, 11.0 Hz, 1H), 4.78 (d, J=6.0 Hz, 2H), 4.48-4.22 (m, 2H), 3.52 (br, t, J=11.5 Hz, 1H), 3.02-2.77 (m, 2H), 2.05-1.89 (m, 2H), 1.86-1.64 (m, 2H), 1.50 (s, 9H), 1.15-1.01 (m, 1H), 0.49-0.31 (m, 4H).Intermediate 36tert-Butyl (E)-4-(1-(cyclopropylmethyl)-5-fluoro-2-(2-nitroprop-1-en-1-yl)-1H-indol-7-yl)piperidine-1-carboxylate

[0184]

[0185] Intermediate 36 was prepared following a procedure similar to the preparation of Intermediate 30, using appropriate reactants. LC-MS m / z: 402.3 [M+H] +< . 1< H NMR (300 MHz, chloroform-d) δ ppm: 8.18 (s, 1H), 7.15 (dd, J=2.5, 8.1 Hz, 1H), 6.94 (dd, J=2.3, 11.0 Hz, 1H), 6.82 (s, 1H), 4.47-4.26 (m, 4 H), 3.60-3.44 (m, 1H), 3.01-2.79 (m, 2H), 2.58 (s, 3H), 2.01-1.90 (m, 2H), 1.84-1.70 (m, 2H), 1.50 (s, 9H), 1.15-1.05 (m, 1H), 0.62-0.52 (m, 2H), 0.29 (q, J=5.3 Hz, 2H).Intermediate 37Ethyl 3-(2-chloro-3-nitropyridin-4-yl)-2-hydroxyacrylate

[0186]

[0187] Sodium ethoxide in ethanol (28.2 g, 87 mmol) was added to diethyl oxalate (12.70 g, 87 mmol) in toluene (50 ml). The reaction mixture was stirred for 10 min at a room temperature, followed by the addition of 2-chloro-4-methyl-3-nitropyridine (10 g, 57.9 mmol). The reaction mixture was stirred at a room temperature for 16 hours, concentrated, the residue thus obtained was diluted with water (20 ml), and acidified with acetic acid (10 ml) to bring pH to about 4. The solids thus obtained were filtered and dried to afford ethyl 3-(2-chloro-3-nitropyridin-4-yl)-2-hydroxyacrylate (15 g, 95%) as an off-white solid. LC-MS m / z: 273.0 [M+H] -< . 1< H NMR (300 MHz, DMSO-d 6 ) δ ppm: 8.61 (d, J=5.7 Hz, 1H), 8.31 (d, J=5.7 Hz, 1H), 5.92 (s, 1H), 4.30 (q, J=7.1 Hz, 2H), 1.28 (t, J=7.0 Hz, 3H).Intermediate 38Ethyl 7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

[0188]

[0189] Iron (15.36 g, 275 mmol) and ammonium chloride (23.54 g, 440 mmol) in water (30 ml) were added to a stirred solution of Intermediate 37 (15.0 g, 55.0 mmol) in ethanol (50 ml) and THF (100 ml). The reaction mixture was stirred at 65°C for 3 hours, filtered through a celite bed, the filtrate obtained was diluted with water (50 ml), and quenched with saturated NaHCO 3 solution, followed by extraction with ethyl acetate (2×100 ml). The combined organic layers were dried over sodium sulphate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified using a silica gel column (0-50% ethyl acetate in hexane) to afford ethyl 7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (6.5 g, 53%). LC-MS m / z: 225.0 [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 12.73 (br, s, 1H), 7.99 (d, J=5.5 Hz, 1H), 7.68 (d, J=5.5 Hz, 1H), 7.30 (s, 1H), 4.39 (q, J=7.0 Hz, 2H), 1.36 (t, J=7.0 Hz, 3H).Intermediate 39Ethyl 7-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

[0190]

[0191] tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (11.63 g, 37.6 mmol) and K 2 CO 3 in water (36.2 ml, 72.3 mmol) were added to a stirred solution of Intermediate 38 (6.5 g, 28.9 mmol) in 1,4-dioxane (65 ml). The reaction mixture was degassed with argon for 10 min, followed by the addition of PdCl 2 (dppf)-CH 2 Cl 2 adduct (1.418 g, 1.736 mmol), and stirred at 110°C for 16 hours. The reaction mixture was filtered through a celite bed, the filtrate was diluted with water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over sodium sulphate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified using a silica gel column (0-60% ethyl acetate in hexane) to afford ethyl 7-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (10.2 g, 95%). LC-MS m / z: 372.2 [M+H] +< . 1< H NMR (300 MHz, DMSO-d 6 ) δ ppm: 11.95 (br, s, 1H), 8.16 (d, J=5.3 Hz, 1H), 7.53 (d, J=5.7 Hz, 1H), 7.23 (s, 1H), 6.36 (br s, 1H), 4.38 (q, J=7.1 Hz, 2H), 4.15-4.08 (m, 2H), 4.03 (d, J=7.2 Hz, 1H), 3.94 (s, 2H), 3.59 (br t, J=5.3 Hz, 2H), 2.72-2.62 (m, 2H), 1.46 (s, 9H), 1.35 (t, J=7.2 Hz, 3H).Intermediate 40Ethyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

[0192]

[0193] Pd / C (50% wet, 2.92 g, 2.75 mmol) was added to a stirred solution of Intermediate 39 (10.2 g, 27.5 mmol) in ethanol (10 ml). The reaction mixture was stirred under hydrogen atmosphere for 16 hours, filtered through a celite bed, and the filtrate was concentrated to obtain ethyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (8.1 g, 79%). LC-MS m / z: 374.1 [M+H] +< . 1< H NMR (300 MHz, DMSO-d 6 ) δ ppm: 12.38 (s, 1H), 8.09 (d, J=5.3 Hz, 1H), 7.46 (d, J=5.7 Hz, 1H), 7.18 (d, J=1.5 Hz, 1H), 4.43-4.34 (m, 2H), 4.16-4.05 (m, 2H), 3.94 (s, 2H), 3.80-3.62 (m, 2H), 3.44-3.42 (m, 2H), 1.76 (br, s, 1H), 1.43 (s, 9H), 1.39-1.23 (m, 3H).Intermediate 41Ethyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

[0194]

[0195] Cesium carbonate (4.45 g, 13.66 mmol) and TBAI (0.841 g, 2.276 mmol) were added to a stirred solution of Intermediate 40 (1.7 g, 4.55 mmol) in DMF (10 ml), followed by the addition of (bromomethyl)cyclopropane (1.229 g, 9.10 mmol). The reaction mixture was stirred at 60°C for 3 hours, diluted with water (20 ml), and extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum to obtain a crude product, which was purified using a silica gel column (0-20% ethyl acetate in hexane) to afford ethyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (1.3 g, 67%). LC-MS m / z: 428.2 [M+H] +< . 1< H NMR (300 MHz, DMSO-d 6 ) δ ppm: 8.18 (d, J=5.3 Hz, 1H), 7.53 (d, J=5.3 Hz, 1H), 7.33 (s, 1H), 4.80 (br, d, J=6.4 Hz, 2H), 4.35 (q, J=7.2 Hz, 2H), 4.19-3.98 (m, 2H), 3.68-3.52 (m, 1H), 2.94 (br, s, 2H), 1.85 (br, s, 4 H), 1.43 (s, 9H), 1.36-1.32 (m, 3H), 1.27-0.99 (m, 1H), 0.53-0.35 (m, 2H), 0.33-0.17 (m, 2H).Intermediate 42tert-Butyl 4-(1-(cyclopropylmethyl)-2-(hydroxymethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperidine-1-carboxylate

[0196]

[0197] LiBH 4 (4.56 ml, 18.24 mmol) was added to a stirred solution of Intermediate 41 (1.3 g, 3.04 mmol) in THF (30 ml). The reaction mixture was stirred at a room temperature for 36 hours, quenched with saturated ammonium chloride solution (10 ml), diluted with water (20 ml), and extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum to obtain a crude product, which was purified using a silica gel column (0-20% ethyl acetate in hexane) to afford tert-butyl 4-(1-(cyclopropylmethyl)-2-(hydroxymethyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperidine-1-carboxylate (1.02 g, 87%). LC-MS m / z: 386.2 [M+H] +< . 1< H NMR (300 MHz, DMSO-d 6 ) δ ppm: 8.04 (d, J=5.3 Hz, 1H), 7.32 (d, J=5.3 Hz, 1H), 6.45 (s, 1H), 5.42 (t, J=5.3 Hz, 1H), 4.65 (d, J=5.7 Hz, 2H), 4.34 (br d, J=6.0 Hz, 2H), 4.11 (br d, J=10.6 Hz, 2H), 3.57 (br d, J=11.0 Hz, 1H), 2.90 (br s, 2H), 1.88 (br d, J=9.8 Hz, 2H), 1.83-1.64 (m, 2H), 1.43 (s, 9H), 1.24 (br s, 1H), 0.53-0.42 (m, 2H), 0.31 (q, J=4.9 Hz, 2H).Intermediate 43tert-Butyl 4-(1-(cyclopropylmethyl)-2-formyl-1H-pyrrolo[2,3-c]pyridin-7-yl)piperidine-1-carboxylate

[0198]

[0199] Manganese dioxide (2.255 g, 25.9 mmol) was added to a stirred solution of Intermediate 42 (1 g, 2.59 mmol) in THF (10 ml). The reaction mixture was stirred at 40°C for 3 hours, filtered through a celite bed, and the filtrate was concentrated to obtain tert-butyl 4-(1-(cyclopropylmethyl)-2-formyl-1H-pyrrolo[2,3-c]pyridin-7-yl)piperidine-1-carboxylate (0.9 g, 90%). LC-MS m / z: 384.2[M+H] +< . 1< H NMR (300 MHz, DMSO-d 6 ) δ ppm: 10.03 (s, 1H), 8.22 (d, J=5.3 Hz, 1H), 7.61 (d, J=5.3 Hz, 1H), 7.56 (s, 1H), 4.80 (d, J=6.0 Hz, 2H), 4.18-4.00 (m, 2H), 3.67-3.55 (m, 1H), 3.13-2.81 (m, 2H), 1.94-1.75 (m, 4H), 1.47-1.35 (m, 9H), 1.29-1.12 (m, 1H), 0.51-0.37 (m, 2H), 0.36-0.23 (m, 2H).Intermediate 44tert-Butyl (E)-4-(1-(cyclopropylmethyl)-2-(2-nitroprop-1-en-1-yl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperidine-1-carboxylate

[0200]

[0201] Ammonium acetate (0.271 g, 3.52 mmol) was added to a stirred solution of Intermediate 43 (0.9 g, 2.347 mmol) in nitroethane (1.678 ml, 23.47 mmol). The reaction mixture was stirred at 90°C for 2 hours, diluted with water (50 ml), and extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over sodium sulphate, filtered, and concentrated under reduced pressure to obtain tert-butyl (E)-4-(1-(cyclopropylmethyl)-2-(2-nitroprop-1-en-1-yl)-1H-pyrrolo[2,3-c]pyridin-7-yl)piperidine-1-carboxylate (0.85 g, 82%). LC-MS m / z: 441.2 [M+H] +< .Intermediate 45Ethyl 7-bromo-1-(cyclopropylmethyl)-1H-indole-2-carboxylate

[0202]

[0203] Potassium carbonate (41.2 g, 298 mmol) was added to a stirred solution of ethyl 7-bromo-1H-indole-2-carboxylate (20 g, 74.6 mmol) in DMF (80 ml), followed by addition of (bromomethyl)cyclopropane (14.47 ml, 149 mmol). The reaction mixture was stirred at 50°C for 16 hours, diluted with water (100 ml), and extracted with ethyl acetate (2×200 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum to obtain a crude product, which was purified using a silica gel column (0-10% ethyl acetate in hexane) to afford (22 g, 92%) of ethyl 7-bromo-1-(cyclopropylmethyl)-1H-indole-2-carboxylate as off white solid. LC-MS m / z: 322.0 [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 7.76 (d, J=8.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 7.07 (t, J=8.0 Hz, 1H), 5.01 (d, J=8.0 Hz, 2H), 4.34 (q, J=8.0 Hz, 2H), 2.33 (br, s, 1H), 1.34 (t, J=8.00 Hz, 3H), 1.27-1.15 (m, 1H), 0.42-0.29 (m, 4H).Intermediate 46Ethyl 7-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate

[0204]

[0205] Tris(trimethylsilyl)silane (5.67 g, 22.81 mmol) and sodium carbonate (4.61 g, 43.5 mmol) were added to a stirred solution of Intermediate 45 (9.84 g, 34.8 mmol) in 1,2-dimethoxyethane (35 ml) in a first vial, and the reaction mixture was purged with argon followed by the addition of Ir[DF(CF 3 )PPY] 2 (DTBBPY)PF 6 (0.244 g, 0.217 mmol). A mixture of 4,4'-di-tert-butyl-2,2'-dipyridyl (0.292 g, 1.086 mmol) and Nickel(II) chloride ethylene glycol dimethyl ether complex (0.239 g, 1.086 mmol) in 1,2-dimethoxy ethane (0.5 ml) was prepared in another vial and the contents were sonicated for 10 min to obtain a catalyst (green suspension). The catalyst was added into the reaction mixture in the first vial, and the vial containing the reaction mixture was placed under Blue LED light (34 W) for 16 hours. The reaction mixture was diluted with water (100 ml), and extracted with ethyl acetate (2×200 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum to obtain a crude product, which was purified using a silica gel column (0-20% ethyl acetate in hexane) to afford (5.6 g, 64%) of ethyl 7-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate as pale yellow liquid. LC-MS m / z: 343.3 [M-56] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 7.63 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.36 (s, 1H), 7.19 (t, J=8.0 Hz, 1H), 4.63 (d, J=8.0 Hz, 2H), 4.57-4.52 (m, 1H), 4.41-4.29 (m, 2H), 4.12-3.94 (m, 2H), 3.82-3.80 (m, 2H), 2.12 (quin, J=7.5 Hz, 1H), 1.41 (s, 9H), 1.33(t, J=8.0 Hz, 3H), 0.94-0.84 (m, 1H), 0.39-0.27 (m, 2H), 0.21-0.02 (m, 2H).Intermediate 47tert-Butyl 3-(1-(cyclopropylmethyl)-2-(hydroxymethyl)-1H-indol-7-yl)azetidine-1-carboxylate

