Substituted pyrazolopyridines

Abstract

Disclosed herein are substituted pyrazolopyridines, methods for their preparation, and use thereof.

Description

Substituted PyrazolopyridinesCross-reference to related applications

[0001] This application claims priority from U.S. Provisional Application No. 63 / 517,413, filed August 3, 2023, the disclosure of which is hereby incorporated by reference in its entirety.Field

[0002] This disclosure is directed to substituted pyrozalopyridines, and more particularly to such compounds that inhibit LRRK2 kinase activity and therefore useful in the treatment of diseases or disorders associated with LRRK2 kinase activity. The disclosure is directed to compounds and compositions that inhibit LRRK2 kinase activity, methods of treating a disease or disorder associated with LRRK2 kinase activity (e.g., Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, ischemic stroke, traumatic brain injury, and spinal cord injury), and methods of using LRRK2 kinase inhibitors in combination with one or more additional disorder therapy.Background

[0003] Parkinson’s disease (PD) is a neurodegenerative disorder charactered by selective degeneration and cell death of dopaminergic neurons in the substantial nigra region of the brain. Globally, the prevalence of PD has doubled in the past 25 years, with a global estimate in 2019 of over 8.5 million individuals living with PD. Disability and death due to PD are increasing faster than for any other neurological disorders.

[0004] PD was generally considered to be sporadic and of unknown etiology, but in the past 15 years, there has been an important development of the understanding of the genetic basis of this disease and the pathogenic mechanisms associated therewith. In general, PD is a degenerative condition of the brain associated with motor symptoms (e.g., slow movement, tremor, rigidity, and walking imbalance) and a wide variety of non-motor complications (e.g., cognitive impairment, mental health disorders, pain, and other sensory disturbances). Motor impairments, including involuntary movements (i.e., dyskinesias) and painful involuntary muscle contractions (i.e., dystonias), both contribute to limitations in speech and mobility, and thus restrictions in many areas of life. Progression of these symptoms and complications markedly decrease functioning and quality of life, which result in high rates of disability and care requirements. Pathologically, the disease is identified by the loss of dopaminergic neurons, with a consequent decrease in dopamine levels in the brain and by aggregation of the protein a-synuclein in the dopaminergic neurons. Current PD therapies aim at increasing the dopamine levels in areas innervated by dopaminergic neurons in the brain; however, noneaddress the underlying disease-causing problem. Many alternative approaches to treating PD are therefore under investigation, one of which is inhibition of leucine-rich repeat kinase 2 (LRRK2).

[0005] LRRK2 kinase is a 286 kDa cytoplasmic protein containing kinase and guanine nucleotide-binding proteins (GTPase) domains as well as multiple protein-protein interaction domains. In vitro biochemical studies have demonstrated that LRRK2 proteins harboring the PD-associated proteins generally confer increased kinase activity and decreased GTP hydrolysis compared to the wild type protein, suggesting that small molecule inhibitors may be used to inhibit aberrant LRRK2-dependent signaling in PD. In support of this notion, it has been reported that inhibitors of LRRK2 are protective in models of PD.

[0006] Approximately 10% of PD cases are attributed to inherited genetic mutations, while the rest are considered idiopathic or sporadic. The G2019S mutation in the LRRK2 protein is the most common pathogenic mutation, accounting for about 1 to 6% of sporadic and about 3 to 19% of familial PD cases. Additionally, common variants in the LRRK2 locus are known risk factors for idiopathic PD (IPD). Indeed, it has been argued that LRRK2 provides a link between genetic and idiopathic forms of PD. Oxidative stress and endolysosomal impairment, both of which have critical roles in PD, activate LRRK2 kinase activity. Similarly, environmental toxicants, implicated epidemiologically in PD risks, also activate LRRK2. Moreover, in vivo blockade of LRRK2 activity is protective in genetic and toxicant models of PD. As noted, early- stage clinical trials of LRRK2-based therapeutics are already underway.

[0007] A growing body of evidence suggests a role for LRRK2 in immune cell function in the brain with LRRK2 inhibitors demonstrated to attenuate microglial inflammatory responses. As neuroinflammation is a hallmark of a number of neurodegenerative diseases (e.g., PD, Alzhemimer’s disease (AD), multiple sclerosis (MS), HIV-induced dementia, amyotrophic lateral sclerosis (ALS), ischemic stroke, traumatic brain injury, and spinal cord injury), LRRK2 kinase inhibitors may have utility in the treatment of neuroinflammation in these disorders. LRRK2 mutations have been associated with Alzheimer's-like pathology, and the LRRK2 RI628P variant has been associated with an increased risk of developing AD. Mutations in LRRK2 have also been identified that are clinically associated with the transition from mild cognitive impairment to Alzheimer's disease. Together these data suggest that LRRK2 inhibitors may be useful in the treatment of Alzheimer's disease and other dementias and related neurodegenerative disorders.

[0008] As such, LRRK2 kinase is a prime target for drug development.Summary

[0009] In one aspect, the present disclosure provides compounds of Formula (I):or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, wherein:R1is hydrogen, Ci-Ce alkyl, C3-C6 cycloalkyl, halogen, halo Ci-Ce alkyl, -OR6, cyano, -NR7R8, or -NHC(O)R9, whereinR6is hydrogen, Ci-Ce alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl Ci-Ce alkyl, 3-6 membered heterocyclyl, or 3-6 membered heterocyclyl Ci-Ce alkyl; each of R7and R8is independently hydrogen, Ci-Ce alkyl, or together with the nitrogen to which they are attached form a 3-8 membered monocyclic heterocyclyl group; andR9is Ce-C aryl, 5- or 6-membered heteroaryl, or Ci-Ce alkyl, wherein the Ce-Cw aryl is optionally substituted with Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, -OR9A, cyano, or -NR9BR9C, whereinR9Ais hydrogen or Ci-Ce alkyl, and each of R9Band R9Cis independently hydrogen or Ci-Ce alkyl; the 5- or 6-membered heteraryl comprises one nitrogen atom and is optionally substituted with Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, -OR9A, cyano, or - NR9BR9C, and the Ci-Ce alkyl is optionally substituted with halogen, -SO2CH3, cyano, 5- or 6- membered heteroaryl, -OR9D, or -NR9ER9F, whereinR9Dis hydrogen, Ci-Ce alkyl, or 5- or 6-membered heteroaryl comprising one nitrogen atom and optionally substituted with Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, -OR9A, cyano, or -NR9BR9C, and each of R9Eand R9Fis independently hydrogen, Ci-Ce alkyl, -SO2CH3, or 5- or 6-membered heteroaryl comprising one nitrogen atom;R2is hydrogen, -NHC(O)R10, or -C(O)NHR11, wherein each of R10and R11is independently hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3;R3is hydrogen or halogen;R4is hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy;R5is hydrogen or halogen; andQ is a 3-8 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom; the heterocyclyl group is optionally fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen, oxygen, or sulfur atoms and the remainder are carbons; the heterocyclyl group is optionally substituted with 1-4 R12groups, wherein each R12is independently Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy; and the heterocyclyl group is optionally substituted with one R13group, wherein R13is hydrogen, Ci-Ce alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or Ci-Ce alkyl, and R15is hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3.

[0010] In another aspect, the present disclosure provides for a pharmaceutical composition comprising a compound or salt as otherwise described herein together with a pharmaceutically acceptable carrier, excipient, or diluent.

[0011] In another aspect, the present disclosure provides for a method of treating a disease or disorder associated with LRRK2 kinase activity, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound as otherwise described herein or a pharmaceutical composition as otherwise described herein.

[0012] In another aspect, the present disclosure provides for a method of inhibiting LRRK2 kinase activity, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound as otherwise described herein or a pharmaceutical composition as otherwise described herein.

[0013] In another aspect, the present disclosure provides for a method of treating Parkinson’s disease, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound as otherwise described herein or a pharmaceutical composition as otherwise described herein.

[0014] In another aspect, the present disclosure provides intermediates as described herein, such intermediates being suitable for use in a process for preparing a compound as described herein.

[0015] Other aspects and embodiments of the disclosure are evident in view of the detailed description provided herein.DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention relates to LRRK2 kinase inhibitors. In particular, the present invention relates to compounds that inhibit LRRK2 kinase activity, pharmaceuticalcompositions comprising a therapeutically effective amount of the compounds, and methods of use therefor.DEFINITIONS

[0017] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents, patent applications, and publications referred to herein are incorporated by reference to the extent they are consistent with the present disclosure. Terms and ranges have their generally defined definition unless expressly defined otherwise.

[0018] For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms may also be used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an “alkyl” moiety generally refers to a monovalent radical (e.g. CH3-CH2-), in certain circumstances a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term “alkylene.” Similarly, in circumstances in which a divalent moiety is required and is stated as being “aryl,” those skilled in the art will understand that the term “aryl” refers to the corresponding divalent moiety, arylene. All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S).

[0019] The term “amino” refers to -NH2.

[0020] The term “acetyl” refers to -C(O)CH3.

[0021] As herein employed, the term “acyl” refers to an alkylcarbonyl or arylcarbonyl substituent wherein the alkyl and aryl portions are as defined herein.

[0022] The term “alkyl” as employed herein refers to saturated straight and branched chain aliphatic groups having from 1 to 12 carbon atoms. As such, “alkyl” encompasses Ci , C2, C3, C4, C5, Ce, C7, Cs, C9, C10, C11 , and C12 groups. Alkyl groups may be branched or unbranched. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0023] The term “alkenyl" as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms. As such, “alkenyl” encompasses C2, C3, C4, C5, Ce, C7, Cs, C9, C10, C11, and C12 groups. Examples of alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0024] The term “alkynyl" as used herein means an unsaturated straight or branched chainaliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms. As such, “alkynyl” encompasses C2, C3, C4, C5, Ce, C7, Cs, C9, C10, Cn, and C12 groups. Examples of alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0025] An “alkylene,” “alkenylene,” or “alkynylene” group is an alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Examples of alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene. Examples of alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene. Examples of alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.

[0026] The term “alkoxy” refers to -O(Ci-Ce alkyl).

[0027] The term “cycloalkyl” as employed herein is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons. As such, “cycloalkyl” includes C3, C4, C5, Ce, C7, Cs, C9, C10, C11 , and C12 cyclic hydrocarbon groups. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0028] The term “C3-C6 cycloalkyloxy” refers to groups of the formula -O(C3-Ce cycloalkyl).

[0029] The term “heteroalkyl” refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are independently replaced O, S, or NRX, wherein Rxis hydrogen or C1-C3 alkyl. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl, and methoxypropyl.

[0030] An “aryl” group is a C6-C14 aromatic moiety comprising one to three aromatic rings. As such, “aryl” includes Ce, C10, C13, and C14 cyclic hydrocarbon groups. A representative aryl group is a Ce-C aryl group. Particular aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl. An “aryl” group also includes fused multicyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is non-aromatic, provided that at least one ring is aromatic, such as indenyl.

[0031] An “aralkyl” or “arylalkyl” group comprises an aryl group covalently linked to an alkyl group wherein the moiety is linked to another group via the alkyl moiety. An representative aralkyl group is -(Ci-Ce)alkyl(Ce-Cio)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl. For example, an arCi-Csalkyl is an aryl group covalently linked to a C1-C3 alkyl.

[0032] As used herein, the term “fused” when used to define rings, e.g., bicyclic fused ring systems, refers to bicyclic, tricyclic, etc. ring systems sharing 2 or more atoms, includingbridged systems. Examples of such fused ring systems are (1S,4R)-2- azabicyclo[2.2.1]heptane; 2-azabicyclo[2.2.2]octane; 2,5-diazabicyclo[2.2.2]octane; 2-oxa-5- azabicyclo[2.2.2]octane; isoindoline; 1 ,2,3,4-tetrahydro-2,6-naphthyridine; 1 ,2,3,4- tetrahydroisoquinoline; 1 ,2,3,4-tetrahydro-1 ,4-(epiminomethano)naphthalene; and 3- azabicyclo[3.1 ,0]hexane.

[0033] A “heterocyclyl” or “heterocyclic” or “heterocycloalkyl” group is a mono- or bicyclic (e.g., fused) ring structure having from 3 to 12 atoms, (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms), for example 4 to 8 atoms, wherein one or more ring atoms are independently N, O, or S, and the remainder of the ring atoms are quaternary or carbonyl carbons. Examples of heterocyclic groups include, without limitation, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thiatanyl, dithianyl, trithianyl, azathianyl, oxathianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidonyl, thiomorpholinyl, dimethyl-morpholinyl, and morpholinyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and / or S atoms. The heterocyclic groups can be attached to a parent group (i.e., the point of attachment) via any ring atom, including one of the heteroatoms or one of the carbon atoms, in the heterocyclic ring group. As chemically required, the heterocyclic ring may be attached to one or more other groups, for instance if operating as a bridging group. The term “heterocyclyl” also includes fused multicyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is aromatic or non-aromatic, provided that at least one ring is non-aromatic contains an N, O, or S ring atom. Examples of such fused multicyclic ring systems are indolinyl, indolin-2-yl, 2,3-dihydrobenzofuran-2-yl, and 2, 3,4,5- tetrahydrobenzo[d]oxazol-2-yl. Each of these examples is a 9-membered heterocyclyl.

[0034] As used herein, the term “heteroaryl” refers to a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13, or 14 ring atoms; having 6, 10, or 14 TT electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms that are each independently N, O, or S. “Heteroaryl” also includes fused multicyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is non-aromatic, provided that at least one ring is aromatic and at least one ring contains an N, O, or S ring atom. The heteroaryl groups can be attached to a parent group (i.e., the point of attachment) via any ring atom, including one of the heteroatoms or one of the carbon atoms, in the heteroaryl ring group. As chemically required, the heteroaryl may be attached to one or more other groups, for instance if operating as a bridging group.

[0035] Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1 ,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1 H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1 ,2,5-thiadiazinyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1 ,2,3- triazolyl, 1 ,2,4-triazolyl, 1 ,2,5-triazolyl, 1 ,3,4-triazolyl, and xanthenyl.

[0036] An “arylene,” “heteroarylene,” or “heterocyclylene” group is a bivalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.

[0037] As employed herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as “optionally substituted” without expressly stating the substituents, it is meant that the group optionally has multiple non-hydrogen substituents, for example, from one to five, or from one to four, or from one to three, or one, or two non-hydrogen substituents.

[0038] The term “halogen” or “halo” as employed herein refers to chlorine, bromine, fluorine, or iodine.

[0039] The term “haloalkyl” refers to an alkyl chain in which one or more hydrogens have been replaced by a halogen. Representative haloalkyls are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.

[0040] The term “hydroxyalkyl” refers to -alkylene-OH.

[0041] It is to be understood that each individual atom present in Formula (I) and the compounds within Formula (I), may be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred. Thus, by way of example, each individual hydrogen atom present in Formula (I), or in the formulae depicted hereinafter, may be present as a1H,2H (deuterium; D), or3H (tritium; T) atom, preferably1H. Similarly, by way of example, each individual carbon atom present in formula (I), or in the formulae depicted hereinafter, may be present as a12C,13C, or14C atom, preferably12C.

[0042] As used herein, “an effective amount” of a compound is an amount that is sufficient tonegatively modulate or inhibit the activity of LRRK2 kinase.

[0043] As used herein, a “therapeutically effective amount” of a compound is an amount that is sufficient to ameliorate or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of LRRK2 kinase. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.

[0044] As used herein, “treatment” means any manner in which the symptoms or pathology of a condition, disorder or disease in a patient are ameliorated or otherwise beneficially altered.

[0045] As used herein, “amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition” refers to any lessening, whether permanent or temporary, lasting or transient, that can be attributed to or associated with administration of the composition.COMPOUNDS

[0046] In one aspect, the present disclosure provides compounds of Formula (I):or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, deuterated forms, and tautomers thereof, wherein:R1is hydrogen, Ci-Ce alkyl, C3-C6 cycloalkyl, halogen, halo Ci-Ce alkyl, -OR6, cyano, -NR7R8, or -NHC(O)R9, whereinR6is hydrogen, Ci-Ce alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl Ci-Ce alkyl, 3-6 membered heterocyclyl, or 3-6 membered heterocyclyl Ci-Ce alkyl; each of R7and R8is independently hydrogen, Ci-Ce alkyl, or together with the nitrogen to which they are attached form a 3-8 membered monocyclic heterocyclyl group; andR9is Ce-C aryl, 5- or 6-membered heteroaryl, or Ci-Ce alkyl, wherein the Ce-Cw aryl is optionally substituted with Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, -OR9A, cyano, or -NR9BR9C, whereinR9Ais hydrogen or Ci-Ce alkyl, and each of R9Band R9Cis independently hydrogen or Ci-Ce alkyl;the 5- or 6-membered heteraryl comprises one nitrogen atom and is optionally substituted with Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, -OR9A, cyano, or - NR9BR9C, and the Ci-Ce alkyl is optionally substituted with halogen, -SO2CH3, cyano, 5- or 6- membered heteroaryl, -OR9D, or -NR9ER9F, whereinR9Dis hydrogen, Ci-Ce alkyl, or 5- or 6-membered heteroaryl comprising one nitrogen atom and optionally substituted with Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, -OR9A, cyano, or -NR9BR9C, and each of R9Eand R9Fis independently hydrogen, Ci-Ce alkyl, -SO2CH3, or 5- or 6-membered heteroaryl comprising one nitrogen atom;R2is hydrogen, -NHC(O)R10, or -C(O)NHR11, wherein each of R10and R11is independently hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3;R3is hydrogen or halogen;R4is hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy;R5is hydrogen or halogen; andQ is a 3-8 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom; the heterocyclyl group is optionally fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen, oxygen, or sulfur atoms and the remainder are carbons; the heterocyclyl group is optionally substituted with 1-4 R12groups, wherein each R12is independently Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy; and the heterocyclyl group is optionally substituted with one R13group, wherein R13is hydrogen, Ci-Ce alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or Ci-Ce alkyl, and R15is hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3.

[0047] In certain embodiments of Formula (I) as otherwise described herein, R1is hydrogen.

[0048] In certain embodiments of Formula (I) as otherwise described herein, R1is methyl.

[0049] In certain embodiments of Formula (I) as otherwise described herein, R1is cyclopropyl.

[0050] In certain embodiments of Formula (I) as otherwise described herein, R1is fluoro, chloro or bromo.

[0051] In certain embodiments of Formula (I) as otherwise described herein, R1is trifluoromethyl.

[0052] In certain embodiments of Formula (I) as otherwise described herein, R1is -OR6, wherein R6is hydrogen.

[0053] In certain embodiments of Formula (I) as otherwise described herein, R1is -OR6,wherein R6is isopropyl.

[0054] In certain embodiments of Formula (I) as otherwise described herein, R1is -OR6, wherein R6is cyclopropylmethyl.

[0055] In certain embodiments of Formula (I) as otherwise described herein, R1is -OR6, wherein R6is methyloxetane.

[0056] In certain embodiments of Formula (I) as otherwise described herein, R1is cyano.

[0057] In certain embodiments of Formula (I) as otherwise described herein, R1is -NR7R8, wherein each of R7and R8is independently hydrogen.

[0058] In certain embodiments of Formula (I) as otherwise described herein, R1is -NR7R8, wherein each of R7and R8is independently C1-C3 alkyl.

[0059] In certain embodiments of Formula (I) as otherwise described herein, R1is -NR7R8, wherein R7and R8together with the nitrogen to which they are attached form a 3-7 membered monocyclic heterocyclyl group.

[0060] In certain embodiments of Formula (I) as otherwise described herein, R1is morpholine.

[0061] In certain embodiments of Formula (I) as otherwise described herein, R1is -NHC(O)R9, wherein R9is C6-Ci0aryl.

[0062] In certain embodiments of Formula (I) as otherwise described herein, R1is -NHC(O)R9, wherein R9is phenyl.

[0063] In certain embodiments of Formula (I) as otherwise described herein, R1is -NHC(O)R9, wherein R9is 5- or 6-membered heteroaryl.

[0064] In certain embodiments of Formula (I) as otherwise described herein, R1is -NHC(O)R9, wherein R9is 2-pyridyl.

[0065] In certain embodiments of Formula (I) as otherwise described herein, R1is -NHC(O)R9, wherein R9is C1-C3 alkyl substituted with -NHSO2CH3.

[0066] In certain embodiments of Formula (I) as otherwise described herein, R1is -NHC(O)R9, wherein R9is C1-C3 alkyl substituted with -SO2CH3.

[0067] In certain embodiments of Formula (I) as otherwise described herein, R1is -NHC(O)R9, wherein R9is C1-C3 alkyl substituted with cyano.

[0068] In certain embodiments of Formula (I) as otherwise described herein, R1is -NHC(O)R9, wherein R9is C1-C3 alkyl substituted with 5- or 6-membered heteroaryl.

[0069] In certain embodiments of Formula (I) as otherwise described herein, R1is -NHC(O)R9, wherein R9is 2-pyridyl methyl or 3-pyridyl methyl.

[0070] In certain embodiments of Formula (I) as otherwise described herein, R1is -NHC(O)R9and R9is C1-C3 alkyl substituted with -OR9D, wherein R9Dis hydrogen, Ci-Ce alkyl, or 5- or 6- membered heteroaryl.

[0071] In certain embodiments of Formula (I) as otherwise described herein, R1is -NHC(O)R9and R9is methyl substituted with -OR9D, wherein R9Dis 5- or 6-membered heteroaryl.

[0072] In certain embodiments of Formula (I) as otherwise described herein, R1is -NHC(O)R9and R9is methyl substituted with -OR9D, wherein R9Dis pyridyl.

[0073] In certain embodiments of Formula (I) as otherwise described herein, R1is -NHC(O)R9and R9is C1-C3 alkyl substituted with -NR9ER9F, wherein each of R9Eand R9Fis independently hydrogen, Ci-Ce alkyl, or 5- or 6-membered heteroaryl.

[0074] In certain embodiments of Formula (I) as otherwise described herein, R1is -NHC(O)R9and R9is methyl substituted with -NR9ER9F, wherein R9Eis hydrogen and R9Fis pyridyl.

[0075] certain embodiments of Formula (I) as otherwise described herein, R1is -NHC(O)R9and R9is methyl substituted with -NR9ER9F, wherein R9Eis pyridyl and R9Fis hydrogen.

[0076] In certain embodiments of Formula (I) as otherwise described herein, R2is hydrogen.

[0077] In certain embodiments of Formula (I) as otherwise described herein, R2is -NHC(O)R10, wherein R10is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0078] In certain embodiments of Formula (I) as otherwise described herein, R2is -C(O)NHR11, wherein R11is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0079] In certain embodiments of Formula (I) as otherwise described herein, R3is hydrogen.

[0080] In certain embodiments of Formula (I) as otherwise described herein, R3is fluoro, chloro or bromo.

[0081] In certain embodiments of Formula (I) as otherwise described herein, R4is hydrogen.

[0082] In certain embodiments of Formula (I) as otherwise described herein, R4is fluoro, chloro, or bromo.

[0083] In certain embodiments of Formula (I) as otherwise described herein, R4is C1-C3 alkoxy.

[0084] In certain embodiments of Formula (I) as otherwise described herein, R5is hydrogen.

[0085] In certain embodiments of Formula (I) as otherwise described herein, R5is fluoro, chloro or bromo.

[0086] In certain embodiments of Formula (I) as otherwise described herein, Q is a 3-7 membered heterocyclyl group including at least one nitrogen atom.

[0087] In certain embodiments of Formula (I) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen atoms and the remainder are carbons.

[0088] In certain embodiments of Formula (I) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one to four R12groups, wherein each R12is independently C1-C3 alkyl.

[0089] In certain embodiments of Formula (I) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one R13group, wherein R13is hydrogen, C1-C3 alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or C1-C3 alkyl, and R15is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0090] In certain embodiments of Formula (I) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one or two R12groups and with one R13group. Each R12is independently C1-C3 alkyl. R13is hydrogen, C1-C3 alkyl, -SO2R14, or -C(O)R15, wherein R14is hydrogen or C1-C3 alkyl, and R15is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0091] In another aspect, the present disclosure provides compounds of Formula (II):or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, deuterated forms, and tautomers thereof, wherein:R1is fluoro, chloro, or bromo;R2is hydrogen, -NHC(O)R10, or -C(O)NHR11, wherein each of R10and R11is independently hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3;R3is hydrogen or halogen;R4is hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy;R5is hydrogen or halogen; andQ is a 3-8 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom;the heterocyclyl group is optionally fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen, oxygen or sulfur atoms and the remainder are carbons; the heterocyclyl group is optionally substituted with one to four R12groups, wherein each R12is independently Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy; and the heterocyclyl group is optionally substituted with one R13group, wherein R13is hydrogen, Ci-Ce alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or Ci-Ce alkyl, and R15is hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3.

[0092] In certain embodiments of Formula (II) as otherwise described herein, R2is hydrogen.

[0093] In certain embodiments of Formula (II) as otherwise described herein, R2is -NHC(O)R10, wherein R10is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0094] In certain embodiments of Formula (II) as otherwise described herein, R2is -C(O)NHR11, wherein R11is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0095] In certain embodiments of Formula (II) as otherwise described herein, R3is hydrogen.