[0206]

[0207] LiBH 4 (14.05 ml, 56.2 mmol) was added to a stirred solution of Intermediate 46 (5.6 g, 14.05 mmol) in THF (50 ml). The reaction mixture was stirred at a room temperature for 4 days, quenched with saturated ammonium chloride solution (10 ml), diluted with water (20 ml), and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum to obtain a crude product, which was purified using a silica gel column (0-20% ethyl acetate in hexane) to afford (2.0 g, 39%) of tert-butyl 3-(1-(cyclopropylmethyl)-2-(hydroxymethyl)-1H-indol-7-yl)azetidine-1-carboxylate. LC-MS m / z: 357.0 [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 7.41 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.06 (t, J=8.0 Hz, 1H), 6.41 (s, 1H), 5.23 (t, J=4.0 Hz, 1H), 4.66-4.55 (m, 2H), 4.36 (br, t, J=8.5 Hz, 2H), 4.24 (d, J=6.0 Hz, 2H), 3.96 (br, t, J=8.0 Hz, 2H), 1.99 (s, 1H), 1.46-1.38 (m, 9H), 1.09-1.00 (m, 1H), 0.47-0.37 (m, 2H), 0.24 (q, J=5.0 Hz, 2H).Intermediate 48tert-Butyl 3-(1-(cyclopropylmethyl)-2-formyl-1H-indol-7-yl)azetidine-1-carboxylate

[0208]

[0209] Manganese dioxide (4.88 g, 56.1 mmol) was added to a stirred solution of Intermediate 47 (2 g, 5.61 mmol) in THF (10 ml). The reaction mixture was stirred at 40°C for 3 hours, filtered through a celite bed, and the filtrate was concentrated to obtain (1.9 g, 96%) of tert-butyl 3-(1-(cyclopropylmethyl)-2-formyl-1H-indol-7-yl)azetidine-1-carboxylate. LC-MS m / z: 299 [M-56] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 9.86 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.23 (t, J=8.0 Hz, 1H), 4.65 (d, J=8.0 Hz, 2H), 4.38 (br t, J=8.0 Hz, 2H), 4.06-3.96 (m, 2H), 1.77 (td, J=3.4, 6.3 Hz, 1H), 1.41 (s, 9H), 1.02-0.99 (m, 1H), 0.41-0.30 (m, 2H), 0.26-0.15 (m, 2H).Intermediate 49tert-Butyl (E)-3-(1-(cyclopropylmethyl)-2-(2-nitroprop-1-en-1-yl)-1H-indol-7-yl)azetidine-1-carboxylate

[0210]

[0211] Ammonium acetate (0.620 g, 8.04 mmol) was added to a stirred solution of Intermediate 48 (1.9 g, 5.36 mmol) in nitroethane (3.83 ml, 53.6 mmol). The reaction mixture was stirred at 90°C for 2 hours, diluted with water (20 ml), and extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum to afford (2.2 g, 100%) of tert-butyl (E)-3-(1-(cyclopropylmethyl)-2-(2-nitroprop-1-en-1-yl)-1H-indol-7-yl)azetidine-1-carboxylate. LC-MS m / z: 412.3 [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.21 (s, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.18 (t, J=8.0 Hz, 1H), 7.09 (s, 1H), 4.58-4.53 (m, 1H), 4.43-4.33 (m, 2H), 4.30 (d, J=6.0 Hz, 2H), 4.09-3.95 (m, 2H), 2.48-2.38 (m, 1H), 1.47-1.37 (m, 9H), 1.06-0.96 (m, 1H), 0.49-0.39 (m, 2H), 0.29-0.15 (m, 2H).Intermediate 50(E)-7-(benzyloxy)-1-(cyclopropylmethyl)-2-(2-nitroprop-1-en-1-yl)-1H-indole

[0212]

[0213] Ammonium acetate (0.606 g, 7.86 mmol) was added to a stirred solution of 7-(benzyloxy)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (2 g, 6.55 mmol) in nitroethane (18.73 ml, 262 mmol). The reaction mixture was heated to 90°C for 2 hours, allowed to cool to a room temperature, diluted with water (100 ml), and extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over sodium sulphate, filtered, and concentrated under reduced pressure to obtain crude (E)-7-(benzyloxy)-1-(cyclopropylmethyl)-2-(2-nitroprop-1-en-1-yl)-1H-indole (1.9 g, 80%) LC-MS m / z: 361.7 [M+H] +< .Intermediate 517-Chloro-1H-pyrrolo[2,3-c]pyridine

[0214]

[0215] Vinyl magnesium bromide (189 ml, 189 mmol) was added to a stirred solution of 2-chloro-3-nitropyridine (10 g, 63.1 mmol) in THF (80 ml) at -78°C. The reaction mixture was stirred for 1 hour, warmed to -20°C, and the resulting solution was stirred at -20°C for 12 hours. The reaction mixture was quenched with saturated ammonium chloride solution (20 ml), diluted with water (2×50 ml), and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum to obtain a crude product, which was purified using a silica gel column (0-50% ethyl acetate in hexane) to afford 7-chloro-1H-pyrrolo[2,3-c]pyridine (3.4 g, 35%) as brown solid. LC-MS m / z: 153.1 [M+H] +< . 1< H NMR (300 MHz, DMSO-d 6 ) δ ppm: 8.35-8.30 (m, 1H), 8.29 (s, 1H), 7.88-7.78 (m, 1H), 7.78-7.70 (m, 1H), 7.66 (s, 1H).Intermediate 527-Chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridine

[0216]

[0217] Sodium hydride (1.049 g, 26.2 mmol) was added to a stirred solution of Intermediate 51 (2 g, 13.11 mmol) in DMF (20 ml) at 0°C, the contents were stirred for 20 minutes, followed by the addition of (bromomethyl)cyclopropane (1.910 ml, 19.66 mmol). The resulting reaction mixture was stirred for 16 hours, quenched with ice-flakes and cold water (20 ml), and extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum to obtain a crude product, which was purified using a silica gel column (0-20% ethyl acetate in hexane) to afford 7-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridine (2.2 g, 81%) of. LC-MS m / z: 207.1 [M+H] +< . 1< H NMR (300 MHz, DMSO-d 6 ) δ ppm: 7.90 (d, J=5.3 Hz, 1H), 7.76 (d, J=3.0 Hz, 1H), 7.58 (d, J=5.3 Hz, 1H), 6.63 (d, J=3.4 Hz, 1H), 4.40 (d, J=6.8 Hz, 2H), 1.40-1.22 (m, 1H), 0.53-0.39 (m, 4H).Intermediate 537-Chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde

[0218]

[0219] sec-Butyllithium (11.41 ml, 15.97 mmol) was added to a stirred solution of Intermediate 52 (2.2 g, 10.64 mmol) in tetrahydrofuran (30 ml) at -78°C, the contents were stirred for 1 hour, followed by the addition of DMF (1.236 ml, 15.97 mmol). The resulting reaction mixture was stirred at the same temperature for 1 hour, quenched with saturated ammonium chloride solution (10 ml), diluted with water (20 ml), and extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum to obtain a crude product, which was purified using a silica gel column (eluting with 0-20% ethyl acetate in hexane) to afford 7-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde (1.2 g, 78%) as an off white solid. LC-MS m / z: 235.0 [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 10.10 (s, 1H), 8.08 (d, J=5.0 Hz, 1H), 7.84 (d, J=5.5 Hz, 1H), 7.67 (s, 1H), 4.92 (d, J=7.0 Hz, 2H), 1.35-1.24 (m, 1H), 0.47-0.41 (m, 2H), 0.41-0.33 (m, 2H).Intermediate 54(E)-7-Chloro-1-(cyclopropylmethyl)-2-(2-nitroprop-1-en-1-yl)-1H-pyrrolo[2,3-c]pyridine

[0220]

[0221] (E)-7-chloro-1-(cyclopropylmethyl)-2-(2-nitroprop-1-en-1-yl)-1H-pyrrolo[2,3-c]pyridine (1.2g, 97%) was prepared following a procedure similar to the preparation of Intermediate 57. LC-MS m / z 292.2 [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.18 (s, 1H), 8.01 (d, J=5.5 Hz, 1H), 7.69 (d, J=5.5 Hz, 1H), 7.14 (s, 1H), 4.64 (d, J=7.0 Hz, 2H), 2.54-2.52 (m, 3H), 1.33-1.09 (m, 1H), 0.43-0.23 (m, 4H).Intermediate 557-Chloro-1-methyl-1H-pyrrolo[2,3-c]pyridine

[0222]

[0223] Sodium hydride (1.311 g, 32.8 mmol) was added to a stirred solution of Intermediate 51 (5 g, 32.8 mmol) in DMF (100 ml) at 0°C, the contents were stirred for 5 min, followed by the addition of iodomethane (2.049 ml, 32.8 mmol). The resulting reaction mixture was stirred at a room temperature for 16 hours, quenched with ice water, and extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over Na 2 SO 4 , and concentrated to obtain a crude product, which was purified using a silica gel column (0-50% ethyl acetate in hexane) to afford 7-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridine (4 g, 73%) as off-white solid. LC-MS m / z: 167.0 [M+H] +< .Intermediate 567-Chloro-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde

[0224]

[0225] sec-Butyl lithium (6.43 ml, 9 mmol) was added to a solution of Intermediate 55 (1 g, 6 mmol) in tetrahydrofuran (10 ml) at -78°C, the contents were stirred for 0.5 hours, followed by the addition of DMF (0.697 ml, 9 mmol). The resulting reaction mixture was stirred for 1 hour, quenched with saturated NH 4 Cl solution (50 ml), extracted with ethyl acetate (3×50 ml), dried over Na 2 SO 4 , and concentrated to obtain a crude product, which was purified using a silica gel column (0-50% ethyl acetate in hexane) to afford 7-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde (1.0 g, 86%) as a brown oil. LC-MS m / z: 195.0 [M+H] +< .Intermediate 57(E)-7-Chloro-1-methyl-2-(2-nitroprop-1-en-1-yl)-1H-pyrrolo[2,3-c]pyridine

[0226]

[0227] Ammonium acetate (0.594 g, 7.71 mmol) was added to a solution of Intermediate 56 (1 g, 5.14 mmol) in nitroethane (10 ml). The reaction mixture was heated to 90°C, stirred for 2 hours, diluted with ethyl acetate (50 ml), washed with saturated NH 4 Cl, dried over Na 2 SO 4 , and concentrated to obtain a crude product, which was purified using a silica gel column (0-50% ethyl acetate in hexane) to afford (E)-7-chloro-1-methyl-2-(2-nitroprop-1-en-1-yl)-1H-pyrrolo[2,3-c]pyridine (1.1 g, 85%) as a yellow solid. LC-MS m / z: 252.3 [M+H] +< .Intermediate 584-Bromobenzo[b]thiophene-3-carbaldehyde

[0228]

[0229] A solution of 4-bromobenzo[b]thiophene (10 g, 46.9 mmol) and dichloro(methoxy)methane (5.39 g, 46.9 mmol) in DCM (500 ml) was stirred and cooled to 0°C, followed by the addition of TiCl 4 (65.17 ml, 591 mmol) dropwise at a room temperature. The resulting reaction mixture was stirred for 16 hours at a room temperature. Thereafter, saturated ammonium chloride (500 ml) was added dropwise to the reaction mixture, and the contents were extracted with DCM (2×500 ml). The combined organic layers were washed with water (200 ml) and brine solution (200 ml), followed by drying over sodium sulphate. The organic layers were filtered, and volatiles were evaporated to dryness under reduced pressure to obtain a crude product, which was purified using a silica gel column (0-20% ethyl acetate in hexane) to afford 4-bromobenzo[b]thiophene-3-carbaldehyde (6 g, 53%). 1< H NMR (300 MHz, DMSO-d 6 ) δ ppm: 10.80-10.95 (m, 1H), 8.80 (s, 1H), 8.21 (dd, J=8.31, 0.76 Hz, 1H), 7.79-7.85 (m, 1H), 7.41 (t, J=7.93 Hz, 1H).Intermediate 59(4-Bromobenzo[b]thiophen-3-yl)(cyclopropyl)methanol

[0230]

[0231] Cyclopropylmagnesium bromide (12.44 ml, 12.44 mmol) was added dropwise under nitrogen atmosphere to a stirred solution of Intermediate 58 (2 g, 8.30 mmol) in THF (30 ml) cooled to -20°C. The reaction mixture stirred for 2 hours, diluted with water (50 ml), and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (100 ml) and brine solution (100 ml), followed by drying over sodium sulphate. The organic layers were filtered, and volatiles were evaporated to dryness under reduced pressure to afford (4-bromobenzo[b]thiophen-3-yl) (cyclopropyl)methanol (2.2 g, 94%). 1< H NMR (300 MHz, DMSO-d 6 ) δ ppm: 7.99-8.08 (m, 1H), 7.84-7.90 (m, 1H), 7.60-7.68 (m, 1H), 7.19-7.28 (m, 1H), 5.52-5.65 (m, 1H), 5.11-5.23 (m, 1H), 1.33-1.48 (m, 1H), 0.27-0.49 (m, 4H).Intermediate 604-Bromo-3-(cyclopropylmethyl)benzo[b]thiophene

[0232]

[0233] Triethylsilane (14 ml, 49.4 mmol) was added to a stirred solution of Intermediate 50 (14 g, 49.4 mmol) in DCM (200 ml), followed by the addition of TFA (14 ml, 182 mmol) after 5 minutes. The resulting reaction mixture was stirred for 1 hour at a room temperature. Thereafter, the volatiles were evaporated to dryness under reduced pressure, saturated NaHCO 3 (100 ml) was added, and the contents were extracted with DCM (2×150 ml). The combined organic extracts were washed with water (100 ml) and brine solution (100 ml), dried over sodium sulphate, filtered, and volatiles were evaporated to dryness under reduced pressure to obtain a crude product, which was purified using a silica gel column (0-10% ethyl acetate in hexane) to afford 4-bromo-3-(cyclopropylmethyl)benzo[b]thiophene (6 g, 45%). 1< H NMR (300 MHz, DMSO-d 6 ) δ ppm: 8.02 (dd, J=7.93, 0.76 Hz, 1H), 7.70 (s, 1H), 7.63 (dd, J=7.55, 1.13 Hz, 1H), 7.24 (t, J=7.74 Hz, 1H), 3.05 (d, J=6.80 Hz, 2H), 1.24 (br, d, J=3.78 Hz, 1H), 0.54-0.44 (m, 2H), 0.31-0.17 (m, 2H).Intermediate 614-Bromo-3-(cyclopropylmethyl)benzo[b]thiophene-2-carbaldehyde

[0234]

[0235] LDA (2M in THF, 11.23 ml, 22.46 mmol) was added dropwise to a stirred solution of Intermediate 60 (3 g, 11.23 mmol) in THF (30 ml) cooled to -78°C, the contents were stirred for 1 hour at -78°C, followed by the addition of DMF (1.739 ml, 22.46 mmol). The resulting reaction mixture was stirred for 3 hours, water (100 ml) was added, and the contents were extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with water (100 ml) and brine solution (100 ml), dried over sodium sulphate, filtered, and volatiles were evaporated to dryness under reduced pressure to afford 4-bromo-3-(cyclopropylmethyl)benzo[b]thiophene-2-carbaldehyde (3g, 91%). 1< H NMR (300 MHz, DMSO-d 6 ) δ ppm: 10.32 (s, 1H), 8.15 (dd, J=8.3, 0.70 Hz, 1H), 8.07-7.92 (m, 1H), 7.45 (t, , J=8.0Hz, (1H), 3.57 (d, J=6.4 Hz, 2H), 1.24-1.03 (m, 1H), 0.54-0.23 (m, 4H). LC-MS m / z: 295.31 [M+H] +< .Intermediate 62(E)-4-Bromo-3-(cyclopropylmethyl)-2-(2-nitroprop-1-en-1-yl)benzo[b]thiophene

[0236]

[0237] Ammonium acetate (0.261 g, 3.39 mmol) was added to a stirred solution of Intermediate 61 (1 g, 3.39 mmol) in nitroethane (0.242 ml, 3.39 mmol). The reaction mixture was stirred for 2 hours at 90°C, water (100 ml) was added to the reaction mixture, and the contents were extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with water (100 ml), dried over sodium sulphate, filtered, and volatiles were evaporated to dryness under reduced pressure to afford (E)-4-bromo-3-(cyclopropylmethyl)-2-(2-nitroprop-1-en-1-yl)benzo[b]thiophene (1 g, 84%) as a yellow solid. 1< H NMR (300 MHz, DMSO-d 6 ) δ ppm: 8.39 (s, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.44-7.34 (m, 1H), 3.34 (m, 2 H), 1.29-1.2 (m, 1H), 0.47-0.42 (m, 2H), 0.27 ( d, J=4.5 Hz, 2H).Example 1((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone

[0238] Intermediate 1A 3-(tert-Butyl)-6-methyl 2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxypyrazolo[1,5-a]pyridine-3,6-dicarboxylate

[0239]

[0240] 1-Amino-3-methoxy-5-(methoxycarbonyl)pyridin-1-ium (Intermediate 1, 0.618 g, 3.37 mmol) and K 2 CO 3 (0.933 g, 6.75 mmol) were added to a stirred solution of tert-butyl 3-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)propiolate (Intermediate 2, 1 g, 3.37 mmol) in DMF (20 ml). The reaction mixture was stirred at a room temperature for 16 hours, diluted with EtOAc (50 ml), washed with water (3×50 ml) and brine (3×50 ml), dried over Na 2 SO 4 , and concentrated under reduced pressure to obtain a crude product. The crude product was purified using a silica gel column (24 g, Redisep ®< SiO 2 column, eluting with 30% EtOAc in hexane) to afford the title compound (650 mg, 40%) as a yellow solid. LC-MS m / z: 477.2 [M+H] +< . 1< H NMR (400 MHz, chloroform-d) δ ppm: 8.92 (d, J=1.0 Hz, 1H), 8.39 (d, J=4.8 Hz, 1H), 7.98-7.93 (m, 1H), 7.16-7.08 (m, 2H), 6.82 (s, 1H), 4.48 (d, J=7.0 Hz, 2H), 4.04 (s, 3H), 3.99 (s, 3H), 1.43 (m, 9 H), 1.37-1.21 (m, 5H), 0.38-0.25 (m, 4H).Intermediate 1B2-(1-(Cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-6-(methoxycarbonyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0241]

[0242] TFA (0.210 ml, 2.73 mmol) was added to a stirred solution of Intermediate 1A (650 mg, 1.364 mmol) in DCM (5 ml). The reaction mixture was stirred at a room temperature for 1 hour, and concentrated to afford the title compound (600 mg, 73%) as a brown solid. The crude compound was used in the next steps without further purification. LC-MS m / z: 421.1 [M+H] +< .Intermediate 1CMethyl 2-(1-(cyclopropylmethyl)-1H-pyrrolo-[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carboxylate

[0243]

[0244] Borane dimethyl sulfide complex (3.57 ml, 7.14 mmol) was added to a stirred solution of Intermediate 1B (600 mg, 1.427 mmol) in THF (10 ml) at 0°C. The reaction mixture was stirred for 30 min, followed by heating to 65°C and stirring for 5 hours, quenched with methanol (5 ml) at 0°C, and concentrated to afford the title compound (520 mg, 93%) as a brown solid. The crude compound was used in the next steps without further purification. LC-MS m / z: 391.2 [M+H] +< . 1< H NMR (400 MHz, chloroform-d) δ ppm: 8.88-8.76 (m, 1H), 8.44-8.27 (m, 1H), 7.99-7.85 (m, 1H), 7.13-6.90 (m, 1H), 6.89-6.85 (m, 1H), 6.76-6.69 (m, 1H), 4.62-4.44 (m, 2H), 4.07-3.96 (m, 6H), 2.58 (s, 3H), 1.05-0.78 (m, 1H), 0.45-0.11 (m, 4H).Intermediate 1D2-(1-(Cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carboxylic acid

[0245]

[0246] Lithium hydroxide (LiOH, 153 mg, 6.40 mmol) was added to a stirred solution of Intermediate 1C (500 mg, 1.281 mmol) in a mixture of THF (3 ml), methanol (3 ml) and water (3 ml). The reaction mixture was stirred at a room temperature for 30 min, concentrated, and the crude residue was acidified with 1.5 N HCl. The solid product obtained was filtered, and dried under vacuum to afford the title compound (360 mg, 75%) as an off-white solid. LC-MS m / z: 377.1 [M+H] +< .Intermediate 1Etert-Butyl-((7R)-2-(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate

[0247]

[0248] (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 707 mg, 1.860 mmol) and N,N-diisopropylethylamine (DIPEA, 0.487 ml, 2.79 mmol) were added to a stirred solution of Intermediate 1D (350 mg, 0.930 mmol) and tert-butyl ((7R)-2-azabicyclo[2.2.1]- heptan-7-yl)carbamate (197 mg, 0.930 mmol) in DMF (5 ml). The reaction mixture was stirred at a room temperature for 12 hours, poured into ice water (10 ml), and the solid product separated was filtered and dried under vacuum to obtain a crude product, which was purified using a silica gel column (24 g, Redisep ®< SiO 2 column, eluting with 50% EtOAc in hexane) to afford the title compound (300 mg, 57%) as an off-white solid. LC-MS m / z: 571.2 [M+H] +< .Example 1

[0249] TFA (0.364 ml, 4.73 mmol) was added to a stirred solution of Intermediate 1E (270 mg, 0.473 mmol) in DCM (5 ml). T he reaction mixture was stirred at a room temperature for 1 hour, concentrated, and the crude compound obtained was purified using Prep-HPLC. The purified sample was further purified using RP-HPLC to afford the title compound (76 mg, 34%). LC-MS m / z: 471.2 [M+H] +< . LC-MS retention time: 1.76 min (Method E). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.55 (s, 0.5 H), 8.39 (s, 0.5H), 8.31-8.33 (m, 1H), 8.03-8.05 (m, 1H), 7.14-7.17(m, 1H), 6.81 (s, 1H), 6.59-6.65 (m, 1H), 4.47 (br, d, J=7.03 Hz, 2H), 4.09 (br, s, 0.5H), 3.94-4.04 (m, 3H), 3.82 (br s, 0.5H), 3.62-3.77 (m, 0.5 H), 3.03-3.29 (m, 3.5H), 2.52-2.55 (m, 3H), 2.13-2.32 (m, 2H), 1.88-2.08 (m, 3H), 1.58-1.70 (m, 1H), 1.33-1.47 (m, 1H), 1.09-1.19 (m, 1H), 0.17-0.30 (m, 4H).Example 2((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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

[0250] Intermediate 2A3-(tert-Butyl)-6-methyl 2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxypyrazolo[1,5-a]pyridine-3,6-dicarboxylate

[0251]

[0252] 1-Amino-3-methoxy-5-(methoxycarbonyl)pyridin-1-ium (Intermediate 1, 1.384 g, 7.56 mmol) and K 2 CO 3 (2.089 g, 15.11 mmol) were added to a stirred solution of tert-butyl 3-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)propiolate (Intermediate 4, 2.5 g, 7.56 mmol) in DMF (5 ml). The reaction mixture was stirred at a room temperature for 16 hours, diluted with EtOAc (50 ml), washed with water (3×50 ml), dried over Na 2 SO 4 , and concentrated to obtain a crude product, which was purified using a silica gel column (40 g, Redisep ®< SiO 2 column, eluting with 30% EtOAc in hexane) to afford the title compound (1.5 g, 39%) as a yellow liquid. LC-MS m / z: 511.2 [M+H] +< .Intermediate 2B2-(6-Chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-6-(methoxycarbonyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0253]

[0254] 2,6-Lutidine (0.684 ml, 5.87 mmol) and trimethylsilyl trifluoromethanesulfonate (0.530 ml, 2.94 mmol) were added to a solution of Intermediate 2A (1.5 g, 2.94 mmol) in DCM (20 ml). The reaction mixture was stirred at a room temperature for 30 min, diluted with DCM (30 ml), washed with 10% NaHCO 3 solution (3×50 ml), dried over Na 2 SO 4 , and concentrated to afford the title compound (1.5 g, 79%) as a brown solid. LC-MS m / z: 455.1 [M+H] +< .Intermediate 2CMethyl-2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carboxylate

[0255]

[0256] Borane dimethyl sulphide complex (3.30 ml, 6.60 mmol) was added to a stirred solution of Intermediate 2B (1 g, 2.198 mmol) in THF (10 ml) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, then heated to 65°C and stirred for 5 hours, quenched with methanol (5 ml), and the reaction contents were concentrated to afford the title compound as an off-white solid (200 mg, 22%). The crude compound was used in the next steps without further purification. LC-MS m / z: 425.1 [M+H] +< .Intermediate 2D2-(6-Chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carboxylic acid

[0257]

[0258] LiOH (141 mg, 5.88 mmol) was added to a stirred solution of Intermediate 2C (500 mg, 1.177 mmol) in a mixture of THF (3 ml), methanol (3 ml) and water (3 ml), and the reaction mixture was stirred at a room temperature for 30 min. The reaction mixture was concentrated under reduced pressure and the residue obtained was acidified with 1.5 N HCl. The separated solids were filtered, and dried under vacuum to afford the title compound (400 mg, 83%) as an off-white solid. LC-MS m / z: 411.1 [M+H] +< .Intermediate 2Etert-Butyl-((7R)-2-(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate

[0259]

[0260] HATU (555 mg, 1.460 mmol) and DIPEA (0.383 ml, 2.191 mmol) were added to a stirred solution of Intermediate 2D (300 mg, 0.730 mmol) and tert-butyl ((7R)-2-azabicyclo[2.2.1]- heptan-7-yl)carbamate (155 mg, 0.730 mmol) in DMF (5 ml). The reaction mixture was stirred at a room temperature for 12 hours, poured into ice water (10 ml), the solid product thus obtained was filtered, and dried under vacuum to afford the title compound (400 mg, 91%). LC-MS m / z: 605.4 [M+H] +< .Example 2