[0096] In certain embodiments of Formula (II) as otherwise described herein, R3is fluoro, chloro or bromo.

[0097] In certain embodiments of Formula (II) as otherwise described herein, R4is hydrogen.

[0098] In certain embodiments of Formula (II) as otherwise described herein, R4is fluoro, chloro, or bromo.

[0099] In certain embodiments of Formula (II) as otherwise described herein, R4is C1-C3 alkoxy.

[0100] In certain embodiments of Formula (II) as otherwise described herein, R5is hydrogen.

[0101] In certain embodiments of Formula (II) as otherwise described herein, R5is fluoro, chloro or bromo.

[0102] In certain embodiments of Formula (II) as otherwise described herein, Q is a 3-7 membered heterocyclyl group including at least one nitrogen atom.

[0103] In certain embodiments of Formula (II) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen atoms and the remainder are carbons.

[0104] In certain embodiments of Formula (II) as otherwise described herein, Q is a3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one to four R12groups, wherein each R12is independently C1-C3 alkyl.

[0105] In certain embodiments of Formula (II) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one R13group, wherein R13is hydrogen, C1-C3 alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or C1-C3 alkyl, and R15is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0106] In certain embodiments of Formula (II) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one or two R12groups and with one R13group. Each R12is independently C1-C3 alkyl. R13is hydrogen, C1-C3 alkyl, -SO2R14, or -C(O)R15, wherein R14is hydrogen or C1-C3 alkyl, and R15is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0107] In another aspect, the present disclosure provides compounds of Formula (III):or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, deuterated forms, and tautomers thereof, wherein:R2is hydrogen, -NHC(O)R10, or -C(O)NHR11, wherein each of R10and R11is independently hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3;R3is hydrogen or halogen;R4is hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy;R5is hydrogen or halogen; andQ is a 3-8 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom; the heterocyclyl group is optionally fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen, oxygen or sulfur atoms and the remainder are carbons; the heterocyclyl group is optionally substituted with one to four R12groups, wherein each R12is independently Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy; andthe heterocyclyl group is optionally substituted with one R13group, wherein R13is hydrogen, Ci-Ce alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or Ci-Ce alkyl, and R15is hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3.

[0108] In certain embodiments of Formula (III) as otherwise described herein, R2is hydrogen.

[0109] In certain embodiments of Formula (III) as otherwise described herein, R2is -NHC(O)R10, wherein R10is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0110] In certain embodiments of Formula (III) as otherwise described herein, R2is -C(O)NHR11, wherein R11is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0111] In certain embodiments of Formula (III) as otherwise described herein, R3is hydrogen.

[0112] In certain embodiments of Formula (III) as otherwise described herein, R3is fluoro, chloro or bromo.

[0113] In certain embodiments of Formula (III) as otherwise described herein, R4is hydrogen.

[0114] In certain embodiments of Formula (III) as otherwise described herein, R4is fluoro, chloro, or bromo.

[0115] In certain embodiments of Formula (III) as otherwise described herein, R4is C1-C3 alkoxy.

[0116] In certain embodiments of Formula (III) as otherwise described herein, R5is hydrogen.

[0117] In certain embodiments of Formula (III) as otherwise described herein, R5is fluoro, chloro or bromo.

[0118] In certain embodiments of Formula (III) as otherwise described herein, Q is a 3-7 membered heterocyclyl group including at least one nitrogen atom.

[0119] In certain embodiments of Formula (III) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen atoms and the remainder are carbons.

[0120] In certain embodiments of Formula (III) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one to four R12groups, wherein each R12is independently C1-C3 alkyl.

[0121] In certain embodiments of Formula (III) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one R13group, wherein R13is hydrogen, C1-C3 alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or C1-C3 alkyl, and R15is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0122] In certain embodiments of Formula (III) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one or two R12groups and with one R13group. Each R12is independently C1-C3 alkyl. R13is hydrogen, C1-C3 alkyl, -SO2R14, or -C(O)R15, wherein R14is hydrogen or C1-C3 alkyl, and R15is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0123] In another aspect, the present disclosure provides compounds of Formula (IV):or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, deuterated forms, and tautomers thereof, wherein:R2is hydrogen, -NHC(O)R10, or -C(O)NHR11, wherein each of R10and R11is independently hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3;R3is hydrogen or halogen;R4is hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy;R5is hydrogen or halogen;R6is hydrogen, Ci-Ce alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl Ci-Ce alkyl, 3-6 membered heterocyclyl, or 3-6 membered heterocyclyl Ci-Ce alkyl; andQ is a 3-8 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom; the heterocyclyl group is optionally fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen, oxygen or sulfur atoms and the remainder are carbons; the heterocyclyl group is optionally substituted with one to four R12groups, wherein each R12is independently Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy; andthe heterocyclyl group is optionally substituted with one R13group, wherein R13is hydrogen, Ci-Ce alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or Ci-Ce alkyl, and R15is hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3.

[0124] In certain embodiments of Formula (IV) as otherwise described herein, R2is hydrogen.

[0125] In certain embodiments of Formula (IV) as otherwise described herein, R2is -NHC(O)R10, wherein R10is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0126] In certain embodiments of Formula (IV) as otherwise described herein, R2is -C(O)NHR11, wherein R11is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0127] In certain embodiments of Formula (IV) as otherwise described herein, R3is hydrogen.

[0128] In certain embodiments of Formula (IV) as otherwise described herein, R3is fluoro, chloro or bromo.

[0129] In certain embodiments of Formula (IV) as otherwise described herein, R4is hydrogen.

[0130] In certain embodiments of Formula (IV) as otherwise described herein, R4is fluoro, chloro, or bromo.

[0131] In certain embodiments of Formula (IV) as otherwise described herein, R4is C1-C3 alkoxy.

[0132] In certain embodiments of Formula (IV) as otherwise described herein, R5is hydrogen.

[0133] In certain embodiments of Formula (IV) as otherwise described herein, R5is fluoro, chloro or bromo.

[0134] In certain embodiments of Formula (IV) as otherwise described herein, R6is hydrogen.

[0135] In certain embodiments of Formula (IV) as otherwise described herein, R6is isopropyl.

[0136] In certain embodiments of Formula (IV) as otherwise described herein, R6is cyclopropylmethyl.

[0137] In certain embodiments of Formula (IV) as otherwise described herein, R6is methyloxetane.

[0138] In certain embodiments of Formula (IV) as otherwise described herein, Q is a3-7 membered heterocyclyl group including at least one nitrogen atom.

[0139] In certain embodiments of Formula (IV) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen atoms and the remainder are carbons.

[0140] In certain embodiments of Formula (IV) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one to four R12groups, wherein each R12is independently C1-C3 alkyl.

[0141] In certain embodiments of Formula (IV) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one R13group, wherein R13is hydrogen, C1-C3 alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or C1-C3 alkyl, and R15is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0142] In certain embodiments of Formula (IV) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one or two R12groups and with one R13group. Each R12is independently C1-C3 alkyl. R13is hydrogen, C1-C3 alkyl, -SO2R14, or -C(O)R15, wherein R14is hydrogen or C1-C3 alkyl, and R15is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0143] In another aspect, the present disclosure provides compounds of Formula (V):or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, deuterated forms, and tautomers thereof, wherein:R2is hydrogen, -NHC(O)R10, or -C(O)NHR11, wherein each of R10and R11is independently hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3;R3is hydrogen or halogen;R4is hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy;R5is hydrogen or halogen;R7and R8are independently hydrogen or Ci-Ce alkyl, or together with the nitrogen to which they are attached form a 3-8 membered monocyclic heterocyclyl group; andQ is a 3-8 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom; the heterocyclyl group is optionally fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen, oxygen or sulfur atoms and the remainder are carbons; the heterocyclyl group is optionally substituted with one to four R12groups, wherein each R12is independently Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy; and the heterocyclyl group is optionally substituted with one R13group, wherein R13is hydrogen, Ci-Ce alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or Ci-Ce alkyl, and R15is hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3.

[0144] In certain embodiments of Formula (V) as otherwise described herein, R2is hydrogen.

[0145] In certain embodiments of Formula (V) as otherwise described herein, R2is -NHC(O)R10, wherein R10is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0146] In certain embodiments of Formula (V) as otherwise described herein, R2is -C(O)NHR11, wherein R11is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0147] In certain embodiments of Formula (V) as otherwise described herein, R3is hydrogen.

[0148] In certain embodiments of Formula (V) as otherwise described herein, R3is fluoro, chloro or bromo.

[0149] In certain embodiments of Formula (V) as otherwise described herein, R4is hydrogen.

[0150] In certain embodiments of Formula (V) as otherwise described herein, R4is fluoro, chloro, or bromo.

[0151] In certain embodiments of Formula (V) as otherwise described herein, R4is C1-C3 alkoxy.

[0152] In certain embodiments of Formula (V) as otherwise described herein, R5is hydrogen.

[0153] In certain embodiments of Formula (V) as otherwise described herein, R5is fluoro, chloro or bromo.

[0154] In certain embodiments of Formula (V) as otherwise described herein, each ofR7and R8is independently hydrogen.

[0155] In certain embodiments of Formula (V) as otherwise described herein, each of R7and R8is independently C1-C3 alkyl.

[0156] In certain embodiments of Formula (V) as otherwise described herein, R7and R8together with the nitrogen to which they are attached form a 3-7 membered monocyclic heterocyclyl group.

[0157] In certain embodiments of Formula (V) as otherwise described herein, R7and R8together with the nitrogen to which they are attached form a morpholine ring.

[0158] In certain embodiments of Formula (V) as otherwise described herein, Q is a 3-7 membered heterocyclyl group including at least one nitrogen atom.

[0159] In certain embodiments of Formula (V) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen atoms and the remainder are carbons.

[0160] In certain embodiments of Formula (V) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one to four R12groups, wherein each R12is independently C1-C3 alkyl.

[0161] In certain embodiments of Formula (V) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one R13group, wherein R13is hydrogen, C1-C3 alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or C1-C3 alkyl, and R15is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0162] In certain embodiments of Formula (V) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one or two R12groups and with one R13group. Each R12is independently C1-C3 alkyl. R13is hydrogen, C1-C3 alkyl, -SO2R14, or -C(O)R15, wherein R14is hydrogen or C1-C3 alkyl, and R15is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0163] In another aspect, the present disclosure provides compounds of Formula (VI):or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, wherein:R2is hydrogen, -NHC(O)R10, or -C(O)NHR11, wherein each of R10and R11is independently hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3;R3is hydrogen or halogen;R4is hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy;R5is hydrogen or halogen;R9is Ce-C aryl, 5- or 6-membered heteroaryl, or Ci-Ce alkyl, wherein the Ce-Cw aryl is optionally substituted with Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, - OR9A, cyano, or -NR9BR9C, whereinR9Ais hydrogen or Ci-Ce alkyl, and each of R9Band R9Cis independently hydrogen or Ci-Ce alkyl; the 5- or 6-membered heteraryl comprises one nitrogen atom and is optionally substituted with Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, -OR9A, cyano, or -NR9BR9C, and the Ci-Ce alkyl is optionally substituted with halogen, -SO2CH3, cyano, 5- or 6- membered heteroaryl, -OR9D, or -NR9ER9F, whereinR9Dis hydrogen, Ci-Ce alkyl, or 5- or 6-membered heteroaryl comprising one nitrogen atom and optionally substituted with Ci-Ce alkyl, halogen, halo Ci- Ce alkyl, -OR9A, cyano, or -NR9BR9C, and each of R9Eand R9Fis independently hydrogen, Ci-Ce alkyl, -SO2CH3, or 5- or 6-membered heteroaryl comprising one nitrogen atom;Q is a 3-8 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom; the heterocyclyl group is optionally fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen, oxygen or sulfur atoms and the remainder are carbons; the heterocyclyl group is optionally substituted with one to four R12groups, wherein each R12is independently Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy; and the heterocyclyl group is optionally substituted with one R13group, wherein R13is hydrogen, Ci-Ce alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or Ci-Ce alkyl, and R15is hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3.

[0164] In certain embodiments of Formula (IV) as otherwise described herein, R2is hydrogen.

[0165] In certain embodiments of Formula (VI) as otherwise described herein, R2is -NHC(O)R10, wherein R10is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0166] In certain embodiments of Formula (VI) as otherwise described herein, R2is -C(O)NHR11, wherein R11is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0167] In certain embodiments of Formula (VI) as otherwise described herein, R3is hydrogen.

[0168] In certain embodiments of Formula (VI) as otherwise described herein, R3is fluoro, chloro or bromo.

[0169] In certain embodiments of Formula (VI) as otherwise described herein, R4is hydrogen.

[0170] In certain embodiments of Formula (VI) as otherwise described herein, R4is fluoro, chloro, or bromo.

[0171] In certain embodiments of Formula (VI) as otherwise described herein, R4is C1-C3 alkoxy.

[0172] In certain embodiments of Formula (VI) as otherwise described herein, R5is hydrogen.

[0173] In certain embodiments of Formula (VI) as otherwise described herein, R5is fluoro, chloro or bromo.

[0174] In certain embodiments of Formula (VI) as otherwise described herein, R9is phenyl.

[0175] In certain embodiments of Formula (VI) as otherwise described herein, R9is 2- pyridyl.

[0176] In certain embodiments of Formula (VI) as otherwise described herein, R9is C1- C3 alkyl substituted with -NHSO2CH3.

[0177] In certain embodiments of Formula (VI) as otherwise described herein, R9is C1- C3 alkyl substituted with -SO2CH3.

[0178] In certain embodiments of Formula (VI) as otherwise described herein, R9is C1- C3 alkyl substituted with cyano.

[0179] In certain embodiments of Formula (VI) as otherwise described herein, R9is 2- pyridyl methyl or 3-pyridyl methyl.

[0180] In certain embodiments of Formula (VI) as otherwise described herein, R9is methyl substituted with -OR9D, wherein R9Dis pyridyl.

[0181] In certain embodiments of Formula (VI) as otherwise described herein, R9ismethyl substituted with -NR9ER9F, wherein R9Eis hydrogen and R9Fis pyridyl.

[0182] In certain embodiments of Formula (VI) as otherwise described herein, R9is methyl substituted with -NR9ER9F, wherein R9Eis pyridyl and R9Fis hydrogen.

[0183] In certain embodiments of Formula (VI) as otherwise described herein, Q is a 3-7 membered heterocyclyl group including at least one nitrogen atom.

[0184] In certain embodiments of Formula (VI) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen atoms and the remainder are carbons.

[0185] In certain embodiments of Formula (VI) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one to four R12groups, wherein each R12is independently C1-C3 alkyl.

[0186] In certain embodiments of Formula (VI) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one R13group, wherein R13is hydrogen, C1-C3 alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or C1-C3 alkyl, and R15is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0187] In certain embodiments of Formula (VI) as otherwise described herein, Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one or two R12groups and with one R13group. Each R12is independently C1-C3 alkyl. R13is hydrogen, C1-C3 alkyl, -SO2R14, or -C(O)R15, wherein R14is hydrogen or C1-C3 alkyl, and R15is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0188] In certain embodiments of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V) or Formula (VI) as otherwise described herein, Q is a group of the formula:wherein each v represents 0, 1 , 2, 3 or 4; each R12is independently hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy;R13is hydrogen, Ci-Ce alkyl, -SO2R14, or -C(O)R15, wherein R14is hydrogen or Ci-Ce alkyl, and R15is hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3; andX is CR16or nitrogen, wherein R16is hydrogen or Ci-Ce alkyl.

[0189] In certain embodiments of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V) or Formula (VI) as otherwise described herein, Q represents a nitrogen-containing ring selected from:wherein each v represents 0, 1 , 2, 3, or 4;R12is hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy; andR13is hydrogen, Ci-Ce alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or Ci- Ce alkyl, and R15is hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3.

[0190] In certain embodiments of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V) or Formula (VI) as otherwise described herein, Q represents a nitrogen-containing ring selected from:wherein each v represents 0, 1 , 2, 3 or 4; and each R12is independently hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy.

[0191] In certain embodiments of Formula (I), Formula (II), Formula (III), Formula (IV),Formula (V) or Formula (VI) as otherwise described herein, Q represents a fused bicyclic group selected from:wherein each v represents 0, 1 , 2, 3 or 4; each R12is independently hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy, and can be on either ring.

[0192] In one aspect, the present disclosure provides compounds of Formula (VII):or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, deuterated forms, and tautomers thereof, wherein:R1is hydrogen, Ci-Ce alkyl, C3-C6 cycloalkyl, halogen, halo Ci-Ce alkyl, -OR6, cyano, -NR7R8, or -NHC(O)R9, whereinR6is hydrogen, Ci-Ce alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl Ci-Ce alkyl, 3-6 membered heterocyclyl, or 3-6 membered heterocyclyl Ci-Ce alkyl; each of R7and R8is independently hydrogen, Ci-Ce alkyl, or together with the nitrogen to which they are attached form a 3-8 membered monocyclic heterocyclyl group; andR9is Ce-C aryl, 5- or 6-membered heteroaryl, or Ci-Ce alkyl, wherein the Ce-Cw aryl is optionally substituted with Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, -OR9A, cyano, or -NR9BR9C, whereinR9Ais hydrogen or Ci-Ce alkyl, and each of R9Band R9Cis independently hydrogen or Ci-Ce alkyl; the 5- or 6-membered heteraryl comprises one nitrogen atom and is optionally substituted with Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, -OR9A, cyano, or - NR9BR9C, and the Ci-Ce alkyl is optionally substituted with halogen, -SO2CH3, cyano, 5- or 6- membered heteroaryl, -OR9D, or -NR9ER9F, whereinR9Dis hydrogen, Ci-Ce alkyl, or 5- or 6-membered heteroaryl comprising one nitrogen atom and optionally substituted with Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, -OR9A, cyano, or -NR9BR9C, and each of R9Eand R9Fis independently hydrogen, Ci-Ce alkyl, -SO2CH3, or 5- or 6-membered heteroaryl comprising one nitrogen atom;R2is hydrogen, -NHC(O)R10, or -C(O)NHR11, wherein each of R10and R11is independently hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3;R3is hydrogen or halogen;R4is hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy;R5is hydrogen or halogen; each R12is independently hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy;R13is hydrogen, Ci-Ce alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or Ci-Ce alkyl, and R15is hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3;X is CR16or nitrogen, wherein R16is hydrogen or Ci-Ce alkyl; and each v represents 0, 1 , 2, 3 or 4.

[0193] In certain embodiments of Formula (VII) as otherwise described herein, R1is hydrogen.

[0194] In certain embodiments of Formula (VII) as otherwise described herein, R1is methyl.

[0195] In certain embodiments of Formula (VII) as otherwise described herein, R1is cyclopropyl.

[0196] In certain embodiments of Formula (VII) as otherwise described herein, R1is fluoro, chloro or bromo.

[0197] In certain embodiments of Formula (VII) as otherwise described herein, R1is trifluoromethyl.

[0198] In certain embodiments of Formula (VII) as otherwise described herein, R1is -OR6, wherein R6is hydrogen.

[0199] In certain embodiments of Formula (VII) as otherwise described herein, R1is -OR6, wherein R6is isopropyl.

[0200] In certain embodiments of Formula (VII) as otherwise described herein, R1is -OR6, wherein R6is cyclopropyl methyl.

[0201] In certain embodiments of Formula (VII) as otherwise described herein, R1is -OR6, wherein R6is methyloxetane.

[0202] In certain embodiments of Formula (VII) as otherwise described herein, R1is cyano.

[0203] In certain embodiments of Formula (VII) as otherwise described herein, R1is -NR7R8, wherein each of R7and R8is independently hydrogen.

[0204] In certain embodiments of Formula (VII) as otherwise described herein, R1is -NR7R8, wherein each of R7and R8is independently C1-C3 alkyl.

[0205] In certain embodiments of Formula (VII) as otherwise described herein, R1is -NR7R8, wherein R7and R8together with the nitrogen to which they are attached form a 3-7 membered monocyclic heterocyclyl group.

[0206] In certain embodiments of Formula (VII) as otherwise described herein, R1is morpholine.

[0207] In certain embodiments of Formula (VII) as otherwise described herein, R1is -NHC(O)R9, wherein R9is Ce-C aryl.

[0208] In certain embodiments of Formula (VII) as otherwise described herein, R1is -NHC(O)R9, wherein R9is phenyl.

[0209] In certain embodiments of Formula (VII) as otherwise described herein, R1is -NHC(O)R9, wherein R9is 5- or 6-membered heteroaryl.

[0210] In certain embodiments of Formula (VII) as otherwise described herein, R1is -NHC(O)R9, wherein R9is 2-pyridyl.

[0211] In certain embodiments of Formula (VII) as otherwise described herein, R1is -NHC(O)R9, wherein R9is C1-C3 alkyl substituted with -NHSO2CH3.

[0212] In certain embodiments of Formula (VII) as otherwise described herein, R1is -NHC(O)R9, wherein R9is C1-C3 alkyl substituted with -SO2CH3.

[0213] In certain embodiments of Formula (VII) as otherwise described herein, R1is -NHC(O)R9, wherein R9is C1-C3 alkyl substituted with cyano.

[0214] In certain embodiments of Formula (VII) as otherwise described herein, R1is -NHC(O)R9, wherein R9is C1-C3 alkyl substituted with 5- or 6-membered heteroaryl.

[0215] In certain embodiments of Formula (VII) as otherwise described herein, R1is -NHC(O)R9, wherein R9is 2-pyridyl methyl or 3-pyridyl methyl.

[0216] In certain embodiments of Formula (VII) as otherwise described herein, R1is -NHC(O)R9and R9is C1-C3 alkyl substituted with -OR9D, wherein R9Dis hydrogen, Ci-Ce alkyl, or 5- or 6-membered heteroaryl.

[0217] In certain embodiments of Formula (VII) as otherwise described herein, R1is -NHC(O)R9and R9is methyl substituted with -OR9D, wherein R9Ais 5- or 6-membered heteroaryl.

[0218] In certain embodiments of Formula (VII) as otherwise described herein, R1is -NHC(O)R9and R9is methyl substituted with -OR9D, wherein R9Dis pyridyl.

[0219] In certain embodiments of Formula (VII) as otherwise described herein, R1is -NHC(O)R9and R9is C1-C3 alkyl substituted with -NR9ER9F, wherein each of R9Eand R9Fis independently hydrogen, Ci-Ce alkyl, or 5- or 6-membered heteroaryl.

[0220] In certain embodiments of Formula (VII) as otherwise described herein, R1is -NHC(O)R9and R9is methyl substituted with -NR9ER9F, wherein R9Eis hydrogen and R9Fis pyridyl.

[0221] certain embodiments of Formula (VII) as otherwise described herein, R1is -NHC(O)R9and R9is methyl substituted with -NR9ER9F, wherein R9Eis pyridyl and R9Fis hydrogen.

[0222] In certain embodiments of Formula (VII) as otherwise described herein, R2is hydrogen.

[0223] In certain embodiments of Formula (VII) as otherwise described herein, R2is -NHC(O)R10, wherein R10is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0224] In certain embodiments of Formula (VII) as otherwise described herein, R2is -C(O)NHR11, wherein R11is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

[0225] In certain embodiments of Formula (VII) as otherwise described herein, R3is hydrogen.

[0226] In certain embodiments of Formula (VII) as otherwise described herein, R3is fluoro, chloro or bromo.

[0227] In certain embodiments of Formula (VII) as otherwise described herein, R4is hydrogen.

[0228] In certain embodiments of Formula (VII) as otherwise described herein, R4is fluoro, chloro, or bromo.

[0229] In certain embodiments of Formula (VII) as otherwise described herein, R4is C1-C3 alkoxy.

[0230] In certain embodiments of Formula (VII) as otherwise described herein, R5is hydrogen.

[0231] In certain embodiments of Formula (VII) as otherwise described herein, R5is fluoro, chloro or bromo.

[0232] In certain embodiments of Formula (VII) as otherwise described herein, R12is hydrogen.

[0233] In certain embodiments of Formula (VII) as otherwise described herein, R12is methyl.

[0234] In certain embodiments of Formula (VII) as otherwise described herein, R13is hydrogen.

[0235] In certain embodiments of Formula (VII) as otherwise described herein, R13is methyl.

[0236] In certain embodiments of Formula (VII) as otherwise described herein, R13is - SO2R14, wherein R14is hydrogen or Ci-Ce alkyl.

[0237] In certain embodiments of Formula (VII) as otherwise described herein, R13is - SO2R14, wherein R14is methyl.

[0238] In certain embodiments of Formula (VII) as otherwise described herein, R13is - C(O)R15, wherein R15is Ci-Ce alkyl substituted with -NHSO2CH3.

[0239] In certain embodiments of Formula (VII) as otherwise described herein, R13is - C(O)R15, wherein R15is -CH2NHSO2CH3.

[0240] In certain embodiments of Formula (VII) as otherwise described herein, X isCR16, wherein R16is hydrogen.

[0241] In certain embodiments of Formula (VII) as otherwise described herein, X is N.

[0242] In certain embodiments of Formula (VII) as otherwise described herein, each v is 0.