[0261] TFA (0.127 ml, 1.653 mmol) was added to a solution of Intermediate 2E (100 mg, 0.165 mmol) in DCM (5 ml). The reaction mixture was stirred at a room temperature for 1 hour, concentrated under reduced pressure, and the crude product obtained was purified using Prep-HPLC. The product was further purified using RP-HPLC to afford the title compound (12 mg, 14%). LC-MS m / z: 505.3 [M+H] +< . LC-MS retention time: 1.79 min ((Method E). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.55 (s, 0.5H), 8.39 (s, 0.5 H), 8.11 (d, J=8.03 Hz, 1H), 7.22 (d, J=8.53 Hz, 1H), 6.87 (s, 1H), 6.60-6.66 (m, 1H), 4.42 (br, d, J=7.03 Hz, 2H), 4.09 (s, 0.5H),3.99 (s, 3H), 3.81 (br, s, 0.5H), 3.48- 61 (m, 2H), 3.12-3.29 (m, 2H), 3.06-3.25 (m, 2H), 2.57-2.66 (m, 1H), 2.53 (br, s, 3H), 1.60-2.23 (m, 4H), 1.39-1.41 (m, 1H), 1.13-1.15 (m, 1H), 0.31 (br, d, J=8.03 Hz, 2H), 0.20 (br, d, J=4.02 Hz, 2H).Example 36-(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

[0262] Intermediate 3Atert-Butyl-((7R)-2-(2-(1-(cyclopropylmethyl)-6-(3-oxoisoindolin-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate

[0263]

[0264] PdCl 2 (dppf).CH 2 Cl 2 (13.50 mg, 0.017 mmol) was added to a degasified solution of Intermediate 2E (100 mg, 0.165 mmol), (3-oxoisoindolin-5-yl)boronic acid (43.9 mg, 0.248 mmol) and K 2 CO 3 (68.5 mg, 0.496 mmol) in dioxane (5 ml) and water (0.556 ml). The reaction mixture was heated to 100°C and stirred for 12 hours, filtered through a celite bed, and the filtrate was concentrated to afford a crude product, which was purified using Prep-HPLC to afford the title compound (16 mg, 14%). LC-MS m / z: 702.4 [M+H] +< . 1< H NMR (400 MHz, chloroform-d) δ ppm: 8.60 (s, 1H), 8.49-8.46 (m, 1H), 8.28-8.20 (m, 1H), 8.07-7.95 (m, 1H), 7.73-7.64 (m, 1H), 7.62-7.53 (m, 1H), 6.78 (s, 1H), 6.53 (s, 1H), 6.20-6.10 (m, 1H), 4.64-4.41 (m, 5H), 4.01 (s, 3H), 3.89-3.72 (m, 2H), 3.33-3.18 (m, 1H), 2.64-2.50 (m, 4H), 1.95 (br s, 2H), 1.41 (s, 9H), 1.34-1.14 (m, 2H), 0.38-0.25 (m, 4H).Example 3

[0265] TFA (0.016 ml, 0.214 mmol) was added to a solution of Intermediate 3A (15 mg, 0.021 mmol) in DCM (5 ml). The reaction mixture was stirred for 1 hour, concentrated, and the crude product obtained was purified using Prep-HPLC. The purified product was further purified using RP-HPLC to afford the title compound (7.42mg, 57%). LC-MS m / z: 602.2 [M+H] +< . HPLC retention time: 6.364 min (Method C). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.70-8.57 (m, 1H), 8.46-8.32 (m, 3H), 8.18-8.08 (m, 1H), 7.88-7.77 (m, 1H), 7.72-7.58 (m, 1H), 6.89-6.76 (m, 1H), 6.66-6.52 (m, 1H), 4.71-4.48 (m, 2H), 4.47-4.35 (m, 2H), 4.10-3.88 (m, 5H), 3.87-3.42 (m, 1H), 3.06-3.22 (m, 1H), 2.54-2.41 (m, 3H), 1.76-2.26 (m, 4H), 1.48-1.31 (m, 1H), 1.27-1.15 (m, 1H), 0.44-0.20 (m, 4H).

[0266] Compounds of Examples 4 to 12 in Table 1 were prepared following a procedure similar to the preparation of a compound of Example 3, using Suzuki coupling reaction of Intermediate 2E with appropriate boronic acid. Table 1ExampleStructure,Name,Analytical Data: LC-MS m / z [M+H] +< ; HPLC retention time (HPLC method)4 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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.Analytical data: 485.2, 4.452 min (Method C)5 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.Analytical data: 602.2, 6.281 min (Method C)6 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical data: 511.4, 7.977 min (Method C)7 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical data: 579.4, 6.603 min (Method C)8 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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.Analytical data: 602.3, 4.761 min (Method C)9 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical data: 581.3, 7.259 min (Method C)10 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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.Analytical data: 581.4, 4.619 min (Method C)11 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical data: 613.2, 5.878 min (Method C)12 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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.Analytical data: 631.3, 2.417 min (Method E) Example 13((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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

[0267] Intermediate 13Atert-Butyl-((7R)-2-(2-(1-(cyclopropylmethyl)-6-(3-methoxyazetidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate

[0268]

[0269] Pd 2 (dba) 3 (5.67 mg, 6.20 µmol) and 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RUPHOS, 15.42 mg, 0.033 mmol) were added to a degassed solution of Intermediate 2E (100 mg, 0.165 mmol), 3-methoxyazetidine (28.8 mg, 0.331 mmol) and caesium carbonate (162 mg, 0.496 mmol) in dioxane (5 ml). The reaction mixture was heated to 85°C and stirred for 12 hours, filtered, and the filtrate was concentrated under reduced pressure to afford the crude product, which was used in the next step without further purification. LC-MS m / z: 656.5 [M+H] +< .Example 13

[0270] TFA (0.117 ml, 1.525 mmol) was added to a stirred solution of Intermediate 13A (100 mg, 0.152 mmol) in DCM (5 ml). The reaction mixture was stirred for 1 hour, concentrated under reduced pressure, and the crude product obtained was purified using Prep-HPLC. The purified sample was further purified using RP-HPLC to afford the title compound (8.5mg, 10%). LC-MS m / z: 556.4 [M+H] +< . HPLC retention time: 7.703 min (Method C). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.56-8.34 (m, 1H), 7.78 (d, J=8.5 Hz, 1H), 6.62-6.57 (m, 2H), 6.27 (d, J=8.5 Hz, 1H), 4.35 (br, d, J=6.0 Hz, 4H), 4.27-4.13 (m, 2H), 3.98 (s, 6H), 3.84-3.58 (m, 5H), 3.29 3.06 (m, 1H),2.67-2.57 (m, 3H), 2.20-1.40 (m, 5H), 1.24-1.12 (m, 1H), 0.32-0.22 (m, 4H).Example 14((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

[0271] Intermediate 14Atert-Butyl-((3R,5R)-1-(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-5-fluoropiperidin-3-yl)carbamate

[0272]

[0273] Intermediate 14A was prepared following a procedure similar to the preparation of Intermediate 2E (20 mg, 52%). LC-MS m / z: 577.1 [M+H] +< .Example 14

[0274] TFA (0.027 ml, 0.347 mmol) was added to a stirred solution of Intermediate 14A (20 mg, 0.035 mmol) in DCM (1 ml) at a room temperature. The reaction mixture was stirred for 1 hour, concentrated under reduced pressure, and the crude product obtained was purified using Prep-HPLC. The purified product was further purified using RP-HPLC to afford the title compound (6 mg, 36%). LC-MS m / z: 477.1 [M+H] +< . LC-MS retention time: 1.374 min (method E). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.39 (s, 1H), 8.32 (dd, J=1.5, 4.6 Hz, 1H), 8.04 (dd, J=1.7, 7.8 Hz, 1H), 7.16 (dd, J=4.6, 7.8 Hz, 1H), 6.81 (s, 1H), 6.56 (s,1H), 4.89 (br, s, 1H), 4.47 (d, J=7.1 Hz, 2H), 3.98 (s, 4H), 3.03-2.98 (m, 2H), 2.55 (s, 3H), 2.21-2.11 (m, 1H), 1.35-1.09, (m, 3H), 0.32-0.14 (m, 4H).Example 15((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

[0275] Intermediate 15Atert-Butyl-((3R,5R)-1-(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-5-fluoropiperidin-3-yl)carbamate

[0276]

[0277] HATU (1296 mg, 3.41 mmol) and DIPEA (0.893 ml, 5.11 mmol) were added to a stirred solution of Intermediate 2D (700 mg, 1.704 mmol) and tert-butyl ((3R,5R)-5-fluoropiperidin-3-yl)carbamate (372 mg, 1.704 mmol) in DMF (5 ml). The reaction mixture was stirred at a room temperature for 12 hours, poured into ice water (40 ml), and the solids obtained were filtered, dried under vacuum to afford the title compound (1g, 67%) as an off-white solid. LC-MS m / z: 611.4 [M+H] +< .Example 15

[0278] TFA (0.252 ml, 3.27 mmol) was added to a stirred solution of Intermediate 15A (200 mg, 0.327 mmol) in DCM (5 ml). The reaction mixture was stirred at a room temperature for 1 hour, concentrated under reduced pressure, and the crude product obtained was purified using Prep-HPLC. The purified product was further purified using RP-HPLC to afford the title compound (21 mg, 12%). LC-MS m / z: 608.4 [M+H] +< . LC-MS retention time: 2.054 min (Method E). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.38 (s, 1H), 8.10 (d, J=8.07 Hz, 1H), 7.22 (d, J=8.07 Hz, 1H), 6.87 (s, 1H), 6.56 (s, 1H), 4.96-4.78 (m, 1H), 4.41 (d, J=7.09 Hz, 3H), 3.98 (s, 4H), 2.97 (br, s, 2H), 2.52-2.55 (m, 3H), 2.14 (br, s, 1H), 1.41-1.60 (m, 1H), 1.12-1.20 (m, 1H), 0.27-0.34 (m, 2H), 0.20-0.26 (m, 2H).Example 166-(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

[0279] Intermediate 16Atert-Butyl-((3R,5R)-1-(2-(1-(cyclopropylmethyl)-6-(3-oxoisoindolin-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-5-fluoropiperidin-3-yl)carbamate

[0280]

[0281] PdCl 2 (dppf).CH 2 Cl 2 (9.35 mg, 0.011 mmol) was added to a degassed solution of Intermediate 15A (70 mg, 0.115 mmol), (3-oxoisoindolin-5-yl)boronic acid (30.4 mg, 0.172 mmol) and K 2 CO 3 (47.5 mg, 0.344 mmol) in dioxane (5 ml) and water (0.556 ml). The reaction mixture was stirred at 100°C for 12 hours, filtered, and the filtrate was concentrated under reduced pressure to afford a crude product. The crude product was used in next the step without further purification. LC-MS m / z: 708.5 [M+H] +< .Example 16

[0282] TFA (0.076 ml, 0.989 mmol) was added to a solution of Intermediate 16A (70 mg, 0.099 mmol) in DCM (5 ml). The reaction mixture was stirred for 1 hour, concentrated under reduced pressure, and the crude product obtained was purified using Prep-HPLC. The purified product was further purified using RP-HPLC to afford the title compound (12 mg, 19%). LC-MS m / z: 608.4 [M+H] +< . HPLC retention time: 6.559 min (method E). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.65 (s, 1H), 8.48-8.41 (m, 3H), 8.16 (d, J=8.4 Hz, 1H), 8.10-7.98 (m, 1H), 7.99 (brs, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 6.95 (s, 1H), 6.59 (s, 1H), 5.08-4.55 (m, 1H), 4.59 (d, J=6.8 Hz, 3H), 4.46 (s, 3H), 4.00 (s, 3H), 3.20 (br d, J=10.5 Hz, 1H), 2.57-2.53 (m, 3H), 2.49-2.27 (m, 2H), 1.78-1.58 (m, 1H), 1.34-1.11 (m, 2H), 0.34-0.26 (m, 4H).