[0243] In certain embodiments of Formula (VII) as otherwise described herein, each v is 1.

[0244] In certain embodiments of Formula (VII) as otherwise described herein, each v is 2.

[0245] In certain embodiments of Formula (VII) as otherwise described herein, each v is 3.

[0246] In certain embodiments of Formula (VII) as otherwise described herein, each v is 4.

[0247] In one embodiment, the compound of Formula (I) is selected from:Table 1PHARMACEUTICAL COMPOSITIONS

[0248] The compounds of Formula I may be formulated into pharmaceutical compositions.

[0249] In another aspect, the invention provides pharmaceutical compositions comprising LRRK2 kinase inhibitors according to the invention, or salts of the pharmaceutical compositions together with a pharmaceutically acceptable carrier, excipient, or diluent. Compounds of the invention may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain embodiments, compounds of the invention are administered intravenously in a hospital setting. In certain other embodiments, administration may preferably be by the oral route.

[0250] The characteristics of the carrier will depend on the route of administration. As used herein, the term “pharmaceutically acceptable” means a non-toxic material that is compatible with a biological system such as a cell, a cell culture, a tissue, or an organism, and that does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. Thepreparation of pharmaceutically acceptable formulations is described in, e.g., Remington’s Pharmaceutical Sciences, 18th Edition, A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0251] As used herein, the term “pharmaceutically acceptable salts” refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include, without limitation, acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR+Z; wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O- alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).

[0252] The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated. A dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 300 mg / kg, preferably 0.1 to 100 mg / kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage will range from 0.01-3 % wt / wt in a suitable carrier. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.

[0253] The pharmaceutical compositions comprising compounds of the present invention may be used in the methods described herein.METHODS OF USE

[0254] In another aspect, the present disclosure generally relates to methods for treating a disease or disorder associated with LRRK2 kinase activity. These methods comprise administering to a subject in need thereof a therapeutically effective amount of an LRRK2 inhibitor.

[0255] In some embodiments, the LRRK2 inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, ortautomer thereof. In particular embodiments, the LRRK2 inhibitor comprises a compound selected from Table 1 as described herein.

[0256] In another aspect, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound as described herein (e.g., a method comprising one or more steps described in the Examples).

[0257] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, and a pharmaceutically acceptable diluent or carrier.

[0258] In another aspect, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in the Examples).

[0259] In another aspect, the present disclosure provides a method of inhibiting LRRK2 kinase activity, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof.

[0260] In another aspect, the present disclosure provides a method of treating Parkinson’s disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof.

[0261] The compositions and methods provided herein may be used for the treatment of a wide variety of diseases or disorders associated with LRRK2 kinase activity. More particularly, diseases or disorders that may be treated by the compositions and methods of the invention include, without limitation, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, ischemic stroke, traumatic brain injury, and spinal cord injury.

[0262] The concentration and route of administration to the patient will vary depending on the disease or disorder to be treated. The compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising such compounds and salts, may be coadministered with other compounds, e.g., those increasing dopamine levels in the brain, or used in combination with other treatments, such as surgical intervention, either as an adjuvant prior to surgery or post-operatively.

[0263] The present disclosure provides methods of treating, preventing, or ameliorating a disease or disorder in which LRRK2 kinase plays a role by administering to apatient in need thereof a therapeutically effective amount of an LRRK2 inhibitor. The methods of the present disclosure can be used in the treatment of a variety of LRRK2-dependent diseases and disorders.

[0264] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.GENERAL REACTION SCHEMES, INTERMEDIATES AND EXAMPLES

[0265] The compounds of the present invention may be prepared using commercially available reagents and intermediates in the synthetic methods and reaction schemes described herein, or may be prepared using other reagents and conventional methods well known to those skilled in the art. Abbreviations for some of the reagents as described herein may include the following:

[0266] INTERMEDIATE Atoluene / H2O, 100 °C, 16 hrs lnt-1 lnt-3 Intermediate A

[0267] Step A: A mixture of 2,6-dibromopyridine (lnt-1) (4.6 g, 19.4 mmol), tert-butyl 5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (lnt-2) (5 g, 16.17 mmol), CS2CO3 (10.54 g, 32.34 mmol), and Pd(dppf)Ch (2.37 g, 3.23 mmol) in toluene (50 mL) and H2O (13 mL) is degassed and purged with N2 three times. The mixture is stirred at 100 °C for 16 hours under N2. The reaction mixture is extracted with EtOAc three times. The combined organic layers are washed with brine three times, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-5% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 5-(6-bromo-2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (lnt-3) (3.32 g, 60.5% yield) as yellow oil.

[0268] 1H NMR (400 MHz, DMSO-cfe) 6 = 7.76 - 7.70 (m, 1 H), 7.64 (br d, J = 7.6 Hz, 1 H), 7.52 (d, J = 7.6 Hz, 1 H), 6.84 (br s, 1 H), 4.26 (br s, 2H), 3.46 (br t, J = 5.6 Hz, 2H), 2.30 (br d, J = 3.6 Hz, 2H), 1.43 (s, 9H).

[0269] Step B: To a solution of tert-butyl 5-(6-bromo-2-pyridyl)-3,6-dihydro-2H-pyridine-1- carboxylate (I nt- 3) (1 g, 2.95 mmol) in EtOAc (10 mL) is added PtO2(66.9 mg, 294.8 pmol). The mixture is placed under 15 psi of H2at 25 °C for 16 hr. The reaction mixture is filtered, and the filtrate is concentrated under vacuum to yield the title compound tert-butyl 3-(6-bromo-2- pyridyl)piperidine-1 -carboxylate (Intermediate A) (950 mg) as a white solid. LCMS (ESI MS) m / z = 341.0 [M + H]+1.

[0270] INTERMEDIATE Blnt-6 Intermediate B

[0271] Step A: To a solution of ethyl 5-chloropyrazolo[1 ,5-a]pyridine-3-carboxylate (lnt-4) (800 mg, 3.56 mmol) in H2O (2 mL) and THF (2 mL) is added LiOH«H2O (597.8 mg, 14.24 mmol). The mixture is stirred at 60 °C for 24 hr. The reaction mixture is quenched with HCI (1 M) and extracted with EtOAc (3x). The combined organic layers are washed with brine twice, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the title compound 5-chloropyrazolo[1 ,5-a]pyridine-3-carboxylic acid (lnt-6) (700 mg) as a white solid. LCMS (ESI MS) m / z = 197.1 [M + H]+1. The crude product is used in the next step without additional purification.

[0272] Step B: To a solution of 5-chloropyrazolo[1 ,5-a]pyridine-3-carboxylic acid (I nt- 5) (400 mg, 2.03 mmol) in DMF (1 mL) is added NBS (398 mg, 2.24 mmol) and NaHCO3(256.4 mg, 3.05 mmol, 119 pL). The mixture is stirred at 25 °C for 24 hr. The reaction mixture isquenched with H2O and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the title compound 3-bromo-5-chloro-pyrazolo[1 ,5-a]pyridine (lnt-6) (300 mg, 1.30 mmol, 63% yield) as a yellow solid. LCMS (ESI MS) m / z = 233.0 [M + H] +1. The crude product is used directly in the next step without additional purification.

[0273] Step C: To a solution of 3-bromo-5-chloropyrazolo[1 ,5-a]pyridine (lnt-6) (300 mg, 1.30 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3,2- dioxaborolane (263.3 mg, 1.04 mmol) in dioxane (3 mL) are added Pd(dppf)CI2(211.7 mg, 259.2 pmol) and potassium acetate (254.4 mg, 2.59 mmol). The mixture is stirred at 100 °C for 16 hrs under a N2atmosphere. The reaction mixture is quenched with H2O and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-100% DCM / petroleum ether gradient) to yield the title compound 5-chloro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyrazolo[1 ,5-a]pyridine (Intermediate B) (100 mg) as a white solid. LCMS (ESI MS) m / z = 279.1 [M + H]+1.

[0274] INTERMEDIATE CK2CO3, DMF, 20 °C, 16 hrs1lnt-12

[0275] Step A: A solution of 4-trifluoromethylpyridine (I nt- 7) (3 g, 20.39 mmol) and O-(2,4- dinitrophenyl)hydroxylamine (lnt-8) (4.06 g, 20.39 mmol) in ACN (40 mL) is stirred at 40 °C for 16 hr. The solution is concentrated under reduced pressure. The residue is dissolved in DMF (40 mL), and then K2CO3 (5.64 g, 40.79 mmol) and ethyl propiolate (I nt- 9) (2.00 g, 20.39 mmol, 2.0 mL) are added. The mixture is stirred at 20 °C for 16 hr. The reaction mixture is diluted with H2O and extracted with EtOAc three times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 10% ethyl acetate / petroleum ether gradient) to yield the title compound ethyl 5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-3- carboxylate (lnt-10) (1.3 g) as a yellow solid. LCMS (ESI MS) m / z = 259.0 [M +H]+1.

[0276] 1H NMR (400 MHz, DMSO-cfe) 5 = 9.13 (d, J = 7.2 Hz, 1 H), 8.64 (s, 1 H), 8.32 - 8.37 (m, 1 H), 7.44 (dd, J = 7.2, 2.1 Hz, 1 H), 4.35 (q, J = 7.2 Hz, 2 H), 1.35 (t, J = 7.2 Hz, 3 H).

[0277] Step B: A mixture of ethyl 5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-3-carboxylate (lnt-10) (1.3 g, 5.03 mmol) in H2SCL (10 mL, 40% aq.) is stirred at 100 °C for 16 hr. The reaction mixture is adjusted to pH = 8 using 2N NaOH (aq), and extracted with EtOAc three times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound 5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine crude product (lnt-11) (550 mg, crude) as a brown oil. LCMS (ESI MS) m / z = 187.0 [M +H]+1.

[0278] 1H NMR (400 MHz, DMSO-cfe) 6 = 8.90 (dd, J = 7.2, 0.8 Hz, 1 H), 8.24 - 8.28 (m, 1 H), 8.19 (d, J = 2.4 Hz, 1 H), 7.10 (dd, J = 7.2, 2.1 Hz, 1 H), 6.90 (d, J = 2.0 Hz, 1 H).

[0279] Step C: To a solution of 5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine (lnt-11) (180 mg, 967.05 pmol) in ACN (4 mL) is added NBS (189 mg, 1.06 mmol). The mixture is stirred at 25 °C for 16 hr. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 3% ethyl acetate / petroleum ethergradient) to yield the title compound 3-bromo-5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine (I nt- 12) (180 mg) as a yellow solid. LCMS (ESI MS) m / z = 264.9 [M + H]+1.

[0280] Step D: A mixture of 3-bromo-5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine (I nt- 12) (200 mg, 754.6 pmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 ,3,2-dioxaborolane (287 mg, 1.13 mmol), Pd(dppf)Ch (123 mg, 150.9 pmol), and KOAc (148 mg, 1.51 mmol) in dioxane (2 mL) is purged with N2 three times, and then the mixture is stirred at 100 °C for 12 hr under N2. The reaction mixture is concentrated under reduced pressure, and the residue is diluted with water and extracted with ethyl acetate three times. The combined organic layers are washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-7% ethyl acetate / petroleum ether gradient) to yield the title compound 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyrazolo[1 ,5- a]pyridine (Intermediate C) (230 mg, crude) as a yellow solid. LCMS (ESI MS) m / z = 312.9 [M + H]+1.

[0281] INTERMEDIATE DSn2Me6Pd(PPh3)4, toluene, 110 °C, 2 hrsIntermediate D

[0282] Step A: A mixture of 2,6-dibromopyridine (I nt- 13) (9.2 g, 19.40 mmol), tert-butyl 5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (I nt- 14) (10 g, 32.34 mmol), CS2CO3 (21.05 g, 64.68 mmol), and Pd(dppf)Ch (2.36 g, 2.34 mmol) in toluene (100 mL) and H2O (20 mL) is degassed and purged with N2 three times. The mixture is stirred at 100 °C for 16 hr under a N2 atmosphere. The mixture is diluted with H2O and extracted with EtOAc three times. The combined organic layers are washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a crudeproduct which is purified by flash silica gel chromatography (eluent of 0-5% ethyl acetate / petroleum ether gradient). The title compound tert-butyl 5-(6-bromo-2-pyridyl)-3,6- dihydro-2H-pyridine-1-carboxylate (I nt- 15) (6.3 g, 46%) is obtained as a pink solid.

[0283] 1H NMR (400 MHz, DMSO-cfe) 6 = 7.76 - 7.70 (m, 1 H), 7.64 (d, J = 8.0 Hz, 1 H), 7.51 (d, J = 7.6 Hz, 1 H), 6.84 (br t, J = 4.0 Hz, 1 H), 4.25 (br s, 2H), 3.46 (br t, J = 5.6 Hz, 2H),2.30 (br d, J = 3.6 Hz, 2H), 1.43 (s, 9H).

[0284] Step B: To a solution of tert-butyl 6-bromo-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)- carboxylate (I nt- 15) (6.3 g, 18.57 mmol) in EtOAc (60 mL) is added PtC>2 (600 mg, 2.64 mmol). The mixture is stirred at 25 °C under H2 (15 psi) for 16 hrs. The reaction mixture is filtered, and the filtrate is concentrated under vacuum to yield the title compound tert-butyl 3-(6-bromo-2- pyridyl)piperidine-1 -carboxylate (I nt- 16) (4.4 g, crude) as a white solid.

[0285] 1H NMR (400 MHz, methanol-d4) 6 = 7.65 - 7.58 (m, 1 H), 7.42 (d, J = 8.0 Hz, 1 H),7.30 (d, J = 7.6 Hz, 1 H), 4.26 - 3.97 (m, 2H), 3.18 - 2.97 (m, 1 H), 2.96 - 2.68 (m, 2H), 2.07 - 1.97 (m, 1 H), 1.86 - 1.73 (m, 2H), 1.63 - 1.52 (m, 1 H), 1.46 (s, 9H).

[0286] Step C: A mixture of tert-butyl 3-(6-bromopyridin-2-yl)piperidine-1 -carboxylate (Int- 16) (3 g, 7.30 mmol), 1 ,1 ,1 ,2,2,2-hexamethyldistannane (10.36 g, 31.62 mmol, 6.56 mL), and Pd(PPh3)4(843 mg, 729.69 pmol) in toluene (50 mL) is degassed and purged with N2three times. The mixture is stirred at 110 °C for 2 hr under a N2atmosphere. The mixture is quenched with saturated aqueous KF (30 mL) and stirred at 25 °C for 1 hr. Then the mixture is extracted with ethyl acetate twice. The combined organic layers are washed with brine, dried over anhydrous Na2SO4and evaporated under vacuum to give a residue. The residue is purified by prep-HPLC (column: Xtimate C18, 150x40mmx10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 70%-100% B over 32 min) to afford the title compound tert-butyl 3-(6- (trimethylstannyl)pyridin-2-yl)piperidine-1 -carboxylate (Intermediate D) (1.6 g, 51% yield) as a yellow oil. LCMS (ESI MS) m / z = 427.1 [M + H]+1.

[0287] Example 13-[6-(4-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridineCompound 1

[0288] Step A: A mixture of 2,6-dibromopyridine 2 (5 g, 16.17 mmol), tert-butyl 4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate 1_ (4.21 g, 17.79 mmol), CS2CO3 (10.54 g, 32.34 mmol) and Pd(dppf)CI2(2.37 g, 3.23 mmol) in H2O (5 mL) and toluene (50 mL) is degassed and purged with N2three times. The mixture is stirred at 100 °C for 16 hr under N2. The reaction is concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether gradient) to give the title compound tert-butyl 4-(6-bromo-2-pyridyl)-3,6-dihydro-2H- pyridine- 1 -carboxylate 3 (1 .8 g, 32.8% yield) as a yellow oil. LCMS (ESI MS) m / z = 339.0 [M + H]+1.

[0289] 1H NMR (400 MHz, methanol-d4) 6 = 7.60 - 7.65 (m, 1 H), 7.49 (d, J = 7.8 Hz, 1 H), 7.41 (d, J = 7.8 Hz, 1 H), 6.70 (br s, 1 H), 4.12 (br d, J = 7.2 Hz, 2 H), 3.63 (br t, J = 5.2 Hz, 2 H), 2.56 - 2.62 (m, 2 H), 1.49 (s, 9 H).

[0290] Step B: To a solution of tert-butyl 6-bromo-3',6'-dihydro-[2,4'-bipyridine]-T(2'H)- carboxylate 3 (1.8 g, 5.31 mmol) in EtOAc (20 mL) is added PtO2(241 mg, 1.06 mmol) undera N2atmosphere. The suspension is degassed and purged with H2three times. The mixture is stirred under H2(15 psi) at 30 °C for 16 hrs. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure to give the title compound tert-butyl 4-(6-bromo-2- pyridyl)piperidine-1 -carboxylate 4 (1.3 g) as a colorless oil. LCMS (ESI MS) m / z = 341.0 [M + H]+1.

[0291] Step C: A mixture of 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazolo[1 ,5- a]pyridine 5 (236 mg, 967 pmol), tert-butyl 4-(6-bromopyridin-2-yl)piperidine-1 -carboxylate 4 (0.3 g, 879.1 pmol), K3PO4 (373 mg, 1.76 mmol), and XPhos Pd G3 (74.4 mg, 87.9 pmol) in dioxane (2 mL) and H2O (0.2 mL) is degassed and purged with N2three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 10-20% ethyl acetate / petroleum ether gradient) to give the title compound tert-butyl 4-(6-pyrazolo[1 ,5- a]pyridin-3-yl-2-pyridyl)piperidine-1-carboxylate 6 (180 mg, 40.7% yield) as a yellow solid. LCMS (ESI MS) m / z = 379.2 [M + H]+1.

[0292] 1H NMR (400 MHz, DMSO-cfe) 6 = 8.76 (d, J = 7.2 Hz, 1 H), 8.67 (s, 1 H), 8.56 (d, J = 8.8 Hz, 1 H), 7.69 - 7.74 (m, 2 H), 7.36 - 7.43 (m, 1 H), 7.08 (dd, J = 5.6, 2.8 Hz, 1 H), 7.01 (t, J = 6.4 Hz, 1 H), 4.10 (br d, J = 10.4 Hz, 2 H), 2.84 - 2.99 (m, 3 H), 1.92 (br d, J = 11.6 Hz, 2 H), 1.69 (qd, J = 12.4, 4.1 Hz, 2 H), 1.44 (s, 9 H).

[0293] Step D: To tert-butyl 4-(6-(pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)piperidine-1- carboxylate 6 (180 mg, 475.6 pmol) is added HCI / EtOAc (5 mL / 5 mL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by prep-HPLC (column: Welch Xtimate C18, 150x30mmx5um; mobile phase: [water (FA)-ACN]; B%: 0%-24%, 25min.) to yield the title compound 3-[6-(4-piperidyl)-2- pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 1) (44 mg, 32.6% yield) as a white solid. LCMS (ESI MS) m / z = 279.1 [M + H] +1.

[0294] 1H NMR (400 MHz, methanol-d4) 6 = 8.64 (d, J = 9.2 Hz, 1 H), 8.59 (d, J = 7.2 Hz, 1 H), 8.56 (s, 1 H), 8.52 (s, 1 H), 7.72 - 7.77 (m, 1 H), 7.66 - 7.70 (m, 1 H), 7.37 - 7.43 (m, 1 H), 7.11 (d, J = 7.6 Hz, 1 H), 7.01 (td, J = 6.8, 1.1 Hz, 1 H), 3.52 - 3.60 (m, 2 H), 3.17 - 3.24 (m, 2 H), 3.09 - 3.16 (m, 1 H), 2.18 - 2.25 (m, 4 H).

[0295] Example 23-[6-(1-methyl-4-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine7 Compound 2

[0296] Step A: To a solution of tert-butyl 4-(6-(pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2- yl)piperidine-1-carboxylate 7 (146 mg, 385.8 pmol) in HCOOH (1.5 mL) is added Formaline (1.64 g, 20.15 mmol, 1.5 mL, 37% purity). The mixture is stirred at 60 °C for 16 hrs. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by prep-HPLC (column: Welch Xtimate C18, 150x30mmx5um; mobile phase: [water (FA)-ACN]; gradient: 0%-26% B over 25 min) to yield the title compound 3-[6-(1-methyl-4-piperidyl)-2- pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 2) (48.9 mg 42.9% yield) as a white solid. LCMS (ESI MS) m / z = 293.1 [M + H]+1.

[0297] 1H NMR (400 MHz, methanol-d4) 6 = 8.65 (d, J = 9.2 Hz, 1 H), 8.59 (d, J = 7.2 Hz, 1 H), 8.54 (s, 1 H), 8.51 (s, 1 H), 7.71 - 7.76 (m, 1 H), 7.66 - 7.69 (m, 1 H), 7.40 (ddd, J = 9.2, 6.8, 1.0 Hz, 1 H), 7.11 (d, J = 7.6 Hz, 1 H), 7.01 (td, J = 6.8, 1.3 Hz, 1 H), 3.54 (br d, J = 12.4 Hz, 2 H), 2.98 - 3.09 (m, 3 H), 2.82 (s, 3 H), 2.20 - 2.31 (m, 4 H).

[0298] Example 33-(6-pyrrolidin-3-yl-2-pyridyl)pyrazolo[1 ,5-a]pyridineCompound 3

[0299] Step A: A mixture tert-butyl 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,5- dihydro-1 H-pyrrole-1-carboxylate 9 (3 g, 10.16 mmol), 2,6-dibromopyridine 8 (2.89 g, 12.20 mmol), Pd(dppf)CI2(1.12 g, 1.52 mmol), and CS2CO3 (6.62 g, 20.33 mmol) in toluene (100 mL) and H2O (20 mL) is degassed and purged with N2three times. The mixture is stirred at 80 °C for 10 hr under a N2atmosphere. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-17% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3-(6-bromo-2-pyridyl)-2,5-dihydropyrrole-1- carboxylate 10 (1.45 g, 43.4% yield) as a yellow solid. LCMS (ESI MS) m / z = 325.0 [M + H]+1 .

[0300] Step B: To a solution of tert-butyl 3-(6-bromopyridin-2-yl)-2,5-dihydro-1 H-pyrrole-1- carboxylate 10 (1.7 g, 5.23 mmol) in EtOAc (20 mL) is added PtO2(237.4 mg, 1.05 mmol) under a N2atmosphere. The suspension is degassed and purged with H2three times. The mixture is stirred under H2(20 psi) at 30 °C for 16 hr. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure to give the title compound tert-butyl 3-(6- bromo-2-pyridyl)pyrrolidine-1-carboxylate 11 (1.6 g, 48.6% yield) as a white solid. LCMS (ESI MS) m / z = 327.0 [M + H]+1.

[0301] Step C: A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridine 12 (201.4 mg, 825.1 pmol), 11 (300 mg, 916.8 pmol), XPhos Pd G3 (77.6 mg, 91.7 pmol) and K3PO4 (389.2 mg, 1.8 mmol) in dioxane (8 mL) and H2O (2 mL) is degassed and purged with N2three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by flashsilica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether gradient) to give the title compound tert-butyl 3-(6-pyrazolo[1 ,5-a]pyridin-3-yl-2-pyridyl)pyrrolidine-1 -carboxylate 13 (120 mg, 7.5% yield) as a yellow solid. LCMS (ESI MS) m / z = 365.2 [M + H]+1.

[0302] Step D: To a solution of tert-butyl 3-(6-(pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2- yl)pyrrolidine-1 -carboxylate 13 (120 mg, 329.3 pmol) in DCM (1 mL) is added HCI / EtOAc (3 mL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by prep-HPLC (column: Welch Xtimate C18, 150x30mmx5um; mobile phase: [water(FA)-ACN]; gradient: 0%-26% B over 25 min) to yield the title compound 3-(6-pyrrolidin-3-yl-2-pyridyl)pyrazolo[1 ,5-a]pyridine (Compound 3) (13 mg, 14.8% yield) as a yellow solid. LCMS (ESI MS) m / z = 265.1 [M + H]+1.

[0303] 1H NMR (400 MHz, DMSO-cfe) 6 = 8.77 (d, J = 7.2 Hz, 1 H), 8.70 (s, 1 H), 8.56 (d, J = 8.8 Hz, 1 H), 8.43 (br s, 1 H), 7.72 - 7.79 (m, 2 H), 7.39 - 7.47 (m, 1 H), 7.15 (dd, J = 5.6, 2.8 Hz, 1 H), 7.02 (td, J = 6.8, 1 .1 Hz, 1 H), 3.56 - 3.59 (m, 2 H), 3.34 (br d, J = 3.2 Hz, 1 H), 3.13 - 3.25 (m, 2 H), 2.27 - 2.41 (m, 1 H), 2.04 - 2.19 (m, 1 H).

[0304] Example 4Tert-butyl 3-(6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)pyrrolidine-1 -carboxylate, hrs toluene / H O 100 °C 16 hrs

[0305] Step A: A mixture of 2,6-dibromopyridine 14 (802.5 mg, 3.4 mmol), tert-butyl 3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,5-dihydro-1 H-pyrrole-1 -carboxylate 15 (500 mg, 1.7 mmol), CS2CO3 (1.1 g, 3.4 mmol), Pd(dppf)Cl2*CH2Cl2 (276.6 mg, 338.8 pmol) in toluene (10 mL) and H2O (3 mL) is purged with N2 three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction is diluted with water and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-3% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3-(6-bromopyridin-2-yl)-2,5-dihydro-1 H-pyrrole-1 -carboxylate 16 (150 mg, 27%) as a white solid. LCMS (ESI MS) m / z = 325.0 [M + H]+1.

[0306] Step B: A mixture of tert-butyl 3-(6-bromopyridin-2-yl)-2,5-dihydro-1 H-pyrrole-1 - carboxylate 16 (400 mg, 1.23 mmol) and PtC>2 (27.9 mg, 123.0 pmol) in EtOAc (5 mL) is degassed and purged with H2 three times. The mixture is stirred at 25 °C for 48 hr under a H2 (15 psi). The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure to give a crude product. The crude product is purified by prep-HPLC (neutral condition; column: Xtimate C18, 150x40mmx10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 38%-78% B over 32 min) to yield the title compound tert-butyl 3-(6-bromopyridin-2-yl)pyrrolidine-1- carboxylate 17 (200 mg, 49%) as a white solid. LCMS (ESI MS) m / z = 271.0 [M - 55]+1.

[0307] Step C: A mixture of tert-butyl 3-(6-bromopyridin-2-yl)pyrrolidine-1-carboxylate 17 (100 mg, 305.6 pmol), tributyl(tributylstannyl)stannane (354.5 mg, 611.2 pmol, 306 pL), and di-tert-butyl-[4-(trifluoromethyl)phenyl]phosphane dichloropalladium (23.1 mg, 30.6 pmol) in dioxane (2 mL) is degassed and purged with N2 three times. The mixture is stirred at 100 °C for 4 hr under a N2 atmosphere. The mixture is diluted with H2O and extracted with ethyl acetate three times. The combined organic layers are washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue is purified by flash silica gel chromatography (eluent of 0-30% ethyl acetate / petroleum ether gradient) to afford the title compound tert-butyl 3-(6-(tributylstannyl)pyridin-2-yl)pyrrolidine-1- carboxylate 18 (50 mg, 30% yield) as a white solid. LCMS (ESI MS) m / z = 539.3 [M + H]+1.

[0308] Step D: A mixture of 3-bromo-5-chloropyrazolo[1 ,5-a]pyridine 19 (15 mg, 64.8 pmol), tert-butyl 3-(6-(tributylstannyl)pyridin-2-yl)pyrrolidine-1 -carboxylate 18 (48.7 mg, 90.7 pmol), CsF (39.3 mg, 259.1 pmol, 10 pL), Cui (24.6 mg, 129.6 pmol), and XPhos Pd G3 (10.9 mg, 12.96 pmol) in dioxane (2 mL) is degassed and purged with N2 three times. The mixture is stirred at 90 °C for 2 hr under N2. The reaction mixture is extracted with ethyl acetate three times. The combined organic layers are dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the title compound tert-butyl 3-(6-(5- chloropyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)pyrrolidine-1 -carboxylate 20 (30 mg, crude) as awhite solid. LCMS (ESI MS) m / z = 399.1 [M + H]+1.

[0309] Step E: To a solution of tert-butyl 3-(6-(5-chloropyrazolo[1,5-a]pyridin-3-yl)pyridin- 2-yl)pyrrolidine-1 -carboxylate 20 (20 mg, 50.1 pmol) in DCM (1 mL) is added HCI / EtOAc (1 mL, 4M). The mixture is stirred at 25 °C for 1 h. The reaction mixture is concentrated under vaccum to give the crude product. The crude product is purified by prep-HPLC (FA condition; column: Xtimate C18, 150x40mmxl0um; mobile phase: [water(FA)-ACN]; gradient: 0%-32% B over 25 min) affording the title compound tert-butyl 3-(6-(5-chloropyrazolo[1,5-a]pyridin-3- yl)pyridin-2-yl)pyrrolidine-1-carboxylate (Compound 4) (2 mg, 12%) as a white solid. LCMS (ESI MS) m / z = 299.1 [M + H]+1.

[0310] 1H NMR (400 MHz, methanol-d4) 6 = 7.23 - 7.31 (m, 2 H), 7.18 (s, 1 H), 6.44 - 6.50 (m, 1 H), 6.36 - 6.42 (m, 1 H), 5.88 (br d, J = 7.50 Hz, 1 H), 5.68 (br d, J = 6.63 Hz, 1 H), 2.43 - 2.53 (m, 2 H), 2.24 - 2.36 (m, 2 H), 2.12 - 2.20 (m, 1 H), 1.25 (br dd, J = 11.82, 5.32 Hz, 1 H), 1.00 - 1.12 (m, 1 H).

[0311] Example sRac-5-chloro-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine

[0312] Step A: To a solution of 5-chloro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyrazolo[1,5-a]pyridine 21 (80 mg, 287.2 pmol) and tert-butyl 3-(6-bromopyridin-2- yl)piperidine-1-carboxylate 22 (147 mg, 430.8 pmol) in H2O (2 mL) and toluene (3 mL) are added Pd(dppf)Ch (23.4 mg, 28.7 pmol) and CS2CO3 (93.6 mg, 287.2 pmol). The mixture is stirred at 60 °C for 12 hr under N2. The reaction mixture is quenched with H2O and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried overanhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl-3-[6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)-2- pyridyl]piperidine-1 -carboxylate 23 (30 mg, 72.6 pmol, 25.3% yield) as a yellow solid. LCMS (ESI MS) m / z = 413.1 [M + H]+1.

[0313] Step B: To a solution of tert-butyl 3-(6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)pyridin- 2-yl)piperidine-1-carboxylate 23 (36 mg, 87.2 pmol) in DCM (1 mL) is added HCI (12 M, 29 pL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by prep-HPLC (FA condition column: Welch Xtimate C18, 150x30mmx5um; mobile phase: [water (FA)-ACN]; gradient: 0% - 32% B over 25 min) to yield the title compound Rac-5-chloro-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5- a]pyridine (Compound 5) (31.7 mg, 84.8 pmol, 97.3% yield) as a white solid. LCMS (ESI MS) m / z = 313.1 [M + H]+1.

[0314] 1H NMR (400 MHz, DMSO-cfe) 6 = 8.83 (d, J = 7.6 Hz, 1 H), 8.77 (s, 1 H), 8.63 (d, J = 2.0 Hz, 1 H), 7.74 - 7.79 (m, 2 H), 7.15 (dd, J = 5.6, 3.6 Hz, 1 H), 7.07 - 7.12 (m, 1 H), 3.17 (br d, J = 12.8 Hz, 2 H), 2.99 - 3.09 (m, 2 H), 2.95 (s, 1 H), 2.71 (br d, J = 2.8 Hz, 1 H), 2.68 - 2.69 (m, 1 H), 2.08 (br d, J = 12.0 Hz, 1 H), 1.69 - 1.86 (m, 3 H).

[0315] Examples 6 and 75-chloro-3-[6-[(3R)-3-piperidyl]-2-pyridyl]pyrazolo[1 ,5-a]pyridine and 5-chloro-3-[6-[(3S)-3- piperidyl]-2-pyridyl]pyrazolo[1 ,5-a]pyridineCompound 5 Compound 6 Compound 7

[0316] Step A: Rac-5-chloro-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine(Compound 5) (100 mg) is separated by SFC (column: DAICEL CHIRALPAK IG (250mmx30mm, 10um); mobile phase: [CC>2-EtOH(0.1%NH3H2O)]; B%: 35%, isocratic elution mode) to yield the title compounds Compound 6 (20.3 mg, 32%) as a white solid and Compound 7 (21.8 mg, 33% yield) as a white solid. Stereochemistry not assigned.

[0317] For Compound 6: LCMS (ESI MS) m / z = 313.2 [M + H]+1.1H NMR (400 MHz, methanol-d4) 6 = 8.61 (d, J = 2.4 Hz, 1 H), 8.47 (d, J = 7.2 Hz, 1 H), 8.43 (s, 1 H), 7.59 - 7.66 (m, 1 H), 7.51 - 7.56 (m, 1 H), 7.00 (d, J = 7.6 Hz, 1 H), 6.89 (dd, J = 7.6, 2.4 Hz, 1 H), 3.27 (brs, 1 H), 3.03 - 3.10 (m, 1 H), 2.86 - 2.96 (m, 2 H), 2.65 (td, J = 12.4, 2.8 Hz, 1 H), 2.03 - 2.10 (m, 1 H), 1.75 - 1.85 (m, 2 H), 1.59 - 1.71 (m, 1 H). [a]D= +10 (c = 0.001 , MeOH). SFC fR= 1.628 min.

[0318] For Compound 7: LCMS (ESI MS) m / z = 313.1 [M + H]+1.1H NMR (400 MHz, methanol-d4) 6 = 8.75 (d, J = 2.4 Hz, 1 H), 8.59 (d, J = 7.2 Hz, 1 H), 8.49 - 8.55 (m, 1 H), 7.69 - 7.78 (m, 1 H), 7.59 - 7.68 (m, 1 H), 7.11 (d, J = 7.6 Hz, 1 H), 7.01 (dd, J = 7.6, 2.4 Hz, 1 H), 3.38 (br s, 1 H), 3.09 - 3.20 (m, 1 H), 2.92 - 3.04 (m, 2 H), 2.72 (br t, J = 12.0 Hz, 1 H), 2.11 - 2.24 (m, 1 H), 1.84 - 1.93 (m, 2 H), 1.69 - 1.80 (m, 1 H). [a]D= -10 (c = 0.001 , MeOH). SFC tR= 1.792 min.

[0319] Example s5-bromo-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine

[0320] Step A: To a solution of 5-bromopyrazolo[1 ,5-a]pyridine 24 (500 mg, 2.54 mmol) in MeOH (5 mL) is added / V-iodosuccinimide (NIS) (570.9 mg, 2.54 mmol) at 0 °C. The reaction temperature is allowed to slowly warm to 25 °C, and the reaction solution is then stirred at 25 °C for 12 hrs. The reaction mixture is concentrated under reduced pressure to give the title compound 5-bromo-3-iodo-pyrazolo[1 ,5-a]pyridine 25 (480 mg) as a white solid.LCMS (ESI MS) m / z = 324.7 [M + H]+1.

[0321] Step B: To a solution of 5-bromo-3-iodopyrazolo[1 ,5-a]pyridine 25 (100 mg, 309.7 pmol) and tert-butyl 3-(6-(trimethylstannyl)pyridin-2-yl)piperidine-1-carboxylate 26 (144.8 mg, 340.6 pmol) in dioxane (2 mL) are added Xphos Pd G3 (35.8 mg, 30.97 pmol), CsF (188.2 mg, 1.24 mmol, 45.7 pL) and Cui (117.9 mg, 619.3 pmol). The mixture is stirred at 90 °C for 12 hr under N2. The reaction mixture is concentrated under reduced pressure to give a residuewhich is purified by flash silica gel chromatography (eluent of 0-30% DCM / MeOH gradient) to yield the title compound tert-butyl 3-[6-(5-bromopyrazolo[1 ,5-a]pyridin-3-yl)-2- pyridyl]piperidine- 1 -carboxylate 27 (20 mg) as a yellow solid. LCMS (ESI MS) m / z = 456.9 [M + H]+1.

[0322] Step C: To tert-butyl 3-(6-(5-bromopyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2- yl)piperidine-1-carboxylate 27 (20 mg, 43.73 pmol) is added HCI / DCM (6.38 mg, 174.9 pmol). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by prep-HPLC (FA condition, column: Welch Xtimate C18, 150x30mmx5um; mobile phase: [water (FA)-ACN]; gradient: 0%-36% B over 25 min) to yield the title compound 5-bromo-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 8) (2.1 mg, 5.29 pmol, 12.1% yield) as a white solid. LCMS (ESI MS) m / z = 357.0 [M + H]+1.

[0323] 1H NMR (400 MHz, DMSO-cfe) 6 = 8.69 - 8.83 (m, 3 H), 7.75 - 7.87 (m, 2 H), 7.12 - 7.27 (m, 2 H), 3.51 - 3.60 (m, 1 H), 3.04 - 3.25 (m, 3 H), 2.83 - 2.95 (m, 1 H), 2.06 - 2.17 (m, 1 H), 1.91 - 1.99 (m, 1 H), 1.76 - 1.90 (m, 2 H).

[0324] Example 95-methyl-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridineCompound 9

[0325] Step A: To a solution of 5-methylpyrazolo[1 ,5-a]pyridine 28 (500 mg, 3.78 mmol) in DMF (6 mL) is added NBS (673 mg, 3.78 mmol). The mixture is stirred at 25 °C for 16 hrs. The reaction mixture is quenched with H2O, and the mixture is extracted with EtOAc three times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-30% ethyl acetate / petroleum ether gradient) to yield the title compound 29 (600 mg) as a white solid. LCMS (ESI MS) m / z = 213.0 [M + H]+1.

[0326] Step B: A mixture of 3-bromo-5-methylpyrazolo[1 ,5-a]pyridine 29 (250 mg, 1.18 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane) (601 mg, 2.37 mmol), K2CO3 (245 mg, 1.78 mmol), and Pd(dppf)Cl2*CH2Cl2 (96 mg, 118.45 pmol) in dioxane (5 mL) is purged with N2 three times, and then the mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is quenched with H2O and extracted with EtOAc three times. The combined organic layers re washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 20% ethyl acetate / petroleum ether gradient) to yield the title compound 5-methyl-3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl) pyrazolo[1 ,5-a]pyridine 30 (200 mg) as a white solid. LCMS (ESI MS) m / z = 258.9 [M + H]+1.

[0327] Step C: A mixture of 5-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyrazolo[1 ,5-a]pyridine 30 (70 mg, 271.19 pmol), tert-butyl 3-(6-bromopyridin-2- yl)piperidine-1-carboxylate 31 (185 mg, 542.38 pmol), K3PO4 (115 mg, 542.4 pmol), and XantPhos Pd G3 (25 mg, 27.12 pmol) in dioxane (1 mL) and H2O (0.3 mL) is purged with N2 three times, and then the mixture is stirred at 60 °C for 12 hr under N2. The reaction mixture is diluted with H2O, and the mixture is extracted with EtOAc three times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 20% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3-[6-(5- methylpyrazolo[1 ,5-a]pyridin-3-yl)-2-pyridyl]piperidine-1 -carboxylate 32 (80 mg) as a white solid. LCMS (ESI MS) m / z = 393.3 [M + H]+1.

[0328] Step D: To a solution of tert-butyl 3-(6-(5-methylpyrazolo[1 ,5-a]pyridin-3-yl)pyridin- 2-yl) piperidine-1-carboxylate 32 (50 mg, 127.4 pmol) in DCM (0.5 mL) is added HCI / EtOAc (4M, 0.5 mL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give the crude product which is purified by prep-HPLC (FA condition; column: Welch Xtimate C18, 150x30mmx5um; mobile phase: [water (FA)-ACN]; gradient: 0%-30% B over 25 min) to yield the title compound 5-methyl-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 9) (18 mg, 47%) as a white solid. LCMS (ESI MS) m / z = 293.2 [M + H]+1.

[0329] 1H NMR (400 MHz, methanol-d4) 6 = 8.61 (br d, J = 9.01 Hz, 1 H), 8.55 (d, J = 6.88 Hz, 1 H), 8.41 (d, J = 3.25 Hz, 1 H), 7.41 - 7.49 (m, 1 H), 7.31 - 7.40 (m, 1 H), 7.05 (dd, J = 8.38, 3.25 Hz, 1 H), 6.98 (t, J = 6.82 Hz, 1 H), 3.36 (br d, J = 10.26 Hz, 1 H), 3.18 (br d, J = 12.63 Hz, 1 H), 2.89 - 3.08 (m, 2 H), 2.70 - 2.81 (m, 1 H), 2.04 - 2.15 (m, 1 H), 1.66 - 1.93 (m, 3 H).

[0330] Example 103-[6-(3-piperidyl)-2-pyridyl]-5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine

[0331] Step A: A mixture of 3-bromo-5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine 33 (60 mg, 226.4 pmol), tert-butyl 3-(6-(trimethylstannyl)pyridin-2-yl)piperidine-1-carboxylate 34 (115.5 mg, 271.7 pmol), XPhos Pd G3 (19.1 mg, 22.6 pmol), and K3PO4(96.1 mg, 452.8 pmol) in dioxane (2 mL) is purged with N2 three times. The mixture is stirred at 80 °C for 2 hours under N2. The reaction mixture is concentrated directly to yield the title compound tertbutyl 3-[6-[5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-3-yl]-2-pyridyl]piperidine-1-carboxylate 35 (101.0 mg, crude) as a brown solid. LCMS (ESI MS) m / z = 447.2 [M + H]+1.

[0332] Step B: To a solution of tert- butyl 3-(6-(5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-3- yl)pvridin-2-yl)piperidine-1 -carboxylate 35 (100 mg, 224 pmol) in DCM (2 mL) is added trifluoroacetic acid (TFA) (0.4 mL). The mixture is stirred at 20 °C for 2 hrs. The reactionmixture is extracted with H2O three times. The combined water layers are concentrated under reduced pressure to give a residue which w is as purified by prep-HPLC (column: Xtimate C18, 150x40mmx10um; mobile phase: [water(FA)-ACN]; gradient: 0%-36% B over 25 min] to yield the title compound 3-[6-(3-piperidyl)-2-pyridyl]-5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine (Compound 10) (37.2 mg, 47%) as a white solid. LCMS (ESI MS) m / z = 347.1 [M + H]+1.

[0333] 1H NMR (400 MHz, methanol-d4) 6 = 9.01 (s, 1 H), 8.80 (d, J = 7.2 Hz, 1 H), 8.69 (s, 1 H), 8.53 (s, 1 H), 7.76 - 7.87 (m, 2 H), 7.21 (ddd, J = 14.0, 7.3, 1.6 Hz, 2 H), 3.65 - 3.72 (m, 1 H), 3.48 (br d, J = 12.4 Hz, 1 H), 3.33 - 3.40 (m, 1 H), 3.28 (br d, J = 3.6 Hz, 1 H), 3.02 (td, J = 12.4, 3.4 Hz, 1 H), 2.23 - 2.32 (m, 1 H), 2.07 - 2.15 (m, 1 H), 1.91 - 2.02 (m, 2 H).

[0334] Example 115-methoxy-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine

[0335] Step A: To a solution of ethyl 5-methoxypyrazolo[1 ,5-a]pyridine-3-carboxylate 36 (0.5 g, 2.27 mmol) in MeOH (2.5 mL) and H2O (2.5 mL) is added LiOH H2O (476 mg, 11.35 mmol). The mixture is stirred at 50 °C for 16 hrs. The resulting mixture is then adjusted to pH~5 by aq. HCI (1 M), and the reaction mixture is filtered. The filter cake is dried under reduced pressure to yield the title compound 5-methoxypyrazolo[1 ,5-a]pyridine-3-carboxylic acid 37 (390 mg, 89%) as a white solid.

[0336] 1H NMR (400 MHz, DMSO-cfe) 6 = 8.68 (d, J = 7.6 Hz, 1 H), 8.26 (s, 1 H), 7.33 (d, J = 2.8 Hz, 1 H), 6.78 (dd, J = 2.8, 7.6 Hz, 1 H), 3.90 (s, 3H).

[0337] Step B: To a solution of 3-bromo-5-methoxypyrazolo[1 ,5-a]pyridine 37 (740 mg, 3.85 mmol) in DMF (8 mL) is added NaHCCh (970.4 mg, 11.55 mmol) and / V-bromosuccinimide (NBS) (685.3 mg, 3.85 mmol) at 25 °C. The mixture is stirred at 25 °C for 4 hrs. The mixture is poured into water and extracted with EtOAc. The combined organic layers are washed with brine three times, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 20-40% EtOAc / PE) to yield the title compound 3-bromo-5-methoxy-pyrazolo[1 ,5-a]pyridine 38 (753 mg, 86%) as a white solid.

[0338] 1H NMR (400 MHz, DMSO-cfe) 6 = 8.58 (d, J = 7.6 Hz, 1 H), 8.03 (s, 1 H), 6.79 (d, J = 2.8 Hz, 1 H), 6.64 (dd, J = 2.8, 7.6 Hz, 1 H), 3.88 (s, 3H).

[0339] Step C: A mixture of tert-butyl 3-(6-(trimethylstannyl)pyridin-2-yl)piperidine-1- carboxylate 39 (187.2 mg, 440.4 pmol), 3-bromo-5-methoxypyrazolo[1 ,5-a]pyridine 38 (0.1 g, 440.4 pmol), XPhos Pd G3 (37 mg, 44.0 pmol), and K3PO4 (187 mg, 880.8 pmol) in dioxane (2 mL) and H2O (0.2 mL) is degassed and purged with N2three times. The mixture is stirred at 80 °C for 2 hours under N2. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 20-30% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3-[6-(5- methoxypyrazolo[1 ,5-a]pyridin-3-yl)-2-pyridyl]piperidine-1-carboxylate 40 (80 mg, 44%) as a white solid.

[0340] 1H NMR (400 MHz, methanol-d4) 6 = 8.41 - 8.38 (m, 2H), 8.11 (d, J = 2.0 Hz, 1 H), 7.72 - 7.65 (m, 1 H), 7.62 - 7.55 (m, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 6.67 (dd, J = 2.8, 7.6 Hz, 1H), 4.51 - 4.30 (m, 1 H), 4.18 - 4.11 (m, 1 H), 3.97 (s, 3H), 2.93 - 2.79 (m, 2H), 2.18 (br d, J = 12.8 Hz, 1 H), 2.00 - 1.90 (m, 1 H), 1.87 - 1.80 (m, 1 H), 1.76 - 1.53 (m, 2H), 1.47 (s, 9H).

[0341] Step D: To a solution of tert-butyl 3-(6-(5-methoxypyrazolo[1 ,5-a]pyridin-3- yl)pvridin-2-yl)piperidine-1 -carboxylate 40 (0.07 g, 171.36 pmol, 1 eq) in DCM (1 mL) is added HCI / dioxane (1 mL, 4M). The mixture is stirred at 25 °C for 2 hrs. The reaction mixture is partitioned between DCM and H2O. The organic phase is discarded, and the water phase is lyophilized to yield the title compound 5-methoxy-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5- a]pyridine (Compound 11) (33.7 mg, 68%) as a white solid. LCMS (ESI MS) m / z = 308.8 [M + H]+1.

[0342] 1H NMR (400 MHz, methanol-d4) 6 = 8.69 (s, 1 H), 8.61 (d, J = 7.6 Hz, 1 H), 8.40 (t, J = 8.0 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 7.66 (d, J = 7.6 Hz, 1 H), 7.48 (d, J = 2.4 Hz, 1 H), 6.88 (dd, J = 2.8, 7.6 Hz, 1 H), 4.03 (s, 3H), 3.80 - 3.70 (m, 2H), 3.52 (br d, J = 11.6 Hz, 1 H), 3.47 -3.39 (m, 1 H), 3.19 - 3.08 (m, 1 H), 2.34 - 2.26 (m, 1 H), 2.19 - 2.08 (m, 1 H), 2.06 - 1.96 (m, 2H).

[0343] Example 123-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-ol

[0344] Step A: To a solution of 5-methoxy-3-(6-piperidin-3-yl)pyridine-2-yl)pyrazolo[1 ,5- a]pyridine Compound 11 (30 mg, 97.28 pmol) in DCE (2 mL) is added AICI3 (130 mg, 972.84 pmol). The mixture is stirred at 80 °C for 12 hr. The mixture is quenched with water at 0 °C and filtered. The filtrate is extracted with DCM three times. The aqueous phase is concentrated under reduced pressure to give a residue which is purified by prep-HPLC (column: Xtimate C18, 150x40mmx10um; mobile phase: [water (HCI)-ACN]; gradient: 0%-24% B over 36 min) to yield the title compound 3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-ol (Compound 12) (6 mg, 20%) as a brown solid. LCMS (ESI MS) m / z = 295.0 [M + H]+1.

[0345] 1H NMR (400 MHz, methanol-d4) 6 = 8.51 - 8.66 (m, 2 H), 8.11 (br t, J = 6.94 Hz, 1 H), 7.87 (br d, J = 7.50 Hz, 1 H), 7.58 (br s, 1 H), 7.39 (br d, J = 6.63 Hz, 1 H), 6.77 (br s, 1 H), 3.70 (br d, J = 8.50 Hz, 1 H), 3.49 (br s, 3 H), 3.16 (br d, J = 2.88 Hz, 1 H), 2.25 - 2.34 (m, 1 H), 2.09 - 2.19 (m, 1 H), 1.95 - 2.04 (m, 2 H).