[0283] Compounds of Examples 17 to 21 in Table 2 were prepared following a procedure similar to the preparation of a compound of Example 16, using the Intermediate 15A and the appropriate boronic acid. Table 2ExampleStructureNameAnalytical Data: LC-MS m / z [M+H] +< ; HPLC retention time (HPLC method)17 ((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.Analytical Data: 491.4, 4.563 min (Method C)18 ((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)methanoneAnalytical Data: 585.5, 7.566 min (Method C)19 ((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)methanoneAnalytical Data: 585.5, 7.566 min (Method C)20 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-oneAnalytical Data: 608.3, 5.958 min (Method C)21 ((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)methanoneAnalytical Data: 608.4, 5.179 min (Method C) Example 22((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone

[0284] Intermediate 22A3-(tert-Butyl)-6-methyl 2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxypyrazolo[1,5-a]pyridine-3,6-dicarboxylate

[0285]

[0286] tert-Butyl-3-(1-(cyclopropylmethyl)-1H-indol-2-yl)propiolate (1g, 3.39 mmol) and K 2 CO 3 (0.468 g, 3.39 mmol) were added to a stirred solution of 1-amino-3-methoxy-5-(methoxy-carbonyl)pyridin-1-ium (Intermediate 1, 0.620 g, 3.39 mmol) in DMF (10 ml). The reaction mixture was stirred at a room temperature for 48 hours, quenched with water (100 ml), and extracted with EtOAc (2×100 ml). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a crude product, which was purified using a silica gel column (EtOAc in hexane). The product was isolated at 10-20% EtOAc in hexane, required fractions were collected and volatiles were evaporated to dryness under reduced pressure to afford the title compound (480 mg, 30%). LC-MS m / z: 476.2 [M+H] +< .Intermediate 22B2-(1-(Cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-6-(methoxycarbonyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0287]

[0288] Formic acid (0.028 ml, 0.736 mmol) was added to a solution of Intermediate 22A (350 mg, 0.736 mmol) in DCM (1 ml). The reaction mixture was stirred at a room temperature for 4 hours, quenched with saturated NaHCO 3 solution, and extracted with DCM (2×100 ml). The combined the organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford the crude title compound (150 mg, 49%) LC-MS m / z: 420.2 [M+H] +< .Intermediate 22CMethyl-2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carboxylate

[0289]

[0290] Borane dimethyl sulfide complex (0.834 ml, 1.669 mmol) was added to a stirred solution of Intermediate 22B (350 mg, 0.834 mmol) in THF (2 ml). The reaction mixture was stirred at 50°C for 5 hours, cooled to a room temperature, quenched with methanol, and concentrated under reduced pressure to afford a crude product, which was purified using a silica gel column (EtOAc in hexane (10-20%)) to afford the title compound (100 mg, 31%) LC-MS / z: 390.2 [M+H] +< .Intermediate 22D2-(1-(Cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carboxylic acid

[0291]

[0292] LiOH (9.39 mg, 0.392 mmol) was added to a stirred solution of Intermediate 22C (100 mg, 0.131 mmol) in THF (6 ml) and water (6 ml). The reaction mixture was stirred at a room temperature for 16 hours, concentrated under reduced pressure to evaporate THF, and acidified with 1N HCl. The solid product separated was filtered and dried under vacuum to afford the title compound (80 mg, 163%); LC-MS m / z: 376.2 [M+H] +< .Intermediate 22Etert-Butyl-((7R)-2-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate

[0293]

[0294] HATU (161 mg, 0.424 mmol), DIPEA (0.185 ml, 1.060 mmol) and tert-butyl ((7R)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate (90 mg, 0.424 mmol) were added to a stirred solution of Intermediate 22D (260 mg, 0.353 mmol) in DMF (2 ml) at 0°C. The reaction mixture was stirred at a room temperature for 2 hours, quenched with water (100 ml), and extracted with EtOAc (2×100 ml). The combined the organic layers were dried over sodium sulphate, filtered, and concentrated under reduced pressure to afford the crude product (100 mg, 49%). LC-MS m / z: 570.3 [M+H] +< .Example 22

[0295] TFA (0.022 ml, 0.281 mmol) was added to a stirred solution of Intermediate 24E (80 mg, 0.140 mmol) in DCM (2 ml). The reaction mixture was stirred at a room temperature for 16 hours, evaporated completely under reduced pressure, and the crude product obtained was purified using Prep-HPLC. The purified product was further purified using RP-HPLC to afford the title compound (13.4 mg, 20%). LC-MS m / z: 470.3 [M+H] +< . LC-MS retention time: 2.0 min (Method E). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.63-8.40 (m, 1H), 8.32-8.01 (m, 1H), 7.62 (t, J=7.3 Hz, 2H), 7.33-6.93 (m, 2H), 6.76 (s, 1H), 6.67-6.50 (m, 1H), 4.58-4.25 (m, 3H), 4.08-3.96 (m, 3H), 3.90 (s, 1H), 3.87-3.80 (m, 1H), 3.67-3.54 (m, 2H), 3.30-3.14 (m, 1H), 2.97-2.60 (m, 2H), 2.05-1.58 (m, 2H), 1.29-1.13 (m, 2H), 1.13-1.03 (m, 1H), 0.34-0.21 (m, 2H), 0.12 (q, J=4.8 Hz, 2H).Example 236-(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

[0296] Intermediate 23A3-(tert-Butyl)-6-methyl 2-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl) -4-methoxypyrazolo[1,5-a]pyridine-3,6-dicarboxylate

[0297]

[0298] tert-Butyl 3-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)propiolate (Intermediate 6, 5.5g, 14.69 mmol) and K 2 CO 3 (6.09 g, 44.1 mmol) were added to a solution of 1-amino-3-methoxy-5-(methoxycarbonyl)pyridin-1-ium 2,4-dinitrophenolate (Intermediate 1, 8.07 g, 22.04 mmol) in DMF (50 ml). The reaction mixture was stirred overnight, concentrated under a vacuum at ~45°C over a period of 1 hour, diluted with EtOAc, and filtered through a celite bed. The filtrate was further washed with water, dried over Na 2 SO 4 , filtered, and the organic layer was concentrated under vacuum to obtain a crude compound, which was purified using a silica gel column (40 g, Redisep ®< SiO 2 column, eluting with 30% EtOAc in hexane) to afford the title compound (5.3g, 65%). LC-MS m / z: 500.1 [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 9.04-8.91 (m, 1H), 8.56-7.96-7.84 (m, 1H), 7.63-7.53 (m, 1H), 7.30-7.06 (m, 2H), 6.80-6.70 (m, 1H), 4.44-4.30 (m, 2H), 3.96-3.86 (m, 6H), 1.43-1.36 (m, 8H), 1.12-1.02 (m, 1H), 0.34-0.24 (m, 2H), 0.18-0.12 (m, 2H).Intermediate 23B2-(6-Bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-6-(methoxycarbonyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0299]

[0300] 2,6-Lutidine (8.91 ml, 76 mmol) was added to a stirred solution of Intermediate 23A (5.3g, 9.56 mmol) in DCM (50 ml), followed by the addition of trimethylsilyl trifluoromethanesulfonate (6.91 ml, 38.2 mmol) at 0-5°C. The reaction mixture was stirred for 2 hours at the same temperature, quenched with 10% NaHCO 3 solution, stirred for 10 min, and diluted with EtOAc (50 ml). The organic layer was separated, and aqueous layer was extracted with EtOAc (3×25 ml). The combined organic layers were dried over Na 2 SO 4 , and concentrated under vacuum at a room temperature to obtain the title compound as a pale yellow syrup (5.5 g, 102%). LC-MS m / z: 500 [M+H] +< .Intermediate 23CMethyl-2-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carboxylate

[0301]

[0302] Borane-methyl sulfide complex (2.52 ml, 26.6 mmol) was added to a stirred solution of Intermediate 23B (5.3 g, 10.64 mmol) in THF (50 ml) at 0°C. The reaction mixture was stirred for 30 min, slowly heated to 50°C and stirred for 4 hours, followed by stirring at a room temperature for 12 hours. The reaction mixture was cooled to 0°C, quenched by careful addition of methanol, and concentrated under vacuum to obtain a crude residue. The crude product was triturated with water (3×25 ml), and the sticky off-white residue was purified using a silica gel column (40 g, Redisep ®< SiO 2 column, eluting with 0 to 50% EtOAc in hexane) to afford the title compound (1.1g, 22%). LC-MS m / z: 470.1 [M+H] +< .Intermediate 23D2-(6-Bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carboxylic acid

[0303]

[0304] LiOH (0.169 g, 7.05 mmol) in water (5 ml) was added to a stirred suspension of Intermediate 23C (1.1 g, 2.349 mmol) in a mixture of methanol (20 ml) and THF (5 ml). The reaction mixture was stirred for 4 hours, concentrated under vacuum to obtain a crude salt, which was neutralized using 1.5 N HCl. The solids obtained were filtered and dried under vacuum to afford the title compound (930 mg, 87%) as an off-white solid. LC-MS m / z: 455 [M+H] +< .Intermediate 23E tert-Butyl-((7R)-2-(2-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate

[0305]

[0306] HATU (250 mg, 0.658 mmol), DIPEA (0.265 ml, 1.519 mmol) and tert-butyl ((7R)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate (107 mg, 0.506 mmol) were successively added to a stirred solution of Intermediate 23D (230 mg, 0.506 mmol) in DMF (2 ml). The reaction mixture was stirred for 3 hours, cooled, and treated with ice-cold water and stirred for 10 min. The solids obtained were filtered, and dried in vacuum to afford the title compound (300 mg, 91%) as an off-white solid. LC-MS m / z: 650.3 [M+H]. 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.59-8.50 (m, 1H), 8.42-8.31 (m, 1H), 7.89 (s, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.14 -7.01 (m, 1H), 6.80 (s, 1H), 6.68-6.60 (m, 1H), 4.40 (br, d, J=6.4 Hz, 2H), 4.25-4.12 (m, 1H), 4.00 (br, s, 3H), 3.84-3.64 (m, 1H), 3.58-3.43 (m,1H), 3.21-2.86 (m, 2H), 2.44 (br, s, 3H), 2.33 (br, s, 1H), 2.08-1.74 (m, 3H), 1.35 (br, s, 10H), 0.29 (br d,J=7.6 Hz, 2H), 0.11 (br, s, 2H).Intermediate 23Ftert-Butyl-((7R)-2-(2-(1-(cyclopropylmethyl)-6-(3-oxoisoindolin-5-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate

[0307]

[0308] K 2 CO 3 (29.8 mg, 0.216 mmol) and PdCl 2 (dppf) (7.90 mg, 10.79 µmol) were added to a solution of Intermediate 23E (70 mg, 0.108 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (28.0 mg, 0.108 mmol) in dioxane (3 ml) in a 8 ml chemglass vial. The reaction mixture was degassed using argon, heated to 85°C and stirred for 8 hours, filtered, and concentrated under vacuum to afford a crude product, which was purified using Prep-HPLC to obtain the title compound (40 mg, 53%) as a white solid. LC-MS retention time: 0.94 min. LC-MS m / z: 701.5 [M+H] +< .Example 23

[0309] TFA (0.1ml, 1.298 mmol) was added to a solution of Intermediate 23F (40 mg, 0.057 mmol) in DCM (1 ml). The reaction mixture was stirred for 2 hours, concentrated under vacuum, the residue obtained was treated with 28% ammonia solution, and kept on standby for 30 min. The aqueous layer was decanted, and solids left in the flask were dried under vacuum. The crude product was further purified using RP-HPLC to afford the title compound (25 mg, 0.040 mmol, 70%), which was lyophilized to afford a white solid. LC-MS m / z: 601.4 [M+H] +< . HPLC retention time: 6.958 min (Method C). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.63-8.48 (m, 1H), 8.78-8.43 (m, 1H), 8.43-8.35 (m, 1H), 8.05-7.94 (m, 3H), 7.80-7.65 (m, 2H), 7.50-7.40 (m, 1H), 6.85-6.75 (m, 1H), 6.68-6.57 (m, 1H), 4.56-4.46 (m, 2H), 4.46-4.40 (m, 2H), 4.24-4.18 (m, 1H), 4.03-3.85 (m, 3H), 3.82-3.46 (m, 1H), 3.15-3.06 (m, 1H), 2.53 (s, 3H), 2.30-2.20 (m, 1H), 2.10-1.78 (m, 4H), 1.52-1.37 (m, 1H), 1.19-1.10 (m, 1H), 0.36-0.26 (m, 2H), 0.19-0.13 (m, 2H).

[0310] Compounds of Examples 24 to 28 in Table 3 were prepared following a procedure similar to the preparation of a compound of Example 23, using Suzuki coupling of Intermediate 23E with appropriate boronic acid. Table 3ExampleStructureNameAnalytical Data: LC-MS m / z [M+H] +< ; HPLC retention time (HPLC method )24 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-oneAnalytical Data: 601.4, 6.779 min (Method C)25 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 601.4, 5.325 min (Method C)26 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-(difluoromethoxy)phenyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanoneAnalytical Data: 612.4, 5.954 min (Method C)27 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(cyclopropylmethyl)-6-methyl-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanoneAnalytical Data: 484.3, 5.698 min ( Method C)28 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(6-cyclopropyl-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanoneAnalytical Data: 511.3, 4.777 min (Method C) Example 296-(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

[0311] Intermediated 29Atert-Butyl-((3R,5R)-1-(2-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-5-fluoropiperidin-3-yl)carbamate

[0312]

[0313] HATU (1742 mg, 4.58 mmol) followed by DIPEA (2.401 ml, 13.74 mmol) were added to a stirred solution of Intermediate 23D (2081 mg, 4.58 mmol) and tert-butyl ((3R,5R)-5-fluoropiperidin-3-yl)carbamate (1000 mg, 4.58 mmol) in DMF (3 ml). The reaction mixture was stirred at a room temperature overnight, cooled to 0°C, and ice-cold water was added. The solids obtained were filtered, washed with water, and purified using a silica gel column (0-1% methanol / chloroform) to afford the title compound (1.4g, 47%) as an off-white solid. LC-MS m / z: 655.4 [M+H] +< .Intermediate 29Btert-Butyl-((3R,5R)-1-(2-(1-(cyclopropylmethyl)-6-(3-oxoisoindolin-5-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-5-fluoropiperidin-3-yl)carbamate

[0314]

[0315] K 2 CO 3 (29.6 mg, 0.214 mmol) and PdCl 2 (dppf) (7.82 mg, 10.69 µmol) were added to a solution of Intermediate 29A (70 mg, 0.107 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (27.7 mg, 0.107 mmol) in dioxane (3 ml). The reaction mixture was degassed using argon, heated to 85°C and stirred for 8 hours, filtered, and the filtrate was concentrated under vacuum to obtain a crude compound, which was purified using Prep-HPLC to afford the title compound (40 mg, 53%) as a white solid. LC-MS m / z: 707.5 [M+H] +< .Example 29

[0316] TFA (0.1ml, 1.298 mmol) was added to a solution of Intermediate 29B (40 mg, 0.057 mmol) in DCM (1 ml). The reaction mixture was stirred for 2 hours, concentrated under vacuum, the crude compound obtained was treated with 28% ammonia solution, and kept on standby for 30 minutes. The aqueous layer was decanted, and the solids left in the flask were dried under vacuum. The product was further purified using RP-HPLC to afford the title compound (18 mg, 51%), which was lyophilized to afford white solid. LC-MS m / z: 607.4 [M+H] +< . HPLC retention time: 7.167 min (Method C). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.54 (s, 1H), 8.38 (s, 1H), 7.98 (d, J=5.5 Hz, 2H), 7.89 (d, J=7.5 Hz, 1H), 7.78-7.65 (m, 2H), 7.49 (d, J=8.3Hz, 1H), 6.81 (s, 1H), 6.56 (s, 1H), 5.02-4.92 (m, 1H), 4.55-4.41 (m, 5H), 4.00 (s, 4H), 3.50-3.36 (m, 1H), 3.28-3.05 (m, 1H), 2.47-2.35 (m, 3H), 1.92-1.89 (m, 1H), 1.69 (br d, J=1.0 Hz, 1H), 1.24-1.20 (m, 1H), 0.40-0.29(m, 2H), 0.21-0.11 (m, 2H).

[0317] Compounds of Examples 30 to 33 in Table 4 were prepared following a procedure similar to the preparation of a compound of Example 29, by Suzuki coupling of Intermediate 29A with appropriate boronic acid. Table 4ExampleStructureNameAnalytical Data: LC-MS m / z [M+H] +< ; HPLC retention time (HPLC method 1)30 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-oneAnalytical Data: 607.2, 6.951 min (Method C)31 ((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)methanoneAnalytical Data: 674, 5.471 min (Method C)32 ((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)methanoneAnalytical Data: 586.4, 1.964 min (Method E) Example 33((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

[0318] Intermediate 33Atert-Butyl-((3R,5R)-1-(2-(1-(cyclopropylmethyl)-6-(3-(methoxymethyl)azetidin-1-yl)-1H-indol-2-yl)-4-methoxy-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-5-fluoropiperidin-3-yl)carbamate

[0319]

[0320] Pd 2 (dba) 3 (12 mg, 0.013 mmol), Cs 2 CO 3 (100 mg, 0.307 mmol), and RUPHOS (13 mg, 0.028 mmol) were added to a solution of Intermediate 29A (65 mg, 0.099 mmol) and 3-(methoxymethyl)- azetidine (10.04 mg, 0.099 mmol) in dioxane (3 ml) in a 8 ml chemglass vial. The reaction mixture was degassed using argon, heated to 110°C and stirred for 14 hours, filtered, and concentrated under vacuum to afford a crude compound (70 mg, 104%), which was used in the next step without further purification. LC-MS m / z: 675.5 [M+H] +< .Example 33

[0321] TFA (0.3ml, 3.89 mmol) was added to a solution of Intermediate 33A (70 mg, 0.104 mmol) in DCM (1 ml). The reaction mixture was stirred for 2 hours, concentrated under vacuum, and the crude product obtained was purified using prep-HPLC. The product was further purified using RP-HPLC to afford the title compound (13 mg, 22%). LC-MS m / z: 575 [M+H] +< . LC-MS retention time: 1.963 min (Method E). 1< H NMR (400 MHz, methanol-d 4 ) δ ppm: 8.27 (d, J=1.0 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 6.59 (s, 1H), 6.55 (s, 2H), 6.45 (dd, J=2.0, 8.5 Hz, 1H), 5.01 -4.96 (m, 1H), 4.27 (d, J=6.5 Hz, 2H), 4.09-3.96 (m, 6H), 3.72-3.64 (m, 4H), 3.51-3.35 (m, 1H), 3.31-3.14 (m, 2H), 3.06-2.88(m, 1H), 2.88-2.68 (m, 1H), 2.53 (s, 3H), 2.45-2.19 (m, 1H), 1.75-1.54 (m, 1H), 1.42-1.23 (m, 1H), 1.19-0.99 (m, 1H), 0.35-0.28 (m, 2H), 0.13 -0.01 (m, 2H),

[0322] Compounds of Examples 34 to 37 in Table 5 were prepared following a procedure similar to the preparation of a compound of Example 33, by Buchwald coupling of Intermediate 29A with appropriate amine. Table 5ExampleStructureNameAnalytical Data: LC-MS m / z [M+H] +< ; HPLC retention time (HPLC method)34 ((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)methanoneAnalytical Data: 592.4, 1.216 min (Method E)35 ((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)methanoneAnalytical Data: 589.4, 1.970 min (Method E)36 ((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)methanoneAnalytical Data: 595.4, 1.712 min (Method E)37 ((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)methanoneAnalytical Data: 579.4, 1.428 min (Method F) Example 38((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone

[0323] Intermediate 38A3-(tert-Butyl)-6-methyl 2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoropyrazolo[1,5-a]pyridine-3,6-dicarboxylate

[0324]

[0325] Intermediate 38A was prepared following a procedure similar to the preparation of Intermediate 1A, and using 1-amino-3-fluoro-5-(methoxycarbonyl)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate (Intermediate 9) and tert-butyl 3-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)propiolate (Intermediate 2), as a pale yellow solid (200 mg, 43%). LC-MS m / z: 465.1 [M+H] +< .Intermediate 38B2-(1-(Cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-6-(methoxycarbonyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0326]

[0327] Intermediate 38B was prepared following a procedure similar to the preparation of Intermediate 1B, as a pale yellow solid (170 mg, 56%). LC-MS m / z: 409.2 [M+H] +< .Intermediate 38CMethyl-2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carboxylate

[0328]

[0329] Intermediate 38C was prepared following a procedure similar to the preparation of Intermediate 1C, as a brown solid (142 mg, 90%). LC-MS m / z: 379.2 [M+H] +< .Intermediate 38D2-(1-(Cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carboxylic acid

[0330]

[0331] Intermediate 38D was prepared following a procedure similar to the preparation of Intermediate, as an off white solid (125 mg, 93%). LC-MS m / z: 365.2 [M+H] +< .Intermediate 38Etert-Butyl-((7R)-2-(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate

[0332]

[0333] Intermediate 38E was prepared following a procedure similar to preparation of Intermediate 1E, as an off white solid (60 mg, 66%). LC-MS m / z: 559.3 [M+H] +< .Example 38

[0334] Compound of Example 38 was prepared following a procedure similar to the preparation of a compound of Example 1 (8.07 mg, 19%). LC-MS m / z: 459.3 [M+H] +< . HPLC retention time: 5.349 min (Method C). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.87-8.72 (m, 1H), 8.34 (dd, J=4.52, 1.51 Hz, 1H), 8.07 (dd, J=7.78, 1.76 Hz, 1H), 7.13-7.19 (m, 2H), 6.88 (s, 1H), 4.50 (br, d, J=6.53 Hz, 2H), 4.08-3.81 (m, 1H), 3.75-3.45 (m, 2H), 3.10-3.29 (m, 3H), 2.53 (s, 3H), 2.09-2.32 (m, 2H), 1.96 (br, s, 3H), 1.87-1.65 (m, 1H), 1.36-1.46 (m, 1H), 1.24 (s, 1H), 0.21-0.45 (m, 4H).Example 39((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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

[0335] Intermediate 39A3-(tert-Butyl)-6-methyl 2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoropyrazolo[1,5-a]pyridine-3,6-dicarboxylate:

[0336]

[0337] Intermediate 39A was preparedfollowing a procedure similar to the preparation of Intermediate 2A, as a yellow solid (1.5 g, 33%). LC-MS m / z: 499.1 [M+H] +< .Intermediate 39B2-(6-Chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-6-(methoxycarbonyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid:

[0338]

[0339] Intermediate 39B was prepared following a procedure similar to preparation of Intermediate 2B, as a brown solid (1.3 g, 98%). LC-MS m / z: 443.1 [M+H] +< .Intermediate 39CMethyl-2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carboxylate:

[0340]

[0341] Intermediate 39B was prepared following a procedure similar to the preparation of Intermediate 2C, as a brown solid (1.21 g, 50%). LC-MS m / z: 413.2 [M+H] +< .Intermediate 39D2-(6-Chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carboxylic acid:

[0342]

[0343] Intermediate 39D was prepared following a procedure similar to the preparation of Intermediate 2D, as a brown solid (1.2 g, 67%) as a brown solid. LC-MS m / z: 399.2 [M+H] +< .Intermediate 39Etert-Butyl-((7R)-2-(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate:

[0344]

[0345] Intermediate 39E was prepared following a procedure similar to the preparation of Intermediate 2E, as a brown solid (700 mg, 78%) as a brown solid. LC-MS m / z: 593.3 [M+H] +< .Example 39

[0346] Compound of Example 39 was prepared following a procedure similar to the preparation of a compound of Example 2 (7.2 mg, 8%). LC-MS m / z: 493.3 [M+H] +< . LC-MS retention time: 2.105 min (Method E). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.95-8.71 (m, 1H), 8.13 (d, J=8.3 Hz, 1H), 7.29-7.11 (m, 2H), 6.95 (s, 1H), 4.56-4.18 (m, 2.5H), 4.28-4.21 (s, 0.5H), 3.84-3.75 (m, 0.5 H), 3.57 (br s, 1.5H), 3.19 (br d, J=10.8 Hz, 0.5H), 2.69-2.58 (m, 1.5H), 2.03-1.81 (m, 3H), 1.69-1.58 (m, 1H), 1.28 -1.10 (m, 2H), 0.40-0.14 (m, 4H).Example 403((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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:

[0347] Intermediate 40Atert-Butyl-((7R)-2-(2-(1-(cyclopropylmethyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate:

[0348]

[0349] PdCl 2 (dppf). DCM complex (13.77 mg, 0.017 mmol) was added to a degassed and stirred solution of Intermediate 39E (100 mg, 0.169 mmol), trimethylboraxine (31.7 mg, 0.253 mmol), and K 2 CO 3 (69.9 mg, 0.506 mmol) in dioxane (5 ml) and water (0.556 ml). The reaction mixture was stirred at 100°C for 12 hours, filtered, and concentrated under reduced pressure to afford a crude compound. The crude compound was used in the next step without further purification. LC-MS m / z: 573.3 [M+H] +< .Example 40

[0350] Compound of Example 40 was prepared following a procedure similar to the preparation of Example 3 to obtain the tittle compound as a brown solid (15 mg, 18%). LC-MS m / z: 473.2 [M+H] +< . HPLC retention time: 4.76 min (Method C). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.90-8.77 (m, 1H), 8.04-7.93 (m, 1H), 7.23 (s, 1H), 7.08-7.04 (m, 2H), 6.96-6.81(m, 1H), 4.63-4.47 (m, 2.5H), 4.27 (brs, 0.5H), 3.80 (brs, 1H), 3.58 (brs, 2H), 2.62 (s, 3H), 2.53 (s, 3H), 2.02-1.85 (m, 2H), 1.70-1.66 (m, 1H), 1.28-1.02 (m, 3H), 0.41-0.19 (m, 4H).

[0351] Compounds of Examples 41 to 49 in Table 6 were prepared following a procedure similar to the preparation of a compound of Example 40, using Suzuki coupling of Intermediate 39E with appropriate boronic acid. Table 6ExampleStructureNameAnalytical Data: LC-MS m / z [M+H] +< ; HPLC retention time (HPLC method)41 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 499.4, 6.953 min (Method C)42 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-oneAnalytical Data: 590.2, 12.831 min (Method G)43 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 587.2, 5.439 min (Method C)44 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 619.4, 6.063 min (Method C)45 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 584.2, 5.467 min (Method C)46 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-oneAnalytical Data: 590.3, 6.629 min (Method C)47 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 601.4, 5.976 min (Method C)48 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 567.2, 7.351 min (Method C)49 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 569.3, 7.115 min (Method C) Example 50((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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

[0352] Intermediate 50Atert-Butyl-((7R)-2-(2-(1-(cyclopropylmethyl)-6-(3-methoxyazetidin-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]heptan-7-yl)carbamate

[0353]

[0354] Intermediate 50A was prepared following a procedure similar to the preparation of Intermediate 13A as a brown solid (crude 100 mg, 92%). LC-MS m / z: 644.5 [M+H] +< .Example 50

[0355] Compound of Example 50 was prepared following a procedure similar to the preparation of a compound of Example 13, as a brown solid (23 mg, 26%). LC-MS m / z: 544.4 [M+H] +< . HPLC retention time: 7.768 min (Method C). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.82 (s, 0.5H), 8.66 (s, 0.5 H), 7.80 (d, J=8.5 Hz, 1H), 7.13 (s, 1H), 7.10 (s, 1H), 6.68 (s, 1H), 6.29 (d, J=8.0 Hz, 1H), 4.53-4.28 (m, 4H), 4.27-4.14 (m, 2.5 H), 4.08 (br s, 0.5 H), 3.80 (dd, J=8.8, 4.3 Hz, 4H), 3.62-3.36 (m, 2H), 3.25-3.13 (m, 2H), 2.53 (m, 3H), 2.32-1.83 (m, 5H), 1.40-1.38 (m,1H), 1.22-1.20 (m 2H), 0.34-0.24 (m, 4H).Example 51((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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

[0356]