[0346] Example 135-isopropoxy-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridineCompound 13

[0347] Step A: To a solution of 2-bromopropane 42 (252.1 mg, 2.05 mmol, 193 pL) and pyrazolo[1 ,5-a]pyridin-5-ol 41 (250 mg, 1.86 mmol) in ACN (1 mL) are added K2CO3 (515.1 mg, 3.73 mmol) and KI (61.8 mg, 372.8 pmol). The mixture is stirred at 80 °C for 16 hr. The reaction mixture is concentrated directly to give a crude product which is purified by flash silica gel chromatography (eluent of 0-15% ethyl acetate / petroleum ether gradient) to yield the title compound 5-isopropoxypyrazolo[1 ,5-a]pyridine 43 (140 mg, crude) as a white solid.

[0348] Step B: To a solution of 5-isopropoxypyrazolo[1 ,5-a]pyridine 43 (100 mg, 567.5 pmol) in ACN (3 mL) is added NBS (151.5 mg, 851.2 pmol). The mixture is stirred at 25 °C for 16 hr. The reaction mixture is concentrated to give a crude product which is purified by flash silica gel chromatography (eluent of 0-4% ethyl acetate / petroleum ether gradient) to yield the title compound 3-bromo-5-isopropoxy-pyrazolo[1 ,5-a]pyridine 44 (120 mg, crude) as colorless oil.

[0349] 1H NMR (400 MHz, DMSO-cfe) 6 = 8.56 (d, J = 7.6 Hz, 1 H), 8.00 (s, 1 H), 6.76 (d, J = 2.4 Hz, 1 H), 6.59 (dd, J = 2.8, 7.6 Hz, 1 H), 4.78 (td, J = 6.0, 12.0 Hz, 1 H), 1.31 (d, J = 6.0 Hz, 6H).

[0350] Step C: A mixture of tert-butyl 3-(6-(trimethylstannyl)pyridin-2-yl)piperidine-1- carboxylate 45 (50.0 mg, 117.61 pmol), 3-bromo-5-isopropoxypyrazolo[1 ,5-a]pyridine 44 (30.0 mg, 117.6 pmol), XPhos Pd G3 (9.9 mg, 11.76 pmol), and K3PO4 (49.9 mg, 235.2 pmol) in dioxane (1 mL) and H2O (0.25 mL) is purged with N2 three times, and then the mixture is stirred at 80 °C for 2 hrs under N2. The reaction mixture is concentrated to give a crude product which is purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3-[6-(5-isopropoxypyrazolo[1 ,5-a]pyridin-3-yl)-2- pyridyl]piperidine-1 - carboxylate 46 (70 mg) as yellow oil.

[0351] Step D: To a solution of tert-butyl 3-(6-(5-isopropoxypyrazolo[1 ,5-a]pyridin-3- yl)pyridin-2-yl)piperidine-1-carboxylate 46 (60 mg, 137.4 pmol) in H2O (1 mL) is added HCI (12 M, 171 pL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated to give the crude product which is purified by prep-HPLC (column: Xtimate C18, 150x40mmx10um; mobile phase: [water (HCI)-ACN]; gradient: 0%-38% B over 36 min) to yield the title compound 5-isopropoxy-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 13) (19.2 mg, 40%) as a yellow solid. LCMS (ESI MS) m / z = 337.2 [M +H]+1.

[0352] 1H NMR (400 MHz, methanol-d4) 6 = 8.64 - 8.54 (m, 2H), 8.29 - 8.20 (m, 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.59 - 7.47 (m, 2H), 6.82 (dd, J = 2.4, 7.6 Hz, 1 H), 4.89 - 4.88 (m, 1 H), 3.72 (br dd, J = 1.2, 12.0 Hz, 1 H), 3.64 - 3.56 (m, 1 H), 3.51 (br d, J = 12.4 Hz, 1 H), 3.42 - 3.36 (m, 1 H), 3.16 - 3.03 (m, 1 H), 2.30 (br dd, J = 2.4, 6.0 Hz, 1 H), 2.19 - 2.10 (m, 1 H), 2.06 - 1.96 (m, 2H), 1.44 (dd, J = 1.2, 6.0 Hz, 6H).

[0353] Example 145-(cyclopropylmethoxy)-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine

[0354] Step A: To a solution of (bromomethyl)cyclopropane 48 (251 mg, 1.86 mmol) and pyrazolo[1 ,5-a]pyridin-5-ol 47 (0.25 g, 1 .86 mmol) in ACN (5 mL) is added CS2CO3 (1 .2 g, 3.73 mmol). The mixture is stirred at 80 °C for 3 hrs. The reaction mixture is concentrated underreduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-30% ethyl acetate / petroleum ether gradient) to yield the title compound 5- (cyclopropylmethoxy)pyrazolo[1 ,5-a]pyridine 49 (341 mg, 81%) as a white solid. LCMS (ESI MS) m / z = 189.2 [M +HJ+1.

[0355] Step B: To a solution of 5-(cvclopropvlmethoxv)pvrazolo[1.5-a1pvridine 49 (280 mg, 1.49 mmol) in ACN (5 mL) is added NBS (238 mg, 1.34 mmol). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether gradient) to yield the title compound 3-bromo-5-(cyclopropylmethoxy)pyrazolo[1 ,5-a]pyridine 50 (283 mg, 71%) as a white solid.

[0356] 1H NMR (400 MHz, methanol-d4) 6 = 8.35 (d, J = 7.6 Hz, 1 H), 7.84 (s, 1 H), 6.73 (d, J = 2.4 Hz, 1 H), 6.63 (dd, J = 2.8, 7.6 Hz, 1 H), 3.93 (d, J = 7.2 Hz, 2H), 1.38 - 1.26 (m, 1 H), 0.71 - 0.63 (m, 2H), 0.44 - 0.38 (m, 2H).

[0357] Step C: A mixture of tert-butyl 3-(6-(trimethylstannyl)pyridin-2-yl)piperidine-1- carboxylate 51 (238.7 mg, 561.54 pmol), 3-bromo-5-(cyclopropylmethoxy)pyrazolo[1 ,5- a]pyridine 50 (150 mg, 561.5 pmol, 1 eq), XPhos Pd G3 (47.5 mg, 56.15 pmol), and K3PO4 (238.4 mg, 1.12 mmol) in dioxane (4 mL) and H2O (0.1 mL) is purged with N2three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by prep-HPLC (column: Xtimate C18, 150x40mmx10um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; gradient: 54%-94% B over 32 min) to yield the title compound tert-butyl 3-[6-[5-(cyclopropylmethoxy)pyrazolo[1 ,5- a]pyridin-3-yl]-2-pyridyl]piperidine-1 - carboxylate 52 (70 mg, 27.8%) as a white solid.

[0358] 1H NMR (400 MHz, methanol-d4) 5 = 8.41 - 8.38 (m, 2H), 8.10 (d, J = 2.8 Hz, 1 H), 7.71 - 7.64 (m, 1 H), 7.60 - 7.57 (m, 1 H), 7.04 (d, J = 7.2 Hz, 1 H), 6.68 (dd, J = 2.8, 7.6 Hz, 1 H), 4.17 (br d, J = 11.6 Hz, 1 H), 3.99 (d, J = 7.2 Hz, 2H), 2.93 - 2.79 (m, 2H), 2.17 (br d, J = 13.2 Hz, 1 H), 2.01 - 1.79 (m, 2H), 1.71 - 1.58 (m, 1 H), 1.48 (s, 9H), 1.42 - 1.26 (m, 2H), 0.72 - 0.62 (m, 2H), 0.43 - 0.36 (m, 2H).

[0359] Step D: To a solution of tert-butyl 3-(6-(5-(cyclopropylmethoxy)pyrazolo[1 ,5-a] pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate 52 (40.0 mg, 89.18 pmol) in DCM (0.5 mL) is added HCI / dioxane (4 M, 0.5 mL). The mixture is stirred at 25 °C for 0.5 hr. The reaction mixture is partitioned between DCM and H2O. The organic phase is discarded, and the aqueous phase is lyophilized to give the title compound 5-(cyclopropylmethoxy)-3-[6-(3- piperidyl)- 2-pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 14) (17.7 mg, 56%) as an off-white solid. LCMS (ESI MS) m / z = 349.2 [M + H]+1.

[0360] 1H NMR (400 MHz, methanol-d4) 5 = 8.68 (s, 1 H), 8.61 (d, J = 7.6 Hz, 1 H), 8.39 (t,J = 8.0 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 7.65 (d, J = 7.6 Hz, 1 H), 7.43 (d, J = 2.0 Hz, 1 H), 6.89 (dd, J = 2.4, 7.6 Hz, 1 H), 4.07 (d, J = 7.2 Hz, 2H), 3.77 - 3.69 (m, 2H), 3.52 (br d, J = 12.4 Hz, 1 H), 3.47 - 3.39 (m, 1 H), 3.18 - 3.07 (m, 1H), 2.30 (br d, J = 9.2 Hz, 1 H), 2.19 - 2.11 (m, 1 H), 2.08 - 1.93 (m, 2H), 1.41 - 1.28 (m, 1 H), 0.74 - 0.65 (m, 2H), 0.44 (q, J = 4.8 Hz, 2H).

[0361] Example 155-(oxetan-3-ylmethoxy)-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridineCompound 15

[0362] Step A: To a solution of pyrazolo[1 ,5-a]pyridin-5-ol 53 (300 mg, 2.24 mmol) and 3- (bromomethyl)oxetane 54 (405 mg, 2.68 mmol) in ACN (6 mL) is added CS2CO3 (1.4 g, 4.47 mmol). The mixture is stirred at 80 °C for 12 hrs. The reaction mixture is quenched with H2O, and the mixture is extracted with EtOAc three times. The combined organic layers are washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the title compound 5-(oxetan-3-ylmethoxy)pyrazolo[1 ,5-a]pyridine 55 (400 mg, crude) as a white solid. LCMS (ESI MS) m / z = 205.2.

[0363] Step B: To a solution of 5-(oxetan-3-ylmethoxy)pyrazolo[1 ,5-a]pyridine 55 (380 mg, 1.86 mmol) in ACN (5 mL) is added NBS (264 mg, 1.49 mmol). The mixture is stirred at 25 °C for 1 hr. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluentof 0-25% ethyl acetate / petroleum ether gradient) to yield the title compound 3-bromo-5- (oxetan-3-ylmethoxy)pyrazolo[1 ,5-a]pyridine 56 (250 mg) as a white solid. LCMS (ESI MS) m / z = 285.0 [M + H]+1.

[0364] Step C: A mixture of 3-bromo-5-(oxetan-3-ylmethoxy)pyrazolo[1 ,5-a]pyridine 56 (60 mg, 141.13 pmol), tert-butyl 3-(6-(trimethylstannyl)pyridin-2-yl)piperidine-1-carboxylate 57 (47 mg, 169.35 pmol), XPhos Pd G3 (11 mg, 14.11 pmol), and K3PO4 (59 mg, 282.2 pmol) in dioxane (3 mL) and H2O (1 mL) is purged with N2 three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction is filtered, and the filtrate is concentrated under vacuum to give the title compound tert-butyl 3-[6-[5-(oxetan-3-ylmethoxy)pyrazolo[1 ,5-a]pyridin-3-yl]-2-pyridyl] piperidine-1-carboxylate 58 (120 mg, crude) as a brown oil. LCMS (ESI MS) m / z = 465.2 [M + H]+1.

[0365] Step D: To a solution of tert-butyl 3-(6-(5-(oxetan-3-ylmethoxy)pyrazolo[1 ,5-a] pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate 58 (50 mg, 107.6 pmol) in DCM (1 mL) is added TFA (0.5 mL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give the crude product which is purified by prep-HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (TFA)-ACN]; gradient: 0%-34% B over 36 min) to yield the title compound 5-(oxetan-3-ylmethoxy)-3-[6-(3-piperidyl)-2- pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 15) (8 mg, 17%) as a white solid. LCMS (ESI MS) m / z = 365.0 [M + H]+1.

[0366] 1H NMR (400 MHz, methanol-d4) 6 = 8.49 (s, 1 H), 8.47 - 8.48 (m, 1 H), 8.47 (s, 1 H), 8.46 - 8.47 (m, 1 H), 7.94 (s, 1 H), 7.75 - 7.83 (m, 1 H), 7.70 (d, J = 8.00 Hz, 1 H), 7.16 (d, J = 7.63 Hz, 1 H), 6.78 (dd, J = 7.38, 2.00 Hz, 1 H), 4.96 (s, 2 H), 4.64 - 4.69 (m, 2 H), 4.43 (d, J= 6.13 Hz, 2 H), 3.70 (br d, J = 10.76 Hz, 1 H), 3.51 - 3.62 (m, 2 H), 3.38 - 3.48 (m, 2 H), 3.04 - 3.15 (m, 1 H), 2.30 (br d, J = 11.88 Hz, 1 H), 2.07 - 2.17 (m, 2 H), 1.98 (br t, J = 12.01 Hz, 1 H).

[0367] Example 164-[3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridin-5-yl]morpholine

[0368] Step A: To a solution of ethyl 5-bromopyrazolo[1 ,5-a]pyridine-3-carboxylate 59 (900 mg, 3.34 mmol) and morpholine (874.1 mg, 10.0 mmol, 883 pL) in DMSO (5 mL) is added K2CO3(924.5 mg, 6.69 mmol). The mixture is stirred at 140 °C for 6 hrs. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether gradient) to yield the title compound ethyl 5- morpholinopyrazolo[1 ,5-a]pyridine-3-carboxylate 60 (600 mg) as a yellow solid. LCMS (ESI MS) m / z = 276.0 [M + H]+1.

[0369] Step B: To a solution of ethyl 5-morpholinopyrazolo[1 ,5-a]pyridine-3-carboxylate 60 (500 mg, 1.82 mmol) in THF (3 mL) and H2O (3 mL) is added LiOH«H2O (304.9 mg, 7.26 mmol). The mixture is stirred at 50 °C for 12 hrs. The reaction is quenched with HCI (1M) and extracted with EtOAc three times. The combined organic layers are washed with HCI (1M) twice, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound 5-morpholinopyrazolo[1 ,5-a]pyridine-3-carboxylic acid 61 (500 mg) as a yellow solid. LCMS (ESI MS) m / z = 247.9 [M + H]+1.

[0370] Step C: To a solution of 5-morpholinopyrazolo[1 ,5-a]pyridine-3-carboxylic acid 61 (180 mg, 728 pmol) in DMF (2 mL) are added NIS (327.6 mg, 1.46 mmol) and NaHCO3(244.6 mg, 2.91 mmol, 113 pL). The mixture is stirred at 25 °C for 12 hr. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0- 30% ethyl acetate / petroleum ether gradient) to yield the title compound 4-(3-iodopyrazolo[1 ,5- a]pyridin-5-yl)morpholine 62 (80 mg) as a yellow oil. LCMS (ESI MS) m / z = 330.1 [M + H]+1.

[0371] Step D: To a solution of 4-(3-iodopyrazolo[1 ,5-a]pyridin-5-yl)morpholine 62 (20 mg,60.8 pmol) and tert-butyl 3-(6-(trimethylstannyl)pyridin-2-yl)piperidine-1-carboxylate 63 (51.7 mg, 121.5 pmol) in dioxane (1 mL) are added copper iodide (23.1 mg, 121.5 pmol), CsF (36.9 mg, 243 pmol, 9 pL) and Xphos Pd G3 (10.3 mg, 12.2 pmol). The mixture is stirred at 90 °C for 2 hr under N2. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure to give the title compound tert-butyl 3-[6-(5-morpholinopyrazolo[1 ,5- a]pyridin-3-yl)-2-pyridyl]piperidine- 1 - carboxylate 64 (15 mg) as a white solid. LCMS (ESI MS) m / z = 464.2 [M + H]+1.

[0372] Step E: To a solution of tert-butyl 3-(6-(5-morpholinopyrazolo[1 ,5-a]pyridin-3- yl)pyridin-2-yl)piperidine-1-carboxylate 64 (12 mg, 25.9 pmol) in DCM (1 mL) is added HCI / EtOAc (4 M, 6.5 pL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by prep-HPLC (FA condition; column: Welch Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA)-ACN]; gradient: 0%-32% B over 25 min) to yield the title compound 4-[3-[6-(3-piperidyl)-2- pyridyl]pyrazolo[1 ,5-a]pyridin-5-yl]morpholine (Compound 16) (2.7 mg) as a white solid. LCMS (ESI MS) m / z = 364.0 [M + H]+1.

[0373] 1H NMR (400 MHz, methanol-d4) 6 = 8.34 - 8.44 (m, 2 H), 7.71 - 7.84 (m, 2 H), 7.64 (br d, J = 7.6 Hz, 1 H), 7.10 (d, J = 7.6 Hz, 1 H), 6.92 (dd, J = 7.6, 2.8 Hz, 1 H), 3.82 - 3.99 (m, 4 H), 3.67 (br d, J = 10.4 Hz, 1 H), 3.49 (br d, J = 13.2 Hz, 1 H), 3.38 - 3.45 (m, 1 H), 3.34 - 3.38 (m, 4 H), 3.19 - 3.29 (m, 1 H), 2.96 - 3.09 (m, 1 H), 2.22 - 2.32 (m, 1 H), 1.89 - 2.14 (m, 3 H).

[0374] Example 173-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine-5-carbonitrile

[0375] Step A: A mixture of tert-butyl 3-(6-(trimethylstannyl)pyridin-2-yl)piperidine-1- carboxylate 66 (50 mg, 117.6 pmol), 3-bromopyrazolo[1 ,5-a]pyridine-5-carbonitrile 65 (26.1 mg, 117.6 pmol), XPhos Pd G3 (9.9 mg, 11.8 pmol), and K3PO4 (49.9 mg, 235.2 pmol) in dioxane (1 mL) and H2O (0.25 mL) is purged with N2 three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is concentrated directly to yield the title compound tert-butyl 3-[6-(5-cyanopyrazolo[1 ,5-a]pyridin-3-yl)-2-pyridyl]piperidine-1 -carboxylate 67 (47.4 mg, crude) as a black solid.

[0376] Step B: To a solution of tert-butyl 3-(6-(5-cyanopyrazolo[1 ,5-a]pyridin-3-yl)pyridin- 2-yl)piperidine-1-carboxylate 67 (47 mg, 116.5 pmol) in DCM (5 mL) is added TFA (0.5 mL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated to give the crude product which is purified by prep-HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA)-ACN]; gradient: 0%-32% B over 25 min) to yield the title compound 3-[6- (3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine-5-carbonitrile (Compound 17) (5.8 mg, 16%) as a greenish-white solid. LCMS (ESI MS) m / z =304.3 [M + H]+1.

[0377] 1H NMR (400 MHz, methanol-d4) 6 = 9.01 (d, J = 0.8 Hz, 1 H), 8.77 (dd, J = 0.8, 7.2 Hz, 1 H), 8.69 (s, 1 H), 8.54 (s, 1 H), 7.86 - 7.78 (m, 2H), 7.25 (dd, J = 1.2, 7.2 Hz, 1 H), 7.17 (dd, J = 2.0, 7.2 Hz, 1 H), 3.70 (td, J = 1.6, 12.0 Hz, 1 H), 3.49 - 3.36 (m, 3H), 3.14 - 3.0 (m, 1 H), 2.26 (br d, J = 8.8 Hz, 1 H), 2.13 - 2.07 (m, 1 H), 2.00 - 1.91 (m, 2H).

[0378] Example 185-cyclopropyl-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine

[0379] Step A: To a solution of tributvKcvcIopropyDstannane 69 (922.9 mg, 2.79 mmol) and ethyl 5-bromopyrazolo[1 ,5-a]pyridine-3-carboxylate 68 (500 mg, 1.86 mmol) in toluene (3 mL) and H2O (1 mL) are added Pd(dppf)CI2(151.7 mg, 185.8 pmol) and Cs2CO3(1.21 g, 3.7 mmol). The mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether gradient) to yield the title compound 5-cyclopropylpyrazolo[1 ,5-a]pyridine-3-carboxylate 70 (200 mg, crude) as a white solid. LCMS (ESI MS) m / z = 231.1 [M + H]+1.

[0380] Step B: To a solution of ethyl 5-cyclopropylpyrazolo[1 ,5-a]pyridine-3-carboxylate 70 (200 mg, 868.6 pmol) in THF (1 mL) and H2O (1 mL) is added LiOH«H2O (145.8 mg, 3.47 mmol). The mixture is stirred at 60 °C for 36 hr. The reaction is quenched with HCI (1 M) and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the title compound 5-cyclopropylpyrazolo[1 ,5-a]pyridine-3-carboxylic acid 71 (180 mg) as a black oil. LCMS (ESI MS) m / z = 203.2 [M + H]+1. The crude product is used in the next step without additional purification.

[0381] Step C: To a solution of 5-cyclopropylpyrazolo[1 ,5-a]pyridine-3-carboxylic acid 71 (180 mg, 890.2 pmol) in DMF (2 mL) are added NBS (174 mg, 979.2 pmol) and NaHCO3(112 mg, 1.34 mmol, 52 pL). The mixture is stirred at 25 °C for 12 hr. The reaction is quenched with H2O and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography eluent of 0-10% DCM / petroleum ether gradient) to yield the title compound 3-bromo-5-cyclopropyl- pyrazolo[1 ,5-a]pyridine 72 (120 mg) as a yellow oil. LCMS (ESI MS) m / z = 239.0 [M + H] +1 .

[0382] Step D: To a solution of 3-bromo-5-cyclopropylpyrazolo[1 ,5-a]pyridine 72 (140 mg, 492.8 pmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (187 mg, 739 pmol) in dioxane (3 mL) are added Pd(dppf)CI2(40.3 mg, 49.3 pmol) and K2CO3(102.2 mg, 739.2 pmol). The mixture is stirred at 80 °C for 2 hr under N2. The reaction is quenched with H2O and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give aresidue which is purified by flash silica gel chromatography (eluent of 0-20% DCM / petroleum ether gradient) to yield the title compound 5-cyclopropyl-3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyrazolo[1 ,5-a]pyridine 73 (120 mg, 85.7% yield) as a white solid. LCMS (ESI MS) m / z = 285.1 [M + H]+1.

[0383] Step E: To a solution of tert-butyl 3-(6-(trimethylstannyl)pyridin-2-yl)piperidine-1- carboxylate 74 (70 mg, 246.3 pmol) and 5-cyclopropyl-3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyrazolo[1 ,5-a]pyridine 73 (168.1 mg, 492.7 pmol) in H2O (0.2 mL) and dioxane (0.8 mL) are added K3PO4 (104.6 mg, 492.7 pmol) and Xphos Pd G3 (41.7 mg, 49.3 pmol). The mixture is stirred at 60 °C for 12 hr under a N2 atmosphere. The reaction is quenched with H2O and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl-3-[6-(5- cyclopropylpyrazolo[1 ,5-a]pyridin-3-yl)-2-pyridyl]piperidine-1 -carboxylate 75 (14 mg, 13.6% yield) as a yellow solid. LCMS (ESI MS) m / z = 419.3 [M + H]+1.

[0384] Step F: To a solution of tert-butyl 3-(6-(5-cyclopropylpyrazolo[1 ,5-a]pyridin-3- yl)pyridin-2-yl)piperidine-1-carboxylate 75 (14 mg, 33.45 pmol) is added HCI / dioxane (4 M, 33.5 pL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under reduced pressure give a residue which is purified by prep-HPLC (FA condition, column: Welch Xtimate C18, 150x30mmx5um; mobile phase: [water(FA)-ACN]; gradient: 0%-34% B over 25 min) to yield the title compound 5-cyclopropyl-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5- a]pyridine (Compound 18) (11.8 mg, 94.9% yield) as a white solid. LCMS (ESI MS) m / z = 319.2 [M + H] +1.

[0385] 1H NMR (400 MHz, DMSO-cfe) 6 = 8.56 - 8.65 (m, 2 H), 8.32 (s, 2 H), 7.65 - 7.78 (m, 2 H), 7.00 - 7.11 (m, 1 H), 6.77 (br d, J = 7.6 Hz, 1 H), 3.10 - 3.15 (m, 2 H), 2.97 (br dd, J = 7.6, 4.8 Hz, 3 H), 2.69 - 2.77 (m, 1 H), 2.02 - 2.16 (m, 3 H), 1.76 - 1.86 (m, 2 H), 1.09 - 1.15 (m, 2 H), 0.81 - 0.88 (m, 2 H).

[0386] Example 193-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridin-5-amine

[0387] Step A: To a solution of 3-bromopyrazolo[1 ,5-a]pyridine-5-carboxylic acid 76 (1 g, 4.15 mmol) in t-BuOH (1 mL) and toluene (4 mL) is added dropwise N,N- diisopropylethylamine (DIEA) (536 mg, 4.15 mmol, 722.6 pL) at 25 °C. After addition, the mixture is stirred at this temperature for 30 min, and then diphenylphosphoryl azide (DPPA) (1.37 g, 4.98 mmol, 1.1 mL) is added dropwise at 25 °C. The resulting mixture is stirred at 80 °C for 16 hrs. The reaction mixture is concentrated under reduced pressure to give a crude product which is purified by flash silica gel chromatography (eluent of 20-40% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl / \ / -(3- bromopyrazolo[1 ,5-a]pyridin-5-yl)carbamate 77 (0.9 g, 53%) as a yellow solid.

[0388] 1H NMR (400 MHz, methanol-d4) 6 = 8.37 (d, J = 7.6 Hz, 1 H), 7.86 (s, 1 H), 7.78 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 2.4, 7.6 Hz, 1 H), 1.55 (s, 9H).

[0389] Step B: A mixture of tert-butyl 3-(6-(trimethylstannyl)pyridin-2-yl)piperidine-1- carboxylate 78 (89.8 mg, 211.4 pmol), tert-butyl (3-bromopyrazolo[1 ,5-a]pyridin-5- yl)carbamate 77 (60 mg, 192.2 pmol), XPhos Pd G3 (16.2 mg, 19.2 pmol), and K3PO4 (81.6 mg, 384.4 pmol) in dioxane (2 mL) and H2O (0.1 mL) is degassed and purged with N2 three times. The mixture is stirred at 80 °C for 2 hr under a N2 atmosphere. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 30-40% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3-[6-[5-(tert-butoxycarbonylamino)pyrazolo[1 ,5-a]pyridin-3-yl]-2- pyridyl]piperidine-1-carboxylate 79 (50 mg, 52%) as a white solid. LCMS (ESI MS) m / z = 494.6 [M + H]+1.

[0390] Step C: To a solution of tert-butyl 3-(6-(5-((tert-butoxycarbonyl)amino)pyrazolo[1 ,5- a]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate 79 (40 mg, 80.2 pmol) in DCM (1 mL) is added HCI / dioxane (1 mL, 4M). The mixture is stirred at 25 °C for 1 hr. The reaction mixture isconcentrated under reduced pressure to give a residue which is purified by prep-HPLC (column: Xtimate C18, 150x40mmx10um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; gradient: 10%-50% B over 32 min) to yield the title compound 3-[6-(3-piperidyl)-2- pyridyl]pyrazolo[1 ,5-a]pyridin-5-amine (Compound 19) (7.9 mg, 25%) as a white solid. LCMS (ESI MS) m / z = 294.1 [M + H]+1.

[0391] 1H NMR (400 MHz, methanol-d4) 6 = 8.27 (s, 1 H), 8.22 (d, J = 7.6 Hz, 1 H), 7.69 - 7.64 (m, 1 H), 7.53 (s, 1 H), 7.50 (br d, J = 3.2 Hz, 1 H), 7.00 (d, J = 7.6 Hz, 1 H), 6.52 (dd, J = 2.4, 7.6 Hz, 1 H), 3.55 - 3.44 (m, 1 H), 3.35 (br d, J = 1.6 Hz, 1 H), 3.29 - 3.26 (m, 1 H), 3.19 - 3.07 (m, 1 H), 3.05 - 2.96 (m, 1 H), 2.22 - 2.13 (m, 1 H), 2.02 - 1.93 (m, 2H), 1.91 - 1.81 (m, 1 H).

[0392] Example 20

[0393] Step A: To a solution of tert-butyl (3-bromopyrazolo[1 ,5-a]pyridin-5- yl)carbamate 80 (200 mg, 640.7 pmol) in THF (3 mL) is added NaH (51 mg, 1.28 mmol, 60% purity) at 0 °C. After addition, the mixture is stirred at this temperature for 15 min, and then Mel (109.1 mg, 768.8 pmol, 47 pL) is added dropwise at O °C. The resulting mixture is stirred at 20 °C for 30 min. The reaction mixture is quenched by addition 1 N NH4CI (aq) and extracted with EtOAc three times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue is purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl / V-(3-bromopyrazolo[1 ,5-a]pyridin-5-yl)- / \ / - methyl-carbamate 81 (200 mg, 90%) as a colorless oil. LCMS (ESI MS) m / z = 326.0 [M + H]+1 .

[0394] 1H NMR (400 MHz, DMSO-cfe) 6 = 8.66 (d, J = 7.6 Hz, 1 H), 8.12 (s, 1 H), 7.38 (d,J = 2.4 Hz, 1 H), 7.03 (dd, J = 7.6, 2.1 Hz, 1 H), 3.29 (s, 3 H), 1.45 (s, 9 H).

[0395] Step B: A mixture of tert-butyl (3-bromopyrazolo[1 ,5-a]pyridin-5- yl)(methyl)carbamate 81 (60 mg, 183.9 pmol), tert-butyl 3-(6-(trimethylstannyl)pyridin-2- yl)piperidine-1-carboxylate 82 (93.8 mg, 220.7 pmol), XPhos Pd G3 (15.5 mg, 18.39 pmol), and K3PO4 (78 mg, 367.9 pmol) in dioxane (2 mL) is purged with N2 three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is concentrated directly to yield the title compound tert-butyl 3-[6-[5-[tert-butoxycarbonyl(methyl)amino]pyrazolo[1 ,5- a]pyridin-3-yl]-2-pyridyl] piperidine -1 -carboxylate 83 (93 mg, crude) as a brown solid. LCMS (ESI MS) m / z = 508.2 [M + H]+1.

[0396] Step C: To a solution of tert-butyl 3-(6-(5-((tert-butoxycarbonyl)(methyl)amino)- pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)piperidine-1 -carboxylate 83 (90 mg, 177.3 pmol) in DCM (2 mL) is added TFA (0.4 mL). The mixture is stirred at 20 °C for 2 hrs. The reaction mixture is extracted with H2O three times. The combined water layers are concentrated under reduced pressure to give a residue which is purified by prep-HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA)-ACN]; gradient: 0%-28% B over 25 min) to yield the title compound / V-methyl-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5- a]pyridin-5-amine (Compound 20) (33.1 mg, 58%, FA) as a yellow solid. LCMS (ESI MS) m / z = 308.1 [M + H]+1.

[0397] 1H NMR (400 MHz, methanol-d4) 6 = 8.53 (s, 1 H), 8.28 (s, 1 H), 8.19 (d, J = 7.6 Hz, 1 H), 7.67 - 7.72 (m, 1 H), 7.57 (d, J = 7.6 Hz, 1 H), 7.30 (d, J = 2.4 Hz, 1 H), 7.04 (d, J = 7.4 Hz, 1 H), 6.48 (dd, J = 7.6, 2.6 Hz, 1 H), 3.66 (dd, J = 12.4, 3.8 Hz, 1 H), 3.41 - 3.49 (m, 2 H), 3.23 (tt, J = 10.8, 3.7 Hz, 1 H), 3.02 (td, J = 12.4, 3.3 Hz, 1 H), 2.93 (s, 3 H), 2.20 - 2.29 (m, 1 H), 2.00 - 2.11 (m, 2 H), 1.90 - 1.99 (m, 1 H).

[0398] Example 21 / V-ethyl-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridin-5-amine

[0399] Step A: To a solution of Etl (199.9 mg, 1.28 mmol) and tert-butyl (3- bromopyrazolo[1 ,5-a]pyridin-5-yl)carbamate 84 (0.1 g, 320.3 pmol) in ACN (3 mL) is added CS2CO3 (208 mg, 640.7 pmol). The mixture is stirred at 80 °C for 16 hr. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl / V-(3-bromopyrazolo[1 ,5-a]pyridin-5-yl)- / \ / -ethyl-carbamate 85 (140 mg, crude) as a white solid.

[0400] 1H NMR (400 MHz, methanol-d4) 6 = 8.49 (d, J = 7.6 Hz, 1 H), 7.96 (s, 1 H), 7.37 (d, J = 2.0 Hz, 1 H), 6.89 (dd, J = 2.4, 7.6 Hz, 1 H), 3.78 (q, J = 7.2 Hz, 2H), 1.48 (s, 9H), 1 .21 (t, J = 7.2 Hz, 3H).

[0401] Step B: A mixture of tert-butyl 3-(6-(trimethylstannyl)pyridin-2-yl)piperidine-1- carboxylate 86 (175 mg, 411.5 pmol), tert-butyl (3-bromopyrazolo[1 ,5-a]pyridin-5- yl)(ethyl)carbamate 85 (140 mg, 411 .5 pmol), K3PO4 (175 mg, 823.0 pmol), and XPhos Pd G3 (35 mg, 41.15 pmol) in dioxane (1 mL) and H2O (0.2 mL) is purged with N2 three times, and then the mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-30% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3-[6-[5-[tert-butoxycarbonyl(ethyl)amino]pyrazolo[1 ,5-a]pyridin-3-yl]-2-pyridyl] piperidine-1 - carboxylate 87 (0.14 g) as a white solid.

[0402] 1H NMR (400 MHz, methanol-d4) 6 = 8.58 (d, J = 1.6 Hz, 1 H), 8.53 (d, J = 7.6 Hz, 1 H), 8.50 (s, 1 H), 7.73 - 7.68 (m, 1 H), 7.66 - 7.63 (m, 1 H), 7.08 (d, J = 7.6 Hz, 1 H), 6.97 (dd, J = 2.4, 7.6 Hz, 1 H), 4.40 - 4.26 (m, 1 H), 4.19 - 4.12 (m, 1 H), 3.82 (q, J = 7.2 Hz, 2H), 2.94 - 2.80 (m, 2H), 2.19 - 2.10 (m, 1 H), 1.98 - 1.77 (m, 3H), 1.69 - 1.57 (m, 2H), 1.51 - 1.46 (m, 18H), 1.24 (t, J = 7.2 Hz, 2H).

[0403] Step C: To a solution of tert-butyl 3-(6-(5-((tert-butoxycarbonyl)(ethyl)amino)- pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)piperidine-1 -carboxylate 87 (0.07 g, 134.19 pmol) in DCM (3 mL) is added HCI / dioxane (4 M, 34 pL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is partitioned between DCM and H2O. The organic phase is discarded, and the aqueous phase is lyophilized to yield the title compound A / -ethyl-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1,5-a]pyridin-5-amine (Compound 21) (33.7 mg, 78%) as a white solid. LCMS (ESI MS) m / z = 321.8 [M + H]+1.

[0404] 1H NMR (400 MHz, methanol-d4) 6 = 8.56 (s, 1H), 8.34 (d, J= 7.6 Hz, 1H), 8.26 (br t, J = 8.4 Hz, 1 H), 7.99 (d, J = 8.4 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 6.89 (br s, 1 H), 6.65 (d, J = 7.6 Hz, 1H), 3.71 (brd, J= 12.0 Hz, 1H), 3.66 - 3.57 (m, 1H), 3.51 (br d, J= 12.0 Hz, 1H), 3.45 - 3.37 (m, 1H), 3.30 - 3.27 (m, 2H), 3.15 - 3.07 (m, 1H), 2.33 - 2.26 (m, 1H), 2.18 - 2.12 (m, 1 H), 2.06 - 1.93 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H).

[0405] Example 223-(methylsulfonamido)- / V-(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1,5-a]pyridin-5- yl)propanamideCompound 22

[0406] Step A: To a solution of ethyl 5-bromopyrazolo[1 ,5-a]pyridine-3-carboxylate 88 (2 g, 7.43 mmol), diphenylmethanimine 89 (1.7 g, 9.66 mmol, 1.6 mL) in toluene (20 mL) are added BINAP (2.3 g, 3.72 mmol, 0.5 eq), Pd2(dba)s (1.3 g, 1.49 mmol, 0.2 eq) and t-BuONa (2.1 g, 22.3 mmol). The mixture is stirred at 80 °C for 8.5 hr. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-5% ethyl acetate / petroleum ether gradient) to yield the title compound ethyl 5- (benzhydrylideneamino)pyrazolo[1 ,5-a]pyridine-3-carboxylate 90 (700 mg, 1.89 mmol, 25.5% yield) as a yellow oil. LCMS (ESI MS) m / z = 370.1 [M + H]+1.

[0407] Step B: To a solution of ethyl 5-((diphenylmethylene)amino)pyrazolo[1 ,5-a]pyridine- 3-carboxylate 90 (600 mg, 1.62 mmol) in DCM (5 mL) is added HCI / dioxane (5 mL). The mixture is stirred at 25 °C for 4 hrs. The reaction wa is s quenched with water and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound ethyl 5-aminopyrazolo[1 ,5-a]pyridine-3-carboxylate 91 (400 mg) as a white solid. LCMS (ESI MS) m / z = 206.2 [M + H]+1.

[0408] Step C: To a solution of ethyl 5-aminopyrazolo[1 ,5-a]pyridine-3-carboxylate 91 (400 mg, 1.95 mmol) and 3-(methylsulfonamido)propanoic acid 92 (391 mg, 2.34 mmol) in DMF (10 mL) are added TCFH (1.1 g, 3.90 mmol) and NMI (480 mg, 5.85 mmol, 466 pL). The mixture is stirred at 50 °C for 12 hrs. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-80% ethyl acetate / petroleum ether gradient) to yield the title compound ethyl 5-[3-(methanesulfonamido)propanoylamino]pyrazolo[1 ,5-a] pvridine-3-carboxvlate 93 (400 mg, 1.13 mmol, 57.9% yield) as a yellow solid. LCMS (ESI MS) m / z = 355.1 [M + H]+1.

[0409] Step D: To a solution of ethyl 5-(3-(methylsulfonamido)propanamido)pyrazolo[1 ,5- alpyridine-3-carboxylate 93 (400 mg, 1.13 mmol) in MeOH (1 mL) is added LiOH*H2O (236.8 mg, 5.64 mmol) in H2O (1 mL). The mixture is stirred at 25 °C for 12 hrs. The reaction isquenched with water and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the title compound 5-[3- (methanesulfonamido)propanoylamino]pyrazolo[1 ,5-a]pyridine-3-carboxylic acid 94 (350 mg) as a white solid. LCMS (ESI MS) m / z = 206.2 [M + H]+1.

[0410] Step E: To a solution of 5-(3-(methylsulfonamido)propanamido)pyrazolo[1 ,5- a]pyridine-3-carboxylic acid 94 (340 mg, 1.04 mmol) in DMF (4 mL) are added NaHCCh (131 mg, 1.56 mmol, 61 pL) and NBS (185.4 mg, 1.04 mmol). The mixture is stirred at 25 °C for 1 hr. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-80% ethyl acetate / petroleum ether gradient) to yield the title compound 5-[3-(methanesulfonamido)propanoylamino]pyrazolo[1 ,5-a]pyridine-3-carboxylic acid 95 (150 mg, 415.3 pmol, 39.9% yield) as a white solid. LCMS (ESI MS) m / z = 355.1 [M + H]+1.

[0411] 1H NMR (400 MHz, DMSO-cfe) 6 = 10.43 (s, 1 H), 8.65 (d, J = 7.50 Hz, 1 H), 7.96 - 8.24 (m, 2 H), 7.14 (t, J = 5.82 Hz, 1 H), 6.94 (dd, J = 7.50, 2.25 Hz, 1 H), 3.34 (s, 2 H), 2.93 (s, 3 H), 2.63 (t, J = 6.88 Hz, 2 H).

[0412] Step F: A mixture of / V-(3-bromopyrazolo[1 ,5-a]pyridin-5-yl)-3-(methylsulfonamido)- propanamide 95 (50 mg, 138.4 pmol), tert-butyl 3-(6-(trimethylstannyl)pyridin-2-yl)piperidine- 1-carboxylate 96 (117.7 mg, 276.8 pmol), XPhos Pd G3 (23.4 mg, 27.68 pmol), Cui (52.7 mg, 276.8 pmol), and CsF (84.1 mg, 553.7 pmol, 20.4 pL) in dioxane (3 mL) is purged with N2three times. The mixture is stirred at 90 °C for 2 hr under N2. The reaction mixture is concentrated under vacuum to give the title compound tert-butyl 3-[6-[5-[3- (methanesulfonamido)propanoylamino]-pyrazolo[1 ,5-a] pyridin-3-yl]-2-pyridyl]piperidine-1- carboxylate 97 (80 mg) as a white solid. LCMS (ESI MS) m / z = 443.2 [M + H]+1.

[0413] Step G: To a solution of tert-butyl 3-(6-(5-(3-(methylsulfonamido)propanamido)- pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)piperidine-1 -carboxylate 97 (40 mg, 73.7 pmol) in DCM (1 mL) is added TFA (1 mL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give the crude product which is purified by prep-HPLC (FA condition; column: Welch Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA)-ACN]; gradient:0%-30% B over 25 min) to yield the title compound 3-(methylsulfonamido)- / \ / -(3-(6- (piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl)propanamide (Compound 22) (6 mg, 11.5 pmol, 15.6% yield) as a white solid. LCMS (ESI MS) m / z = 443.2 [M + H]+1.

[0414] 1H NMR (400 MHz, methanol-d4) 6 = 9.49 (s, 1 H), 8.47 (br s, 2 H), 7.70 - 7.79 (m,1 H), 7.63 (d, J = 7.88 Hz, 1 H), 7.12 (d, J = 7.50 Hz, 1 H), 6.82 (br d, J = 0.63 Hz, 1 H), 3.77 - 3.89 (m, 1 H), 3.65 (br dd, J = 12.38, 3.13 Hz, 1 H), 3.53 (t, J = 6.32 Hz, 2 H), 3.40 - 3.49 (m,2 H), 3.27 (br t, J = 10.76 Hz, 1 H), 3.04 (s, 3 H), 2.77 (t, J = 6.32 Hz, 2 H), 2.03 - 2.18 (m, 3 H), 1.97 (br d, J = 11.76 Hz, 1 H).

[0415] Example 233-(methanesulfonamido)- / \ / -[3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridin-6- yl]propanamidedioxane, 90 °C, 2 hrs107Compound 23

[0416] Step A: A mixture of methyl 6-bromopyrazolo[1 ,5-a]pyridine-3-carboxylate 98 (1 g, 3.92 mmol), diphenylmethanimine 99 (1.4 g, 7.84 mmol, 1.32 mL), Pd2(dba)s (718 mg, 784.1 pmol), BINAP (1.2 g, 1.96 mmol), and t-BuONa (1.1 g, 11.76 mmol) in toluene (20 mL) is purged with N2 three times. The mixture is stirred at 80 °C for 8.5 hr under N2. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-5% ethyl acetate / petroleum ether gradient) to yield the title compound methyl 6- (benzhydrylideneamino)pyrazolo[1 ,5-a]pyridine-3-carboxylate 100 (400 mg) as a yellow oil. LCMS (ESI MS) m / z = 356.2 [M + H]+1.

[0417] Step B: To a solution of methyl 6-((diphenylmethylene)amino)pyrazolo[1 ,5- a]pyridine-3-carboxylate 100 (350 mg, 984.8 pmol) in DCM (2 mL) is added HCI / dioxane (2 mL). The mixture is stirred at 25 °C for 4 hr. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is used without purification to give the title compound methyl 6-aminopyrazolo[1 ,5-a]pyridine- 3-carboxylate 101 (200 mg, crude) as a white solid. LCMS (ESI MS) m / z = 192.2 [M + H]+1.

[0418] Step C: To a solution of methyl 6-aminopyrazolo[1 ,5-a]pyridine-3-carboxylate 101 (200 mg, 878.5 pmol) and 3-(methylsulfonamido)propanoic acid 102 (146 mg, 878.55 pmol) in DMF (3 mL) are added TCFH (493 mg, 1.76 mmol) and NMI (216.4 mg, 2.64 mmol, 210 pL). The mixture is stirred at 25 °C for 12 hr. The mixture is stirred at 60 °C for 12 hrs. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-80% ethyl acetate / petroleum ether gradient) to yield the title compound methyl 6- [3-(methanesulfonamido) propanoylamino]pyrazolo[1 ,5-a]pyridine-3-carboxylate 103 (200 mg, 53.5% yield, 80% purity) as a white solid. LCMS (ESI MS) m / z = 340.9 [M + H]+1.

[0419] Step D: To a solution of methyl 6-(3-(methylsulfonamido)propanamido)pyrazolo[1 ,5-a]pyridine-3-carboxylate 103 (200 mg, 587.6pmol) in MeOH (2 mL) is added LiOH*H2O (123mg, 2.94 mmol, 5 eq) in H2O (2 mL). The mixture is stirred at 25 °C for 12 hr. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the title compound 6-[3-(methanesulfonamido)propanoylamino]pyrazolo[1 ,5-a]pyridine-3-carboxylic acid 104 (170 mg, 86.9% yield) as a white solid. LCMS (ESI MS) m / z = 327.0 [M + H]+1.

[0420] Step E: To a solution of 6-(3-(methylsulfonamido)propanamido)pyrazolo[1 ,5- a]pyridine-3-carboxylic acid 104 (140 mg, 429 pmol) in DMF (3 mL) are added NaHCCh (54 mg, 643.5 pmol, 25.0 pL) and NBS (99 mg, 557.7 pmol). The mixture is stirred at 20 °C for 1 hr. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-80% ethyl acetate / petroleum ether gradient) to yield the title compound / V-(3-bromopyrazolo[1 ,5-a]pyridin-6-yl)-3-(methanesulfonamido)propanamide 105 (150 mg, 96.8% yield) as a white solid. LCMS (ESI MS) m / z = 362.9 [M + H]+1.

[0421] 1H NMR (400 MHz, methanol-d4) 6 = 7.58 - 7.72 (m, 1 H), 7.44 (d, J = 7.75 Hz, 1 H), 7.32 (d, J = 7.50 Hz, 1 H), 4.04 - 4.17 (m, 2 H), 3.76 (br s, 2 H), 2.83 - 3.02 (m, 4 H), 1.98 - 2.07 (m, 1 H).

[0422] Step F: A mixture of / V-(3-bromopyrazolo[1 ,5-a]pyridin-6-yl)-3-(methylsulfonamido)- propanamide 105 (20 mg, 7.4 pmol), tert-butyl 3-(6-(trimethylstannyl)pyridin-2-yl)piperidine-1- carboxylate 106 (21 mg, 8.8 pmol), K3PO4 (3 mg, 14.7 pmol), and XPhos Pd G3 (1.3 mg, 1.5 pmol) in dioxane (1 mL) and H2O (0.2 mL) is purged with N2three times. The mixture is stirred at 90 °C for 2 hr under N2. The reaction mixture is concentrated under vacuum to give the title compound tert-butyl 3-[6-[6-[3-(methanesulfonamido)propanoylamino]pyrazolo [1 ,5-a] pyridin- 3-yl]-2-pyridyl]piperidine-1 -carboxylate 107 (80 mg, crude) as a white solid. LCMS (ESI MS) m / z = 543.2 [M + H]+1.

[0423] Step G: To a solution of tert-butyl 3-(6-(6-(3-(methylsulfonamido)- propanamido)pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate 107 (15 mg, 27.6 pmol) in DCM (0.5 mL) is added TFA (0.5 mL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give the crude product which is purified by prep-HPLC (FA condition; column: Welch Xtimate C18, 150x40mmxl0um; mobile phase: [water(FA)-ACN]; gradient: 0%-26% B over 25 min) to give the title compound 3- (methanesulfonamido)- / \ / -[3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridin-6-yl]propanamide (Compound 23) (1 mg, 7.6% yield) as a white solid. LCMS (ESI MS) m / z = 442.8 [M + H]+1.

[0424] 1H NMR (400 MHz, methanol-d4) 6 = 9.40 (s, 1 H), 8.46 - 8.54 (m, 2 H), 7.77 - 7.84(m, 1 H), 7.67 - 7.75 (m, 1 H), 7.38 - 7.46 (m, 1 H), 7.17 (d, J = 7.38 Hz, 1 H), 3.63 - 3.72 (m, 1 H), 3.42 - 3.54 (m, 5 H), 3.10 - 3.19 (m, 1 H), 3.00 (s, 3 H), 2.73 (t, J = 6.50 Hz, 2 H), 2.25 (br dd, J = 10.82, 2.81 Hz, 1 H), 2.04 - 2.13 (m, 1 H), 1.88 - 2.02 (m, 2 H).

[0425] Example 24 / V-[2-(methanesulfonamido)ethyl]-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine-6- carboxamideCompound 24

[0426] Step A: To a solution of 3-bromopyrazolo[1 ,5-a]pyridine-6-carboxylic acid 108 (200 mg, 829.7 pmol) and 109 (229.3 mg, 1.66 mmol) in DMF (5 mL) are added TCFH (465.6 mg, 1.66 mmol) and NMI (204.4 mg, 2.49 mmol, 198.4 pL). The mixture is stirred at 50 °C for 12 hrs. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-4% MeOH / DCM gradient) to yield the title compound 3-bromo- / V- [2-(methanesulfonamido)ethyl]pyrazolo[1 ,5-a]pyridine-6-carboxamide 110 (100 mg, 33%yield) as a white solid. LCMS (ESI MS) m / z = 362.8 [M + H]+1.