[0357] Compound of Example 51 was prepared following a procedure similar to the preparation of a compound of Example 50, by Buchwald coupling of Intermediate 39E with appropriate amine. LC-MS m / z: 558.4 [M+H] +< , HPLC retention time: 5.795 min (method C).Example 52((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

[0358] Intermediate 52Atert-Butyl-((3R,5R)-1-(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-5-fluoropiperidin-3-yl)carbamate

[0359]

[0360] Intermediate 52A was prepared following a procedure similar to the preparation of Intermediate 14A as off-white solid (40 mg, 43%). LC-MS m / z: 565.3 [M+H] +< , LC-MS retention time: 2.01 min.Example 52

[0361] Compound of Example 52 was prepared following a procedure similar to the preparation of a compound of Example 14 as off-white solid (7.73 mg, 23%). LC-MS m / z: 465.2 [M+H] +< . LC-MS retention time: 7.132 min (Method C). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.65-8.74 (m, 1H), 8.23-8.35 (m, 1H), 7.96-8.06 (m, 1H), 7.00-7.20 (m, 2H), 6.84 (s, 1H), 4.80-5.04 (m, 1H), 4.37-4.56 (m, 4H), 2.84-3.03 (m, 4H), 2.57 (s, 3H), 2.04-2.23 (m, 1H), 1.40-1.64 (m, 1H), 1.12-1.24 (m, 2H), 0.14-0.42 (m, 4H).Example 53((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

[0362] Intermediate 53Atert-Butyl-((3R,5R)-1-(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-5-fluoropiperidin-3-yl)carbamate

[0363]

[0364] Intermediate 53A was prepared following a procedure similar to the preparation of Intermediate 15A, as off-white solid (130 mg, 87%). LC-MS m / z: 599.2 [M+H] +< .Example 53

[0365] Compound of Example 53 was prepared following a procedure similar to the preparation of a compound of Example 15, as off-white solid (10.1 mg, 9%). LC-MS m / z: 499.2 [M+H] +< . LC-MS retention time: 2.058 min (Method E). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.79 (br s, 1H), 8.19-7.95 (m, 1H), 7.24 (d, J=8.3 Hz, 1H), 7.20-7.09 (m, 1H), 6.95 (s, 1H), 5.11-4.90 (m, 1H), 4.44 (d,J=7.1 Hz, 2H), 3.46-3.41 (m, 1H), 3.08-2.77 (m, 2H), 2.53 (s, 3H), 2.41-2.34 (m, 1H), 1.96-1.75 (m, 1H), 1.27-1.11 (m, 1H), 0.38-0.19 (m, 4H).Example 54((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

[0366] Intermediate 54Atert-Butyl-((3R,5R)-1-(2-(1-(cyclopropylmethyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-5-fluoropiperidin-3-yl)carbamate

[0367]

[0368] Intermediate 54A was prepared following a procedure similar to the preparation of Intermediate 16A, as off-white solid (70 mg, 91%). LC-MS m / z: 579.3 [M+H] +< .Example 54

[0369] Compound of Example 54 was prepared following a procedure similar to the preparation of a compound of Example 16, as off-white solid (9.8 mg, 15%). LC-MS m / z: 479.3 [M+H] +< . LC-MS retention time: 1.19 min (Method E). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.76-8.67 (m, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.15-6.98 (m, 2H), 6.80 (s, 1H),4.94-4.79 (m, 1H); 4.49-4.39 (m, 3H), 4.10 (ddd, J=6.4, 5.0, 2.6 Hz, 1H), 3.04-2.94 (m, 3H), 2.58 (s, 3H), 2.19-2.06 (m, 1H), 1.64-1.45 (m, 1H), 1.27-1.11 (m, 3H), 0.33-0.18 (m, 4H).

[0370] Compounds of Examples 55 to 57 in Table 7 were prepared following a procedure similar to the preparation of a compound of Example 54, by Suzuki coupling of Intermediate 53A with appropriate boronic acid. Table 7ExampleStructureNameAnalytical Data: LC-MS m / z [M+H] +< ; HPLC retention time (HPLC method)55 ((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)methanoneAnalytical Data: 575.2, 7.279 min (Method C)56 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-fluorobenzamideAnalytical Data: 602.3, 6.922 min (Method C)57 ((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)methanoneAnalytical Data: 505.3, 2.265 min (Method E) Example 58N-(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

[0371] Intermediate 58A3-(tert-Butyl)-6-methyl 2-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-fluoropyrazolo[1,5-a]pyridine-3,6-dicarboxylate

[0372]

[0373] Intermediate 58A was prepared following a procedure similar to the preparation of Intermediate 23A, as a pale yellow solid (2.0 g, 27%). LC-MS m / z: 543.9 [M+H] +< .Intermediate 58B2-(6-Bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-fluoro-6-(methoxycarbonyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0374]

[0375] Intermediate 58B was prepared following a procedure similar to the preparation of Intermediate 23B, as a pale yellow solid (2 g, 3.07 mmol, 89%). LC-MS m / z: 488.0 [M+H] +< .Intermediate 58CMethyl-2-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carboxylate

[0376]

[0377] Intermediate 58C was prepared following a procedure similar to the preparation of 23C as a pale yellow solid (crude 2.0g, 75%). LC-MS m / z: 458.1 [M+H] +< .Intermediate 58D2-(6-Bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carboxylic acid

[0378]

[0379] Intermediate 58D was prepared following a procedure similar to the preparation of Intermediate 23D, as a pale yellow solid (1.6 g, 83%). LC-MS m / z: 444.1 [M+H] +< .Intermediate 58Etert-Butyl-((7R)-2-(2-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate

[0380]

[0381] Intermediate 58E was prepared following a procedure similar to the preparation of Intermediate 23E, as a pale yellow solid (700 mg, 97%). LC-MS: m / z: 638.2 [M+H] +< .Intermediate 58Ftert-Butyl-((7R)-2-(2-(6-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate

[0382]

[0383] Intermediate 58F was prepared following a procedure similar to the preparation of Intermediate 23F as a pale yellow solid (70 mg, 95%). LC-MS m / z: 668.3 [M+H] +< .Example 58

[0384] Compound of Example 58 was prepared following a procedure similar to the preparation of a compound of Example 23, as a pale yellow solid (5 mg, 0.007 mmol, 8%). LC-MS m / z: 715.3 [M+H] +< . LC-MS retention time: 0.85 min (Method G).

[0385] Compounds of Examples 59 to 62 in Table 8 were prepared following a procedure similar to the preparation of a compound of Example 58, by Suzuki coupling of Intermediate 58E with appropriate boronic acid. Table 8ExampleStructureNameAnalytical Data: LC-MS m / z [M+H] +< ; HPLC retention time (HPLC method)59 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanoneAnalytical Data: 568.3, 3.8 min (Method C)60 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(cyclopropylmethyl)-6-(3-fluoro-4-hydroxyphenyl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanoneAnalytical Data: 568.3, 10.01 min (Method A)61 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(cyclopropylmethyl)-6-(4-fluoro-3-hydroxyphenyl)-1H-indol-2-yl)-4-fluoro-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanoneAnalytical Data: 568.3, 3.5 min (Method C)62 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 589.4, 1.16 min (Method C) Example 63((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanone

[0386] Intermediate 63A3-(tert-Butyl)-6-ethyl 2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)pyrazolo[1,5-a]pyridine-3,6-dicarboxylate

[0387]

[0388] K 2 CO 3 (839 mg, 6.07 mmol) and tert-butyl 3-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)propiolate (Intermediate 2, 600 mg, 2.024 mmol) were added to a stirred solution of 1-amino-3-(ethoxycarbonyl)pyridin-1-ium salt (Intermediate 8, 338 mg, 2.024 mmol) in acetone (25 ml). The reaction mixture was bubbled with air for 5 minutes, stirred overnight, filtered, and concentrated in vacuum to afford a crude compound, which was dissolved in EtOAc and washed with water. The organic layer was concentrated under vacuum to afford a crude compound, which was purified using a silica gel column to afford the title compound as a pale yellow solid (300 mg, 32%). LC-MS m / z: 461.2 [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.73 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.69-7.62 (m, 1H), 7.59-7.50 (m, 4H), 7.36 (t, J=6.8 Hz, 1H), 7.13 (br, t, J=7.3 Hz, 2H), 7.04-7.00 (m, 1H), 6.93 (s, 1H), 4.58-4.47 (m, 4H), 4.41 (d, J=1.5 Hz, 2H), 4.10 (s, 3H), 3.42 (s, 3H), 3.39-3.35 (m, 1H), 3.27 (br, s, 1H), 2.61-1.24 (s, 3H), 0.36-0.32 (m, 5H), 0.15 (s, 2H).Intermediate 63B2-(1-(Cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-6-(ethoxycarbonyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0389]

[0390] A solution of Intermediate 63A (300 mg, 0.651 mmol) in DCM (3 ml) and TFA (0.5 m) was stirred for 2 hours, and concentrated under reduced pressure at a room temperature to obtain a pale pink compound, which was dried over high vacuum to afford the title compound (200 mg, 76%). The crude compound was used in the next steps without further purification. LC-MS m / z: 405.2 [M+H] +< .Intermediate 63CEthyl-2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridine-6-carboxylate

[0391]

[0392] Intermediate 63C was prepared following a procedure similar to the preparation of Intermediate 1C, as a pale yellow solid (120 mg, 65%). LC-MS m / z: 375.1 [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 9.27-9.22 (m, 1H), 8.35-8.31 (m, 1H), 8.08-8.03 (m, 1H), 7.87-7.81 (m, 1H), 7.62 (d, J=9.3 Hz, 1H), 7.19-7.13 (m,1H), 6.94 (s, 1H), 4.59 (d, J=7.0 Hz, 2H), 4.40-4.34 (m, 2H), 2.48-2.45 (m, 3H), 1.37 (t, J=7.0 Hz, 3H), 1.29 -1.19 (m, 1H), 0.35-0.24 (m, 4H).Intermediate 63D2-(1-(Cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridine-6-carboxylic acid

[0393]

[0394] Intermediate 63D was prepared following a procedure similar to the preparation of Intermediate 1D, as off-white solid (110 mg, 99%). LC-MS m / z: 347 [M+H] +< .Intermediate 63Etert-Butyl-((7R)-2-(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate

[0395]

[0396] Intermediate 63C was prepared following a procedure similar to the preparation of Intermediate 1E (70 mg, 90%). LC-MS m / z: 541.3 [M+H] +< .Example 63

[0397] Compound of Example 63 was prepared following a procedure similar to preparation of Example 1 (9.0 mg, 15%). LC-MS m / z: 441.3 [M+H] +< . LC-MS retention time: 1.570 min (Method E). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.94-8.78 (m, 1H), 8.32 (d, J=4.6 Hz, 1H), 8.05 (dd, J=1.1, 7.7 Hz, 1H), 7.85-7.75 (m, 1H), 7.39-7.24 (m, 1H), 7.16 (dd, J=4.5, 7.7 Hz, 1H), 6.87 (s, 1H), 4.56 (br d, J=7.1 Hz, 2H), 3.93-3.90 (m, 1H), 3.77-3.68 (m, 1H), 3.65-3.46 (m, 2H), 3.32-3.06 (m, 2H), 2.63-2.52 (m, 1H), 2.48-2.36 (m, 3H), 2.02-1.84 (m, 2H), 1.80-1.65 (m, 1H), 1.54-1.37 (m, 1H), 1.30-1.13 (m, 1H), 0.31-0.19 (m, 4H).Example 645-(2-(6-((7R)-7-Amino-2-azabicyclo[2.2.1]heptane-2-carbonyl)-3-methylpyrazolo[1,5-alpyridin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)isoindolin-1-one

[0398] Intermediate 64A3-(tert-Butyl)-6-ethyl 2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)pyrazolo[1,5-a]pyridine-3,6-dicarboxylate

[0399]

[0400] Intermediate 64A was prepared following a procedure similar to the preparation of Intermediate 2A (2 g, 30%). LC-MS m / z: 495.2 [M+H] +< .Intermediate 64B2-(6-Chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-6-(ethoxycarbonyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0401]

[0402] Intermediate 64B was prepared following a procedure similar to the preparation of Intermediate 2B (1.5 g, 85%). LC-MS m / z: 441.3 [M+H] +< .Intermediate 64CEthyl-2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridine-6-carboxylate

[0403]

[0404] Intermediate 64C was prepared following a procedure similar to the preparation of Intermediate 2C (240 mg, 0.05 mmol, 86%). LC-MS m / z: 409.2 [M+H] +< .Intermediate 64D2-(6-Chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridine-6-carboxylic acid

[0405]

[0406] Intermediate 63D was prepared following a procedure similar to the preparation of Intermediate 2D (900 mg, 88%). LC-MS m / z: 381.1 [M+H] +< .Intermediate 64Etert-Butyl-((7R)-2-(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate

[0407]

[0408] Intermediate 64E was prepared following a procedure similar to the preparation of Intermediate 2E (1.2 g, 88%). LC-MS m / z: 575.3 [M+H] +< .Intermediate 64Ftert-Butyl-((7R)-2-(2-(1-(cyclopropylmethyl)-6-(1-oxoisoindolin-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate

[0409]

[0410] Intermediate 63F was prepared following a procedure similar to the preparation of Intermediate 3A (50 mg, 61%). LC-MS m / z: 672.4 [M+H] +< .Example 64

[0411] Compound of Example 64 was prepared following a procedure similar to the preparation of compound of Example 3 (8.88 mg, 17%). LC-MS m / z: 672.4 [M+H] +< . HPLC retention time: 5.956 min (Method C). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 9.01 -8.88 (m, 1H), 8.61 (s, 1H), 8.37 (s, 1H), 8.32 (d, J=7.8 Hz, 1H), 8.18 (d, J=8.0 Hz, 1H), 8.12-7.91 (m, 3H), 7.90-7.77 (m, 2H), 7.40-7.28 (m, 1H), 6.95 (s, 1H), 4.69 (br d, J=6.0 Hz, 2H), 4.50 (s, 2H), 4.25 (br s, 1H), 3.82 (br dd, J=3.0, 9.5 Hz, 1H), 3.71-3.51 (m, 2H), 3.48-3.36 (m, 1H), 3.19-3.07 (m, 1H), 2.70-2.53 (m, 1H), 2.46-2.43 (m, 3H), 2.06-1.80 (m, 3H), 1.77-1.60 (m, 1H), 1.34-1.15 (m, 1H), 0.38-0.30 (m, 4H).