[0427] Step B: To a solution of 3-bromo- / V-(2-(methylsulfonamido)ethyl)pyrazolo[1 ,5- a]pyridine-6-carboxamide 110 (40 mg, 110.74 pmol) and tert-butyl 3-(6-(trimethvlstannyl)pvridin-2-vl)piperidine-1-carboxvlate 111 (94.16 mg, 221.48 pmol) in dioxane (4 mL) are added Cui (42.2 mg, 221.5 pmol), CsF (67.3 mg, 442.5 pmol, 16.4 pL) and XPhos Pd G3 (18.8 mg, 22.2 pmol). The mixture is stirred at 100 °C for 2 hr under a N2 atmosphere. The reaction mixture is filtered and concentrated under reduced pressure to give the title compound 3-[6-[6-[2-(methanesulfonamido)ethylcarbamoyl] pyrazolo[1 , 5-a]pyridin-3-yl]-2- pyridyl]piperidine-1-carboxylate 112 (15 mg, crude) as a yellow solid. LCMS (ESI MS) m / z = 543.1 [M + H]+1.

[0428] Step C: To a solution of tert-butyl 3-(6-(6-((2-(methylsulfonamido)ethyl)- carbamoyl)pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)piperidine-1 -carboxylate 112 (15 mg, 27.6 pmol, 1 eq) in DCM (1 mL) is added CF3COOH (9.5 mg, 82.9 pmol, 6.2 pL, 3 eq.). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by prep-HPLC (FA condition; column: Welch Xtimate C18, 150x40mmx10um; mobile phase: [water (FA)-ACN]; gradient: 0%-28% B over 25 min) to yield the title compound / V-[2-(methanesulfonamido)ethyl]-3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5- a]pyridine-6-carboxamide (Compound 24) (3.3 mg, 24% yield) as a white solid. LCMS (ESI MS) m / z = 443.1 [M + H]+1.

[0429] 1H NMR (400 MHz, methanol-d4) 6 = 9.18 (s, 1 H), 8.67 (s, 1 H), 8.57 (d, J = 9.6 Hz, 1 H), 7.71 - 7.86 (m, 3 H), 7.21 (d, J = 7.6 Hz, 1 H), 3.69 (br d, J = 12.4 Hz, 1 H), 3.54 - 3.62 (m, 2 H), 3.42 - 3.52 (m, 2 H), 3.35 - 3.39 (m, 2 H), 3.23 - 3.30 (m, 1 H), 3.10 - 3.19 (m, 1 H), 2.99 (s, 3 H), 2.25 (br s, 1 H), 1 .88 - 2.14 (m, 3 H).

[0430] Example 25 / V-[2-oxo-2-[3-(6-pyrazolo[1 ,5-a]pyridin-3-yl-2-pyridyl)-1-piperidyl]ethyl]methanesulfonamide115

[0431] Step A: A mixture of 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazolo[1 ,5- a]pyridine 114 (679.5 mg, 2.78 mmol), tert-butyl 3-(6-bromopyridin-2-yl)piperidine-1- carboxylate 113 (950 mg, 2.78 mmol), XPhos Pd G3 (235.6 mg, 278.4 pmol), and K3PO4 (1.18 g, 5.57 mmol) in dioxane (10 mL) and H2O (2.5 mL) is degassed and purged with N2 three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is concentrated to give a residue which is purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 0-11 % ethyl acetate / petroleum ether gradient @ 25 mL / min) to yield the title compound tert-butyl 3-(6-pyrazolo[1 ,5-a]pyridin-3-yl-2-pyridyl)piperidine-1- carboxylate 115 (230 mg, 16.3% yield) as a white solid. LCMS (ESI MS) m / z = 379.2 [M + H]+1.

[0432] Step B: A solution of tert-butyl 3-(6-(pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2- yl)piperidine-1-carboxylate 115 (230 mg, 607.7 pmol) in 4M HCI / EtOAc (1 mL) and DCM (0.5 mL) is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to yield the title compound 3-[6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine 116 (150 mg) as a yellow solid. LCMS (ESI MS) m / z = 279.1 [M + H]+1.

[0433] Step C: To a solution of (methylsulfonyl)glycine 117 (33 mg, 215.6 pmol) and 3-(6- (piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine 116 (50 mg, 179.6 pmol) in DMF (2 mL) are added HOBt (36.4 mg, 269.4 pmol), DIEA (69.6 mg, 538.9 pmol, 94 pL) and EDCI (51.6 mg, 269.4 pmol). The mixture is stirred at 25 °C for 16 hrs. The reaction mixture is filtered and concentrated. The residue is purified by prep-HPLC (column: Welch Xtimate C18,150x30mmx5um; mobile phase: [water(FA)-ACN]; gradient: 10%-50% B over 25 min) to give the title compound / V-[2-oxo-2-[3-(6-pyrazolo[1,5-a]pyridin-3-yl-2-pyridyl)-1- piperidyl]ethyl]methane-sulfonamide (Compound 25) (14 mg, 18.3% yield) as a white solid. LCMS (ESI MS) m / z = 414.1 [M + H]+1.

[0434] 1H NMR (400 MHz, methanol-d4) 6 = 8.64 (d, J= 8.8 Hz, 1H), 8.58 (d, J = 6.8 Hz, 1 H), 8.51 (d, J = 1.2 Hz, 1 H), 7.73 (q, J = 8.0 Hz, 1 H), 7.69 - 7.63 (m, 1 H), 7.48 - 7.37 (m, 1 H), 7.13 (dd, J= 18.4, 7.2 Hz, 1H), 7.04 - 6.96 (m, 1H), 4.81 - 4.48 (m, 1H), 4.22 - 3.90 (m, 3H), 3.47 (dd, J= 13.6, 11.2Hz, 1H), 3.25-3.16 (m, 1H), 3.12-3.03 (m, 1H), 2.99 (d, J= 17.2 Hz, 3H), 2.94-2.80 (m, 1H), 2.25 - 2.12 (m, 1H), 2.09- 1.86 (m, 2H), 1.83- 1.58 (m, 1H).

[0435] Example 263-[6-(1-methylsulfonyl-3-piperidyl)-2-pyridyl]pyrazolo[1,5-a]pyridine118 Compound 26

[0436] Step A: To a solution of 3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1,5-a]pyridine 118 (70 mg, 251.5 pmol) in DCM (3 mL) are added MsCI (0.19 g, 1.66 mmol, 128.4 pL) and pyridine (99. mg, 1.26 mmol, 101 pL). The mixture is stirred at 20 °C for 48 hr. The reaction mixture is quenched with sat. NaHCOs at 0°C and extracted with CH2CI2 three times and NH4CI three times. The combined organic layers are concentrated to give a residue which is purified by prep-HPLC (column: Welch Xtimate C18, 150x30mmx5um; mobile phase: [water(FA)-ACN]; gradient: 20%-60% B over 25 min) to afford the title compound 3-[6-(1-methylsulfonyl-3- piperidyl)-2-pyridyl]pyrazolo[1,5-a]pyridine (Compound 26) (5.6 mg, 4.7% yield) as a white solid. LCMS (ESI MS) m / z = 357.1 [M + H]+1.

[0437] 1H NMR (400 MHz, DMSO-cfe) 6 = 8.76 (d, J= 7.0 Hz, 1H), 8.69 (s, 1H), 8.58 (d, J = 8.8 Hz, 1H), 7.78 - 7.73 (m, 2H), 7.48 - 7.38 (m, 1H), 7.16 (dd, J= 5.6, 2.8 Hz, 1H), 7.05 - 6.97 (m, 1H), 3.84 (br d, J= 10.4 Hz, 1H), 3.63 (br d, J= 12.4 Hz, 1H), 3.06- 2.94 (m, 2H), 2.91 (s, 3H), 2.81 (dt, J= 11.6, 2.4 Hz, 1H), 2.13-2.03 (m, 1H), 1.90 (td, J= 12.8, 2.8 Hz, 1H), 1.84- 1.61 (m, 2H).

[0438] Example 273-(4-methoxy-6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridineCompound 27

[0439] Step A: A mixture of 2,6-dibromo-4-methoxypyridine 119 (863.2 mg, 3.23 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate 120 (500 mg, 1.62 mmol), Pd(dppf)Ch (264.1 mg, 323.4 pmol), and CS2CO3 (1.05 g, 3.23 mmol) in toluene (5 mL) and H2O (1 mL) is degassed and purged with N2 three times. The mixture is stirred at 80 °C for 2 hours under a N2 atmosphere. The reaction mixture is concentrated under reduced pressure to remove solvent. The residue is diluted with water and extracted with ethyl acetate three times. The combined organic layers are washed with brine twice, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue is purified by flash silica gel chromatography (eluent of 0-23% ethyl acetate / petroleum ether gradient) to afford the title compound tert-butyl 6-bromo-4-methoxy- 5',6'-dihydro-[2,3'-bipyridine]-T(2'H)-carboxylate 121 (320 mg, crude) as a colorless oil. LCMS(ESI MS) m / z = 313.0 [M + H]+1 .

[0440] Step B: To a solution of tert-butyl 6-bromo-4-methoxy-5',6'-dihydro-[2,3'-bipyridine]- 1'(2'H)-carboxylate 121 (270 mg, 731.2 pmol) in EtOAc (5 mL) is added PtC>2 (16.6 mg, 73.1 pmol) under N2. The suspension is degassed under vacuum and purged with H2 several times. The mixture is stirred under H2 (20 psi) at 25 °C for 16 hrs. The reaction mixture is filtered and concentrated under reduced pressure to remove solvent. The residue is purified by flash silica gel chromatography (eluent of 0-13% ethyl acetate / petroleum ether gradient) to afford the title compound tert-butyl 3-(6-bromo-4-methoxypyridin-2-yl)piperidine-1 -carboxylate 122 (100 mg, crude) as a colorless oil. LCMS (ESI MS) m / z = 373.0 [M + H]+1.

[0441] Step C: A mixture of tert-butyl 3-(6-bromo-4-methoxypyridin-2-yl)piperidine-1- carboxylate 122 (80 mg, 215.5 pmol), 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyrazolo[1 ,5-a]pyridine 123 (52.6 mg, 215.5 pmol), K3PO4 (91.4 mg, 430.9 pmol), and XantPhos Pd G3 (40.8 mg, 43.1 pmol) in dioxane (3 mL) and H2O (0.7 mL) is degassed and purged with N2 three times. The mixture is stirred at 80 °C for 2 hours under a N2 atmosphere. The reaction mixture is concentrated under reduced pressure to remove solvent. The residue is diluted with water and extracted with ethyl acetate three times. The combined organic layers are washed with brine twice, dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue is purified by flash silica gel chromatography (eluent of 0-23% ethyl acetate / petroleum ether gradient) to afford the title compound tert-butyl 3-(4- methoxy-6-(pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate 124 (88 mg, crude) as a colorless oil. LCMS (ESI MS) m / z = 409.3 [M + H]+1.

[0442] Step D: To a solution of tert-butyl 3-(4-methoxy-6-(pyrazolo[1 ,5-a]pyridin-3- yl)pyridin-2-yl)piperidine-1 -carboxylate 124 (78 mg, 190.9 pmol) in DCM (0.5 mL) is added HCI / dioxane (4 M, 0.5 mL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under reduced pressure to remove solvent. The resulting residue is washed with acetonitrile twice and concentrated under reduced pressure to afford the title compound 3-(4- methoxy-6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine (Compound 27) (26 mg, 35%) as a white solid. LCMS (ESI MS) m / z = 309.2 [M + H]+1 .

[0443] 1H NMR (400 MHz, DMSO-cfe) 6 = 9.16 - 9.50 (m, 2 H), 8.77 - 8.86 (m, 2 H), 8.43 (br d, J = 7.00 Hz, 1 H), 7.49 (br t, J = 7.32 Hz, 1 H), 7.43 (br s, 1 H), 7.10 (br t, J = 6.19 Hz, 1 H), 6.83 - 7.05 (m, 1 H), 4.00 (br s, 3 H), 3.51 - 3.57 (m, 2 H), 3.31 (br d, J = 10.13 Hz, 2 H), 2.94 (br d, J = 11.01 Hz, 1 H), 2.12 (br d, J = 11.38 Hz, 1 H), 1.92 (br s, 3 H).

[0444] Example 283-(4-chloro-6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridineCompound 28

[0445] Step A: A mixture of 2,6-dibromo-4-chloropyridine 125 (527 mg, 1.94 mmol), tertbutyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H)-carboxylate 126 (300 mg, 970.2 pmol), CS2CO3 (632 mg, 1.94 mmol), and Pd(dppf)Cl2*CH2Cl2 (158 mg, 194.04 pmol) in toluene (4 mL) and H2O (1 mL) is degassed and purged with N2 three times. The mixture is stirred at 80 °C for 2hr under a N2 atmosphere. The reaction mixture is diluted with water and extracted with ethyl acetate three times. The combined organic layers are dried over Na2SC>4, filtered and concentrated under reduced pressure to give a crude product which is purified by flash silica gel chromatography (eluent of 0-15% ethyl acetate / etroleum ether gradient) to yield the title compound tert-butyl 5-(6-bromo-4-chloro-2-pyridyl)-3,6-dihydro-2H- pyridine-1 -carboxylate 127 (270 mg, 74.5% yield) as a colorless oil. LCMS (ESI MS) m / z =318.7 [M - 56J+1.

[0446] Step B: A mixture of tert-butyl 6-bromo-4-chloro-5',6'-dihydro-[2,3'-bipyridine]- 1'(2'H)-carboxylate 127 (250 mg, 669 pmol) and PtC>2 (46 mg, 200.7 pmol) in EtOAc (5 mL) is degassed and purged with H2 three times. The mixture is stirred at 40 °C for 16 hr under a 20 psi H2 atmosphere. The reaction mixture is filtered, and the filtrate is concentrated to give the title compound tert-butyl 3-(6-bromo-4-chloro-2-pyridyl)piperidine-1-carboxylate 128 (140 mg) as a yellow oil. LCMS (ESI MS) m / z = 376.9 [M + H]+1.

[0447] Step C: A mixture of tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)piperidine-1- carboxylate 128 (100 mg, 266.3 pmol), 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyrazolo[1 ,5-a]pyridine 129 (50 mg, 204.8 pmol), Pd(dppf)Cl2’CH2Cl2 (33 mg, 41 pmol), and CS2CO3 (135 mg, 409.7 pmol) in dioxane (2 mL) and H2O (0.5 mL) is degassed and purged with N2 three times. The mixture is stirred at 50 °C for 0.5 hr under a N2 atmosphere. The reaction mixture is diluted with water and extracted with ethyl acetate three times. The combined organic layers are dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product which is purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3-(4-chloro- 6-pvrazolo[1 ,5-alpvridin-3-vl-2-pyridvl)piperidine-1 -carboxylate 130 (27 mg, 31.9% yield) as a yellow oil. LCMS (ESI MS) m / z = 413.2 [M + H]+1.

[0448] Step D: To a solution of tert-butyl 3-(4-chloro-6-(pyrazolo[1 ,5-a]pyridin-3-yl)pyridin- 2-yl)piperidine-1-carboxylate 130 (11 mg, 26.6 pmol) in DCM (0.5 mL) is added HCI / EtOAc (0.5 mL / 0.5 mL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is filtered and concentrated under vacuum to give the crude product which is purified by prep-HPLC (column: Welch Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA)-ACN]; gradient: 0%-36% B over 25 min) to yield the title compound 3-(4-chloro-6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5- a]pyridine (Compound 28) (6.8 mg, 74.5%) as a white solid. LCMS (ESI MS) m / z = 313.1 [M + H]+1.

[0449] 1H NMR (400 MHz, methanol-d4) 6 = 8.61 (br d, J = 6.88 Hz, 1 H), 8.50 - 8.57 (m, 2 H), 7.78 (d, J = 1 .50 Hz, 1 H), 7.42 - 7.48 (m, 1 H), 7.22 (s, 1 H), 6.99 - 7.07 (m, 1 H), 3.67 (br d, J = 11.38 Hz, 1 H), 3.38 - 3.49 (m, 2 H), 3.22 - 3.29 (m, 1 H), 3.06 - 3.16 (m, 1 H), 2.23 (br d, J = 8.00 Hz, 1 H), 2.02 - 2.13 (m, 1 H), 1.90 - 2.01 (m, 2 H).

[0450] Example 293-[5-chloro-6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine137 Compound 29

[0451] Step A: A mixture of 2,6-dibromoDvridin-3-amine 131 (3 g, 11.91 mmol) and CuCI (1.77 g, 17.86 mmol) in ACN (40 mL) is stirred for 15 min at 20 °C. Then isopentyl nitrite (2.79 g, 23.82 mmol) is added. The mixture is stirred for 2 hr at 70 °C. The reaction mixture is concentrated directly. The residue is purified by flash silica gel chromatography (eluent of 5% ethyl acetate / petroleum ether gradient) to yield the title compound 2, 6-dibromo-3-chloro- pyridine 132 (2.38 g) as a white solid. LCMS (ESI MS) m / z = 269.8 [M + H]+1.

[0452] Step B: A mixture of 2,6-dibromo-3-chloropyridine 132 (2.38 g, 8.77 mmol), tertbutyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H)-carboxylate 133 (1.63 g, 5.26 mmol), Pd(dppf)CI2(1.28 g, 1.75 mmol), and Cs2CO3(5.72 g, 17.54 mmol) in toluene (40 mL) and H2O (10 mL) is purged with N2three times, and then the mixture is stirred at 100 °C for 16 hr under N2. The reaction mixture is diluted with H2O and extracted with EtOAc three times. The combined organic layers are washed with brine, dried, filtered and concentrated under reduced pressure to give a residue. The residue is purified by flash silicagel chromatography (eluent of 7% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 5-(6-bromo-3-chloro-2-pyridyl)-3, 6-dihydro-2H-pyridine-1 -carboxylate 134 (240 mg) as a yellow solid. LCMS (ESI MS) m / z = 373.0 [M + H]+1.

[0453] Step C: To a solution of tert-butyl 6-bromo-3-chloro-5',6'-dihydro-[2,3'-bipyridine]- 1'(2'H)-carboxylate 134 (150 mg, 401.42 pmol) in EtOAc (3 mL) is added PtC>2 (18.2 mg, 80.28 pmol) under N2. The suspension is purged with H2 three times. The mixture is stirred under H2 (15 psi) at 25 °C for 24 hr. The reaction mixture is concentrated directly. The residue is purified by flash silica gel chromatography (eluent of 4% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3-(6-bromo-3-chloro-2-pyridyl)piperidine-1-carboxylate 135 (35 mg) as a white solid. LCMS (ESI MS) m / z = 375.0 [M + H]+1.

[0454] Step D: A mixture of tert-butyl 3-(6-bromo-3-chloropyridin-2-yl)piperidine-1- carboxylate 135 (35 mg, 93.16 pmol), 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyrazolo[1 ,5-a]pyridine 136 (22.7 mg, 93.16 pmol), Pd(dppf)Ch (13.6 mg, 18.63 pmol), and CS2CO3 (60.7 mg, 186.32 pmol) in toluene (1 mL) and H2O (0.25 mL) is purged with N2 three times, and then the mixture is stirred at 100 °C for 2 hr under N2. The reaction mixture is diluted with H2O and extracted with EtOAc three times. The combined organic layers are washed with brine, dried, filtered and concentrated under reduced pressure to give the title compound tertbutyl 3-(3-chloro-6-pyrazolo[1 ,5-a]pyridin-3-yl-2-pyridyl)piperidine -1 -carboxylate 137 (38 mg) as a brown oil. LCMS (ESI MS) m / z = 413.1 [M + H]+1.

[0455] Step E: A solution of tert-butyl 3-(3-chloro-6-(pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2- yl)piperidine-1-carboxylate 137 (35 mg, 84.76 pmol) in HCI / dioxane (4 M, 2 mL) is stirred at 25 °C for 2 hr. The reaction mixture is concentrated directly. The residue is purified by prep-HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA)-ACN]; gradient: 0%-34% B over 25 min) to yield the title compound 3-[5-chloro-6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5- a]pyridine (Compound 29) (8.8 mg, 28%, FA) as a white solid. LCMS (ESI MS) m / z = 313.1 [M + H]+1.

[0456] 1H NMR (400 MHz, methanol-d4) 6 = 8.54 - 8.63 (m, 2 H), 8.50 (s, 1 H), 8.44 (d, J = 9.2 Hz, 1 H), 7.76 - 7.82 (m, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 7.41 - 7.47 (m, 1 H), 7.02 (t, J = 6.4 Hz, 1 H), 3.69 - 3.78 (m, 1 H), 3.57 - 3.63 (m, 1 H), 3.54 (d, J = 11 .6 Hz, 1 H), 3.44 - 3.50 (m, 1 H), 3.10 - 3.20 (m, 1 H), 2.19 - 2.27 (m, 1 H), 2.05 - 2.13 (m, 1 H), 1.86 - 2.01 (m, 2 H).

[0457] Example 303-(3-chloro-6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine

[0458] Step A: A mixture of 6-bromo-2-chloropyridin-3-amine 138 (2 g, 9.64 mmol) and CuCI (1.43 g, 14.46 mmol) in ACN (20 mL) is stirred for 15 min at 25 °C. Then isopentyl nitrite (2.26 g, 19.28 mmol) is added, and the mixture is stirred at 70 °C for 2 hr. The mixture is filtered, and the filtrate is evaporated under vacuum to give a residue. The residue is purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether gradient) to yield the title compound 6-bromo-2, 3-dichloropyridine 139 (0.5 g) as a yellow solid. LCMS (ESI MS) m / z = 227.7 [M + 3H],

[0459] Step B: A mixture of 6-bromo-2,3-dichloropyridine 139 (470 mg, 2.07 mmol), tertbutyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H)-carboxylate 140 (640.5 mg, 2.07 mmol), Pd(dppf)CI2*CH2CI2(338.3 mg, 414.30 pmol), and K2CO3(572.5 mg, 4.14 mmol) in toluene (5 mL) and H2O (1 mL) is purged with N2three times, and then the mixture is stirred at 50 °C for 4 hr under N2. The reaction mixture is concentrated under reduced pressure to remove solvent. The residue is diluted with H2O and extracted with ethyl acetatethree times. The combined organic layers are washed with brine twice, dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue is purified by flash silica gel chromatography (eluent of 0-13% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 5,6-dichloro-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)- carboxylate 141 (215 mg) as a colorless oil. LCMS (ESI MS) m / z = 273.1 [M + H]+1.

[0460] Step C: A mixture of tert-butyl 5,6-dichloro-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)- carboxylate 141 (170 mg, 516.37 pmol), 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- vl)pvrazolo[1.5-a1pvridine 142 (100.8 mg, 413.10 pmol), Pd(dppf)Cl2*CH2Cl2 (84.3 mg, 103.27 pmol), and CS2CO3 (336.4 mg, 1.03 mmol) in H2O (0.7 mL) and dioxane (3 mL) is purged with N2three times, and then the mixture is stirred at 80 °C for 2 hours under N2. The reaction mixture is concentrated under reduced pressure to remove solvent. The residue is diluted with H2O and extracted with ethyl acetate three times. The combined organic layers are washed with brine twice, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue is purified by flash silica gel chromatography (eluent of 0-15% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 5-chloro-6- (pyrazolo[1 ,5-a]97yridine-3-yl)-5’,6’-dihydro-[2,3’-bipyridine]-T(2’H)- carboxylate 143 (60 mg) is obtained as a colorless oil. LCMS (ESI MS) m / z = 411.1 [M + H]+1 .

[0461] Step D: To a solution of tert-butyl 5-chloro-6-(pyrazolo[1 ,5-a]pyridin-3-yl)-5',6'- dihydro- [2,3'-bipyridine]-1'(2'H)-carboxylate 143 (80 mg, 194.70 pmol) in EtOAc (8 mL) is added PtO2(4.4 mg, 19.47 pmol) under N2. The suspension is degassed under vacuum and purged with H2several times. The mixture is stirred under H2(15 psi) at 25 °C for 16 hr. The reaction mixture is filtered and concentrated under reduced pressure to remove solvent. The residue is purified by flash silica gel chromatography (eluent of 0-18% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3-(5-chloro-6-(pyrazolo[1 ,5-a]97yridine-3- yl)97yridine-2-yl)piperidine-1 -carboxylate 144 (46 mg) is obtained as a yellow oil. LCMS (ESI MS) m / z = 413.2 [M + H]+1.

[0462] Step E: To a solution of tert-butyl 3-(5-chloro-6-(pyrazolo[1 ,5-a]pyridin-3-yl)pyridin- 2-yl) piperidine- 1 -carboxylate 144 (40 mg, 96.87 pmol) in DCM (0.3 mL) is added HCI / dioxane (4 M, 0.3 mL). The mixture is stirred at 20 °C for 1 h. The reaction mixture is concentrated under reduced pressure to give a residue. The residue is purified by prep-HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA)-ACN]; gradient: 0%-32% B over 25 min) to yield the title compound 3-(3-chloro-6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5- a]pyridine (Compound 30) (10 mg, 32%) as a brown solid. LCMS (ESI MS) m / z = 313.1 [M + H]+1.