[0412] Compounds of Examples 65 to 75 in Table 9 were prepared following a procedure similar to the preparation of a compound of Example 64, by Suzuki coupling of Intermediate 64E with appropriate boronic acid. Table 9ExampleStructureNameAnalytical Data: LC-MS m / z [M+H] +< ; HPLC retention time (HPLC method)65 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-oneAnalytical Data: 572.3, 6.015 min (Method C)66 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(1-(cyclopropylmethyl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanoneAnalytical Data: 455.3, 5.696 min (Method C)67 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 551.3, 6.268 min (Method C)68 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 551.4, 6.502 min (Method C)69 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-fluorobenzamideAnalytical Data: 578.4, 7.954 min (Method C)70 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 572.4, 5.613 min (Method C)71 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-2-yl)(2-(6-cyclopropyl-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridin-6-yl)methanoneAnalytical Data: 481.3, 1.588 min (Method F)72 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 566.3, 1.893 min (Method F)73 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 601.3, 1.987 min (Method F)74 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 569.3, 1.648 min (Method F)75 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 551.3, 1.639 min (Method F) Example 76((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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

[0413] Intermediate 76Atert-Butyl-((7R)-2-(2-(1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-2-azabicyclo[2.2.1]heptan-7-yl)carbamate

[0414]

[0415] Intermediate 76A was prepared following a procedure similar to the preparation of Intermediate 13A (50 mg, 63%). LC-MS m / z: 654.5 [M+H] +< .Example 76

[0416] Compound of Example 76 was prepared following a procedure similar to the preparation of compound of Example 13 (9.1 mg, 16%). LC-MS m / z: 554.4 [M+H] +< . LC-MS retention time: 1.994 min (Method E). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.99-8.71 (m, 1H), 8.11-7.93 (m, 2H), 7.87-7.67 (m, 1H), 7.56-7.20 (m, 2H), 6.82-6.72 (m, 1H), 6.66 (s, 1H), 4.48-4.41 (m, 2H), 4.27-4.20 (m, 1H), 4.09-3.98 (m, 3H), 3.65-3.54 (m, 2H), 3.49-3.41 (m, 2H), 3.26-3.22 (m, 3H), 3.24-3.16 (m, 1H), 2.72-2.59 (m, 2H),2.42 (s, 3H), 2.02-1.84 (m, 5H), 1.76-1.61 (m, 1H), 1.54-1.41 (m, 2 H), 1.27-1.24 (m, 1H), 0.39-0.22 (m, 4H).

[0417] Compounds of Examples 77 to 79 in Table 10 were prepared following a procedure similar to the preparation of a compound of Example 76, by Buchwald coupling of Intermediate 64E with appropriate amines. Table 10ExampleStructureNameAnalytical Data: LC-MS m / z [M+H] +< ; HPLC retention time (HPLC method)77 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 540.4, 1.078 min (Method F)78 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 540.4, 1.235 min (Method F)79 ((7R)-7-Amino-2-azabicyclo[2.2.1]heptan-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)methanoneAnalytical Data: 526.4, 1.393 min (Method F) Example 80((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

[0418] Intermediate 80Atert-Butyl-((3R,5R)-1-(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-5-fluoropiperidin-3-yl)carbamate

[0419]

[0420] Intermediate 80A was prepared following a procedure similar to the preparation of Intermediate 14A (50 mg, 63%). LC-MS m / z: 547.3 [M+H] +< .Example 80

[0421] Compound of Example 80 was prepared following a procedure similar to the preparation of Example 14 (21.2 mg, 43%). LC-MS m / z: 447.3 [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.79 (s, 1H), 8.33 (dd, J=1.6, 4.8 Hz, 1H), 8.05 (dd, J=1.5, 7.8 Hz, 1H), 7.82 (d, J=9.3 Hz, 1H), 7.23 (dd, J=1.2, 9.3Hz, 1H), 7.16 (dd, J=4.6, 7.8 Hz, 1H), 6.87 (s, 1H), 5.04-4.80 (m, 1H), 4.55 (d, J=7.1 Hz, 3H), 3.91 (s, 2H), 3.03-2.95 (m, 1H), 2.45 (s, 3H), 2.22-2.09 (m, 1H), 1.65-1.41 (m, 1H), 1.29-1.15 (m, 1H), 0.34-0.21 (m, 4H).Example 815-(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

[0422] Intermediate 81Atert-Butyl-((3R,5R)-1-(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-5-fluoropiperidin-3-yl)carbamate

[0423]

[0424] Intermediate 81A was prepared following a procedure similar to the preparation of Intermediate 15A (600 mg, 79%). LC-MS m / z: 581.3 [M+H] +< .Intermediate 81Btert-Butyl-((3R,5R)-1-(2-(1-(cyclopropylmethyl)-6-(1-oxoisoindolin-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl)-5-fluoropiperidin-3-yl)carbamate

[0425]

[0426] Intermediate 81B was prepared following a procedure similar to the preparation of Intermediate 16A (50 mg, 61%). LC-MS m / z: 678.4 [M+H] +< .Example 81

[0427] Compound of Example 81 was prepared following a procedure similar to the preparation of Example 16 (7.1 mg). LC-MS m / z: 578.4 [M+H] +< . LC-MS retention time: 1.576 min (Method E). 1< H NMR (400 MHz, DMSO-d 6 ) δ ppm: 8.86-8.77 (m, 1H), 8.66-8.56 (m, 1H), 8.42-8.28 (m, 2H), 8.17 (d, J=8.1 Hz, 1H), 7.88-7.76 (m, 3H), 7.24 (d, J=8.4 Hz, 1H), 6.93 (s, 1H), 5.08-4.82 (m, 1H), 4.73-4.59 (m, 2H), 4.56-4.38 (m, 2H), 4.22-4.12 (m, 1H), 4.12-3.85 (m, 1H), 3.09-2.95 (m, 2H), 2.48-2.38 (m, 3H), 2.24-2.11 (m, 1H), 1.98-1.82 (m, 1H), 1.68-1.42 (m, 1H), 1.39-1.14 (m, 1H), 0.37-0.30 (m, 4H).

[0428] Compounds of Examples 82 to 86 in Table 11 were prepared following a procedure similar to the preparation of a compound of Example 81, by Suzuki coupling of Intermediate 81A with appropriate boronic acid. Table 11ExampleStructureNameAnalytical Data: LC-MS m / z [M+H] +< ; HPLC retention time (HPLC method)82 ((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)methanoneAnalytical Data: 461.4, 1.129 min (Method F)83 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-oneAnalytical Data: 578.3, 1.440 min (Method F)84 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-fluorobenzamideAnalytical Data: 584.3, 1.623 min (Method F)85 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-chlorobenzamideAnalytical Data: 600.3, 1.454 min (Method F)86 ((3R,5R)-3-Amino-5-fluoropiperidin-1-yl)(2-(1-(cyclopropylmethyl)-6-(2-fluoro-3-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl...

Claims

1. A compound of Formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: is selected from X1 is independently selected from CR2, and N; X2 is independently selected from CR4, and N; X4 is independently selected from CR2, and N; provided X1 and X4 are not both N; X5 is independently selected from O and S; X6 is independently selected from CR4, and N; provided 1) X2 and X6 are not both N; 2) when X2 and X6 are both CR4, one of R4 is H; R1 is independently selected from R2 is independently selected from H, F, Cl, C1-4 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH, and -OC1-4 alkyl; R3 is independently selected from H, F, Cl, CN, -C(=O)ORb, and C1-3 alkyl optionally substituted with one or more substituents selected from F, Cl, OH, NH2, and N3; R4 is independently selected from H, F, Cl, C1-5 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH, C3-6 cycloalkyl, R7 is independently selected from H, F, and Cl; R8 is independently selected from H, and C1-6 alkyl optionally substituted with one or more substituents selected from F, Cl, and C3-6 cycloalkyl; Rb is independently selected from H, C1-6 alkyl optionally substituted with one or more Re, C2-6 alkenyl optionally substituted with one or more Re, C2-6 alkynyl optionally substituted with one or more Re, -(CH2)r-C3-10 carbocyclyl optionally substituted with one or more Re, and -(CH2)r-heterocyclyl optionally substituted with one or more Re; Re is independently selected from F, Cl, Br, CN, NH2, -NH-C1-4 alkyl, -N(C1-4 alkyl)2, =O, OH, -OC1-6 alkyl, -CO2H, C1-6 alkyl optionally substituted with one or more Rf, C2-6 alkenyl, C2-6 alkynyl, -(CH2)r-C3-6 cycloalkyl optionally substituted with one or more Rf, -(CH2)r-aryl optionally substituted with one or more Rf, and -(CH2)r-heterocyclyl optionally substituted with one or more Rf, Rf is independently selected from F, Cl, Br, CN, OH, OC1-5 alkyl, C1-5 alkyl optionally substituted with OH, C2-5 alkenyl, C2-5 alkynyl, C3-6 cycloalkyl, and phenyl; and r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.

2. The compound according to claim 1, having Formulae (IIa)-(XIII): or or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, having Formula (IIa): or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from R2 is independently selected from H, F, Cl, C1-3 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH, and OC1-3 alkyl; and R3 is independently selected from H, F, Cl, and C1-3 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH.

4. The compound according to claim 1, having Formula (IIIa): or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from R2 is independently selected from H, F, Cl, C1-3 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH, and OC1-3 alkyl; and R3 is independently selected from H, F, Cl, and C1-3 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH.

5. The compound according to claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from R2 is independently selected from H, F, Cl, CH3, and OCH3; R3 is independently selected from H, F, Cl, CH3, and CH2OH; R7 is H; and R8 is C1-3 alkyl substituted with one C3-6 cycloalkyl.

6. The compound according to claim 1, having Formula (IVa): or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from R2 is independently selected from H, F, Cl, C1-3 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH, and OC1-3 alkyl; R3 is independently selected from H, F, Cl, and C1-3 alkyl optionally substituted with one or more substituents selected from F, Cl, and OH; preferably wherein: R1 is independently selected from R2 is independently selected from H, F, Cl, and OCH3; R3 is independently selected from F, Cl, and CH3; R7 is H; and R8 is C1-2 alkyl optionally substituted with cyclopropyl; more preferably wherein: R4 is independently selected from 7. The compound according to claim 1, having Formula (Va): or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from R2 is independently selected from H, F, Cl, CH3, and OCH3; R3 is independently selected from H, F, Cl, CN, CH3, and CH2OH; preferably wherein: R1 is independently selected from R2 is CH3; R3 is CH3; R4 is independently selected from R7 is H; and R8 is C1-2 alkyl optionally substituted with cyclopropyl.

8. The compound according to claim 1, having Formula (VIa): or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from and R3 is independently selected from H, F, and CH3; preferably wherein: R1 is independently selected from R3 is CH3; R4 is independently selected from F, Cl, R7 is H; and R8 is C1-2 alkyl optionally substituted with cyclopropyl.

9. The compound according to claim 1, having Formula (VII): or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from R2 is independently selected from H, F, Cl, CH3, and OCH3; and R3 is independently selected from H, F, and CH3.

10. The compound according to claim 1, having Formula (VIII): or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from R2 is independently selected from H, F, and OCH3; and R3 is independently selected from H, F, and CH3.

11. The compound according to claim 1, having Formula (XIII): or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from R2 is independently selected from H, F, CH3, and OCH3; and R3 is independently selected from H, F, and CH3.

12. The compound according to claim 1, 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]heptan-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]heptan-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]heptan-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]heptan-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-ethylpyrazolo[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]heptan-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]heptan-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]heptan-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]heptan-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]heptan-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]heptan-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]heptan-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]heptan-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]heptan-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]heptan-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]heptan-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]heptan-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; 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]heptan-7-amine; (7R)-2-{2-[1-(Cyclopropylmethyl)-6-{3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl}-1H-1ndol-2-yl]-4-fluoro-3-methylpyrazolo[1,5-a]pyridine-6-carbonyl}-2-azabicyclo[2.2.1]heptan-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]heptan-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]heptan-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]heptan-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]heptan-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]heptan-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]heptan-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; 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, SR)-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; Methyl 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-carboxylate; (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.

13. A pharmaceutical composition comprising a compound according to any one of the claims 1-12, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

14. A compound according to any one of claims 1-12, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a composition according to claim 13, for use in therapy.

15. A compound according to any one of claims 1-12, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a composition according to claim 13, for use in treating a disease or disorder associated with PAD4 enzyme activity selected from rheumatoid arthritis, Alzheimer's disease, multiple sclerosis, lupus, Parkinson's disease, and cancer.