[0463] 1H NMR (400 MHz, methanol-d4) 6 = 8.62 (s, 1 H), 8.52 (d, J = 7.00 Hz, 1 H), 8.33(d, J = 9.01 Hz, 1 H), 7.72 (d, J = 8.25 Hz, 1 H), 7.25 - 7.36 (m, 1 H), 7.03 (d, J = 8.25 Hz, 1 H), 6.94 (td, J = 6.85, 1.06 Hz, 1 H), 3.17 (br s, 1 H), 2.85 - 3.03 (m, 2 H), 2.82 (d, J = 11.63 Hz, 1 H), 2.57 (s, 1 H), 2.03 (br d, J = 9.38 Hz, 1 H), 1 .67 - 1.81 (m, 2 H), 1.50 - 1.66 (m, 1 H).

[0464] Example 313-[4-fluoro-6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridineCompound 31

[0465] Step A: A mixture of tert-butyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-1(2H)-carboxylate 146 (400 mg, 1.29 mmol), 2,6-dibromo-4-fluoropyridine 145 (659 mg, 2.59 mmol), CS2CO3 (842 mg, 2.59 mmol), and Pd(dppf)Cl2*CH2Cl2 (211 mg, 258.73 pmol) in toluene (5 mL) and H2O (1 mL) is purged with N2three times, and then the mixture is stirred at 80 °C for 2 hr under N2. The reaction is diluted with H2O and extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-15% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 5-(6-bromo-4-fluoro-2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate 147 (400 mg) as a white solid. LCMS (ESI MS) m / z = 300.9 [M + H]+1.

[0466] Step B: A mixture of tert-butyl 6-bromo-4-fluoro-5',6'-dihydro-[2,3'-bipyridine]- 1'(2'H)-carboxylate 147 (280 mg, 783.84 pmol), 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyrazolo[1 ,5-a]pyridine 148 (287 mg, 1.18 mmol), Pd(dppf)Cl2’CH2Cl2 (128 mg, 156.77 pmol), and CS2CO3 (510 mg, 1.57 mmol) in toluene (5 mL) and H2O (1 mL) is purged with N2 three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction is diluted with H2O and extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-15% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 5-(4-fluoro-6-pyrazolo [1 ,5-a]pyridin-3-yl-2-pyridyl)-3,6- dihydro -2H-pyridine -1- carboxylate 149 (200 mg) as a white solid. LCMS (ESI MS) m / z = 395.1 [M + H]+1.

[0467] Step C: A mixture of tert-butyl 4-fluoro-6-(pyrazolo[1 ,5-a]pyridin-3-yl)-5',6'-dihydro- [2,3'-bipyridine]-1'(2'H)-carboxylate 149 (60 mg, 152.11 pmol) and Pd / C (32 mg, 30.42 pmol, 10%) in MeOH (2 mL) is purged with H2 three times, and then the mixture is stirred at 25 °C for 48 hr under a H2 (15 psi) atmosphere. The reaction is filtered, and the filtrate is concentrated under vacuum to give the title compound tert-butyl 3-(4-fluoro-6-pyrazolo[1 ,5-a]pyridin-3-yl-2- pyridyl)piperidine-1 -carboxylate 150 (30 mg) as a brown oil. LCMS (ESI MS) m / z = 397.2 [M + H]+1.

[0468] Step D: To a solution of tert-butyl 3-(4-fluoro-6-(pyrazolo[1 ,5-a]pyridin-3-yl)pyridin- 2-yl)piperidine-1-carboxylate 150 (30 mg, 75.67 pmol) in DCM (0.5 mL) is added HCI / EtOAc (4 M, 0.5 mL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give the crude product which is purified by prep-HPLC (column: Xtimate C18, 150x40mmx10um; mobile phase: [water (FA)-ACN]; gradient: 0%-32% B over 25 min) to yield the title compound 3-[4-fluoro-6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 31) (16.0 mg, 25%) as a white solid. LCMS (ESI MS) m / z = 297.0 [M +H]+1.

[0469] 1H NMR (400 MHz, methanol-d4) 6 = 8.60 (d, J = 7.00 Hz, 2 H), 8.51 - 8.55 (m, 2 H), 7.42 - 7.52 (m, 2 H), 6.95 - 7.08 (m, 2 H), 3.71 (br d, J = 10.76 Hz, 1 H), 3.39 - 3.51 (m, 2 H), 3.25 - 3.31 (m, 1 H), 3.11 (td, J = 12.16, 3.31 Hz, 1 H), 2.21 - 2.28 (m, 1 H), 2.04 - 2.13 (m, 1 H), 1.92 - 2.00 (m, 2 H).

[0470] Example 323-[3-fluoro-6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridineCompound 32

[0471] Step A: A mixture of 2,6-dibromo-3-fluoropyridine 151 (866 mg, 3.0 mmol), tertbutyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H)-carboxylate 152 (700 mg, 2.26 mmol), Pd(dppf)CI2*CH2CI2(166 mg, 226.4 pmol), and Cs2CO3(1.48 g, 4.53 mmol) in toluene (20 mL) and H2O (5 mL) is degassed and purged with N2three times. The mixture is stirred at 80 °C for 16 hours under a N2atmosphere. The reaction mixture is quenched with H2O, and the mixture is extracted with EtOAc three times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 9-10% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 5-(6- bromo-5-fluoro-2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate 153 (330 mg) as a white solid. LCMS (ESI MS) m / z = 357.0 [M + H]+1.

[0472] 1H NMR (400 MHz, DMSO-cfe) 6 = 7.83 - 7.88 (m, 1 H), 7.72 (br dd, J = 8.4, 3.1 Hz, 1 H), 6.80 (br s, 1 H), 4.25 (br s, 2 H), 3.46 (br t, J = 5.2 Hz, 2 H), 2.30 (br d, J = 2.8 Hz, 2 H), 1.42 (s, 9 H).

[0473] Step B: A mixture of tert-butyl 6-bromo-5-fluoro-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)-carboxylate 153 (300 mg, 739 pmol), 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyrazolo[1 ,5-a]pyridine 154 (198 mg, 812.9 pmol), CS2CO3 (482 mg, 1.48 mmol), and Pd(dppf)Cl2’CH2Cl2 (60 mg, 73.9 pmol) in toluene (4 mL) and H2O (1 mL) is degassed and purged with N2 three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-15% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 5-(5-fluoro-6- pyrazolo[1 ,5-a]pyridin-3-yl-2-pyridyl)-3,6-dihydro-2H-pyridine-1 -carboxylate 155 (290 mg) as a white solid. LCMS (ESI MS) m / z = 395.4 [M + H]+1.

[0474] Step C: A mixture of tert-butyl 5-fluoro-6-(pyrazolo[1 ,5-a]pyridin-3-yl)-5',6'-dihydro- [2,3'-bipyridine]-1'(2'H)-carboxylate 155 (200 mg, 507 pmol) and PtC>2 (35 mg, 152.1 pmol) in EtOAc (5 mL) is purged with H2 three times. The mixture is stirred at 25 °C for 12 hr under a H2 (15 psi) atmosphere. The reaction is filtered to remove insoluble matter, and the filtrate is concentrated under vacuum to give the title compound tert-butyl 3-(5-fluoro-6-pyrazolo[1 ,5- a]pyridin-3-yl-2-pyridyl)piperidine-1-carboxylate 156 (120 mg, crude) as a brown oil. LCMS (ESI MS) m / z = 397.6 [M + H]+1.

[0475] Step D: To a solution of tert-butyl 3-(5-fluoro-6-(pyrazolo[1 ,5-a]pyridin-3-yl)pyridin- 2-yl)piperidine-1-carboxylate 156 (100 mg, 252.2 pmol) in DCM (2 mL) is added HCI / dioxane (4 M, 504 pL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give the crude product which is purified by prep-HPLC (column: Xtimate C18, 150x40mmx10um; mobile phase: [water (NHs^O+NhLHCC^-ACN]; gradient: 12%-52% B over 32 min) to yield the title compound 3-[3-fluoro-6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5- a]pyridine (Compound 32) (44.8 mg, 58%) as a white solid. LCMS (ESI MS) m / z = 297.2 [M +H]+1.

[0476] 1H NMR (400 MHz, methanol-d4) 6 = 8.61 (br d, J = 9.01 Hz, 1 H), 8.55 (d, J = 6.88 Hz, 1 H), 8.41 (d, J = 3.25 Hz, 1 H), 7.41 - 7.49 (m, 1 H), 7.31 - 7.40 (m, 1 H), 7.05 (dd, J = 8.38, 3.25 Hz, 1 H), 6.98 (t, J = 6.82 Hz, 1 H), 3.36 (br d, J = 10.26 Hz, 1 H), 3.18 (br d, J = 12.63 Hz, 1 H), 2.89 - 3.08 (m, 2 H), 2.70 - 2.81 (m, 1 H), 2.04 - 2.15 (m, 1 H), 1.66 - 1.93 (m, 3 H).

[0477] Example 333-[5-fluoro-6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridinetoluene / H2O, 100 °C, 2 hrs162 Compound 33

[0478] Step A: A mixture of 2,6-dibromo-3-fluoropyridine 157 (741 .8 mg, 2.91 mmol), tertbutyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H)-carboxylate 158 (600 mg, 1.94 mmol), Pd(dppf)CI2(141.9 mg, 194.04 pmol), and Cs2CO3(1.26 g, 3.88 mmol) in toluene (12 mL) and H2O (3 mL) is purged with N2three times, and then the mixture is stirred at 90 °C for 16 hr under N2. The reaction mixture is diluted with H2O and extracted with EtOAc three times. The combined organic layers are washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue is purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 5-(6-bromo-3-fluoro-2-pyridyl)-3,6-dihydro-2H- pyridine-1 -carboxylate 159 (150 mg) as a white solid. LCMS (ESI MS) m / z = 357.0 [M + H]+1.

[0479] Step B: To a solution of tert-butyl 6-bromo-3-fluoro-5',6'-dihydro-[2,3'-bipyridine]- 1'(2'H)-carboxvlate 159 (190 mg, 531.89 pmol) in EtOAc (5 mL) is added PtO2(24.1 mg, 106.38 pmol) under N2. The suspension is purged with H2three times. The mixture is stirred under H2(15 psi) at 25 °C for 16 hr. The reaction mixture is concentrated to yield the title compound tertbutyl 3-(6-bromo-3-fluoro-2-pyridyl)piperidine-1-carboxylate 160 (170 mg, crude) as a white solid. LCMS (ESI MS) m / z = 359.0 [M + H]+1.

[0480] Step C: A mixture of tert-butyl 3-(6-bromo-3-fluoropyridin-2-yl)piperidine-1- carboxylate 160 (150 mg, 417.56 pmol), 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazolo[1 ,5-a]pyridine 161 (101.9 mg, 417.56 pmol), Pd(dppf)CI2(61.1 mg, 83.51 pmol), and CS2CO3 (272.1 mg, 835.11 pmol) in toluene (2 mL) and H2O (0.5 mL) is purged with N2three times. The mixture is stirred at 100 °C for 2 hr under N2. The reaction mixture is diluted with H2O and extracted with EtOAc three times. The combined organic layers are washed with brine, dried, filtered and concentrated under reduced pressure to give a residue. The residue is purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3-(3-fluoro-6-pyrazolo[1 ,5-a]pyridin-3-yl-2- pyridyl)piperidine-1 -carboxylate 162 (130 mg) as a white solid. LCMS (ESI MS) m / z = 397.2 [M + H]+1.

[0481] Step D: A solution of tert-butyl 3-(3-fluoro-6-(pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2- yl)piperidine-1-carboxylate 162 (110 mg, 277.46 pmol) in HCI / dioxane (4 M, 2 mL) is stirred at 25 °C for 2 hr. The reaction mixture is concentrated directly. The residue is purified by prep- HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA)-ACN]; gradient: 0%-32% B over 25 min) to yield the title compound 3-[5-fluoro-6-(3-piperidyl)-2- pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 33) (5 mg, 5%, FA) as a white solid. LCMS (ESI MS) m / z = 297.1 [M + H]+1.

[0482] 1H NMR (400 MHz, methanol-d4) 6 = 8.54 - 8.59 (m, 2 H), 8.46 (s, 1 H), 8.43 (d, J = 9.2 Hz, 1 H), 7.72 (dd, J = 8.8, 3.6 Hz, 1 H), 7.56 (dd, J = 9.6, 8.8 Hz, 1 H), 7.40 (ddd, J = 8.8, 6.8, 0.8 Hz, 1 H), 6.99 (td, = 6.8, 1.1 Hz, 1 H), 3.57 - 3.65 (m, 2 H), 3.54 (d, J = 12.8 Hz, 1 H), 3.43 - 3.50 (m, 1 H), 3.15 (td, J = 12.4, 3.6 Hz, 1 H), 2.14 - 2.24 (m, 1 H), 2.02 - 2.12 (m, 1 H), 1.91 - 2.01 (m, 2 H).

[0483] Example 345-chloro-3-[4-chloro-6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine

[0484] Step A: A mixture of 2,6-dibromo-4-chloropyridine 163 (658 mg, 2.43 mmol), tertbutyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H)-carboxylate 164 (500 mg, 1.62 mmol), Pd(dppf)CI2*CH2CI2(264 mg, 323.41 pmol), and Cs2CO3(1 g, 3.23 mmol) in toluene (5 mL) and H2O (1 mL) is purged with N2three times, and then the mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is diluted with H2O, and the mixture is extracted with EtOAc three times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-30% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 5-(6-bromo-5-fluoro-2-pyridyl)-3,6-dihydro-2H- pyridine-1 -carboxylate 165 (330 mg) as a yellow oil. LCMS (ESI MS) m / z = 318.9 [M + H]+1.

[0485] Step B: A mixture of tert-butyl 6-bromo-4-chloro-5',6'-dihydro-[2,3'-bipyridine]- 1'(2'H)-carboxylate 165 (60 mg, 159.71 pmol), 5-chloro-3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-vl)pvrazolo[1 ,5-alpyridine 166 (53 mg, 191.65 pmol), Cs2CO3(104 mg, 319.41 pmol), and Pd(dppf)CI2*CH2CI2(26 mg, 31.9 pmol) in toluene (3 mL) and H2O (1 mL) is purged with N2three times, and then the mixture is stirred at 80 °C for 2 hr under N2. The reaction is diluted with H2O and extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3-[4-chloro-6-(5-chloropyrazolo[1 ,5- a]pyridin-3-yl)-2-pyridyl]piperidine-1 -carboxylate 167 (290 mg) as a white solid. LCMS (ESI MS) m / z = 444.9 [M + H]+1.

[0486] Step C: To a solution of tert- butyl 4-chloro-6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)- 5',6'-dihydro- [2,3'-bipyridine]-1'(2'H)-carboxylate 167 (60 mg, 134.73 pmol) and PtO2(3 mg, 13.47 pmol) in EtOAc (3 mL) is purged with H2three times, and then the mixture is stirred at40 °C for 16 hr under a H2atmosphere (20 psi). The reaction is filtered to remove the insolubles and concentrated under vacuum to give the title compound tert-butyl 3-[4-chloro-6-(5- chloropyrazolo[1 ,5-a]105yridine-3-yl)-2-pyridyl]piperidine-1-carboxylate 168 (50 mg, crude) as a brown oil. LCMS (ESI MS) m / z = 447.0 [M + H]+1.

[0487] Step D: To a solution of tert-butyl 3-(4-chloro-6-(5-chloropyrazolo[1 ,5-a]pyridin-3- yl)pyridin-2-yl)piperidine-1-carboxylate 168 (50 mg, 111.77 pmol) in DCM (1 mL) is added HCI / dioxane (4 M, 504 pL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give the crude product which is purified by prep-HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA)-ACN]; gradient: 0%-38% B over 25 min) to yield the title compound 5-chloro-3-[4-chloro-6-(3-piperidyl)-2-pyridyl]pyrazolo[1 ,5- a]pyridine (Compound 34) (2.0 mg, 5%) as a white solid. LCMS (ESI MS) m / z = 347.1 [M + H]+1.

[0488] 1H NMR (400 MHz, methanol-d4) 6 = 8.62 (s, 1 H), 8.60 (s, 1 H), 8.57 (s, 1 H), 8.55 - 8.57 (m, 1 H), 7.79 (s, 1 H), 7.25 (s, 1 H), 7.04 (br d, J = 7.25 Hz, 1 H), 3.68 (br d, J = 11 .26 Hz, 1 H), 3.45 (br d, J = 12.51 Hz, 1 H), 3.22 - 3.31 (m, 2 H), 2.99 - 3.10 (m, 1 H), 2.26 (br d, J = 6.88 Hz, 1 H), 2.10 (br d, J = 6.38 Hz, 1 H), 1.95 (br t, J = 9.57 Hz, 2 H).

[0489] Example 355-chloro-3-[4-fluoro-6-(3-piperidyl)-2-pyridyl] pyrazolo 1 ,5-a]pyridine

[0490] Step A: A mixture of tert-butyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6- dihvdropyridine-1(2H)-carboxvlate 170 (400 mg, 1.29 mmol), 2,6-dibromo-4-fluoropyridine 169(659 mg, 2.59 mmol), CS2CO3 (842 mg, 2.59 mmol), and Pd(dppf)Cl2’CH2Cl2 (211 mg, 258.73 pmol) in toluene (5 mL) and H2O (1 mL) is purged with N2three times, and then the mixture is stirred at 80 °C for 2 hr under N2. The reaction is diluted with H2O and extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-15% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 5-(6-bromo-4-fluoro-2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate 171 (400 mg) as a white solid. LCMS (ESI MS) m / z = 300.9 [M + H]+1.

[0491] Step B: A mixture of tert-butyl 6-bromo-4-fluoro-5',6'-dihydro-[2,3'-bipyridine]- 1'(2'H)-carboxylate 171 (300 mg, 839.82 pmol), and PtO2(19.07 mg, 83.98 pmol) in EtOAc (5 mL) is purged with H2three times, and then the mixture is stirred at 40 °C for 16 hr under H2(20 psi). The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure to give a crude product which is purified by flash silica gel chromatography (eluent of 0-15% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3-(6-bromo-4- fluoro-2-pyridyl) piperidine-1 -carboxylate 172 (150 mg) as a white solid. LCMS (ESI MS) m / z = 305.0 [M + H]+1.

[0492] Step C: A mixture of tert-butyl 3-(6-bromo-4-fluoropyridin-2-yl)piperidine-1- carboxylate 172 (25 mg, 69.6 pmol), 5-chloro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyrazolo[1 ,5-a]pyridine 173 (29 mg, 104.39 pmol), CS2CO3 (45 mg, 139.19 pmol), and Pd(dppf)Cl2’CH2Cl2 (11 mg, 13.92 pmol) in toluene (1 mL) and H2O (0.3 mL) is purged with N2three times and then stirred at 80 °C for 2 hr under N2. The reaction is diluted with H2O and extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-30% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3-[6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)-4-fluoro-2- pyridyl]piperidine-1-carboxylate 174 (25 mg) as a white solid. LCMS (ESI MS) m / z = 431.2 [M + H]+1.

[0493] Step D: To a solution of tert-butyl 3-(6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)-4- fluoropyridin-2-yl) piperidine-1 -carboxylate 174 (40 mg, 92.83 pmol) in DCM (1 mL) is added HCI / dioxane (4 M, 0.5 mL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give the crude product which is purified by prep-HPLC (column: Xtimate C18, 150x40 mmxlOum; mobile phase: [water (FA)-ACN]; gradient: 0%-34% B over 25 min) to yield the title compound 5-chloro-3-[4-fluoro-6-(3-piperidyl)-2-pyridyl] pyrazolo 1 ,5- a]pyridine (Compound 35) (6.0 mg, 18%) as a white solid. LCMS (ESI MS) m / z = 331.1 [M +H]+1.

[0494] 1H NMR (400 MHz, methanol-d4) 6 = 8.61 (s, 1 H), 8.60 (s, 1 H), 8.58 (s, 1 H), 8.56 (d, J = 2.25 Hz, 1 H), 7.49 - 7.57 (m, 1 H), 6.99 - 7.06 (m, 2 H), 3.73 (br d, J = 11 .01 Hz, 1 H), 3.49 (br d, J = 11.88 Hz, 1 H), 3.33 - 3.42 (m, 2 H), 3.08 (td, J = 12.44, 3.38 Hz, 1 H), 2.25 - 2.31 (m, 1 H), 2.09 - 2.19 (m, 1 H), 1.92 - 2.03 (m, 2 H).

[0495] Example 363-(4-chloro-6-(piperidin-3-yl)pyridin-2-yl)-5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine

[0496] Step A: A mixture of 2,6-dibromo-4-chloropyridine 175 (500 mg, 1.84 mmol), tertbutyl 6-bromo-4-chloro-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)-carboxylate 176 (399 mg, 1.29 mmol), Pd(dppf)Ch (301 mg, 368.5 pmol), and K2CO3 (509 mg, 3.69 mmol) in dioxane (5 mL) and H2O (1 mL) is purged with N2 three times, and then the mixture is stirred at 50 °C for 16 hr under N2. The reaction mixture is concentrated under reduced pressure to remove solvent. The residue is diluted with water and extracted with ethyl acetate three times. The combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-7% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 6- bromo-4-chloro-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)-carboxylate 177 (270 mg, crude) as a colorless oil. LCMS (ESI MS) m / z = 318.9 [M + 3]+1.

[0497] Step B: To a solution of tert-butyl 6-bromo-4-chloro-5',6'-dihydro-[2,3'-bipyridine]- 1'(2'H)-carboxylate 177 (200 mg, 535.2 pmol) in EtOAc (10 mL) is added PtC>2 (12 mg, 53.52 pmol) under a H2 (15 psi) atmosphere. The mixture is stirred at 40 °C for 32 hr. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue ispurified by flash silica gel chromatography (eluent of 0-5% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)piperidine-1- carboxvlate 178 (130 mg, crude) as a colorless oil. LCMS (ESI MS) m / z = 320.7 [M + H]+1.

[0498] Step C: A mixture of 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)pyrazolo[1 ,5-a]pyridine 179 (66 mg, 212.94 pmol), tert-butyl 3-(6-bromo-4- chloropyridin-2-yl)piperidine-1-carboxylate 178 (80 mg, 212.9 pmol), CsF (129 mg, 851.77 pmol), Cui (81 mg, 425.89 pmol), and XPhos Pd G3 (36 mg, 42.59 pmol) in dioxane (1 mL) is purged with N2 three times, and then the mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-50% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3-(4-chloro-6-(5-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate 180 (70 mg, crude) as a brown oil. LCMS (ESI MS) m / z = 481.0 [M + H]+1.

[0499] Step D: To a solution tert-butyl 3-(4-chloro-6-(5-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-3-yl) pyridin-2-yl)piperidine-1-carboxylate of 180 (50 mg, 103.97 pmol) in DCM (0.5 mL) is added HCI / dioxane (4 M, 26 pL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under reduced pressure, and the residue is purified by prep-HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA)-ACN]; gradient: 0%-40% B over 25 min) to give the title compound 3-(4-chloro-6-(piperidin-3-yl)pyridin-2-yl)-5- (trifluoromethyl)pyrazolo[1 ,5-a]pyridine (Compound 36) (3.5 mg, FA salt) as a white solid. LCMS (ESI MS) m / z = 380.9 [M + H]+1.

[0500] 1H NMR (400 MHz, DMSO-cfe) 6 = 9.07 (br s, 1 H), 9.01 - 9.05 (m, 1 H), 9.00 (s, 1 H), 8.31 - 8.40 (m, 1 H), 8.03 (d, J = 1.63 Hz, 1 H), 7.31 (s, 2 H), 3.05 - 3.15 (m, 2 H), 2.93 - 3.05 (m, 2 H), 2.89 (br dd, J = 11.57, 4.69 Hz, 1 H), 2.04 - 2.11 (m, 1 H), 1.77 (br d, J = 10.76 Hz, 2 H), 1.58 - 1.69 (m, 1 H).

[0501] Example 373-(6-piperazin-1-yl-2-pyridyl)pyrazolo[1 ,5-a]pyridine185 Compound 37

[0502] Step A: To a solution of tert-butyl piperazine-1 -carboxylate 182 (1 g, 5.37 mmol) and 2,6-dibromopyridine 181 (1 .91 g, 8.05 mmol) in DMF (20 mL) is added K2CO3 (1 .48 g, 10.74 mmol). The mixture is stirred at 90 °C for 16 hrs. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-3% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 4-(6-bromo-2- pvridyl)piperazine-1-carboxvlate 183 (1.7 g, 84.2% yield) as a white solid. LCMS (ESI MS) m / z = 342.0 [M + H]+1.

[0503] Step B: A mixture of tert-butyl 4-(6-bromopyridin-2-yl)piperazine-1-carboxylate 183 (1 g, 2.92 mmol), 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazolo[1 ,5-a]pyridine 184 (855.9 mg, 3.51 mmol), XPhos Pd G3 (247.3 mg, 292.2 pmol), and K3PO4(1.24 g, 5.84 mmol) in dioxane (20 mL) and H2O (5 mL) is degassed and purged with N2three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-21% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 4-(6- pyrazolo[1 ,5-a]pyridin-3-yl-2-pyridyl)piperazine-1-carboxylate 185 (1 g, 84.8% yield) as a yellow solid. LCMS (ESI MS) m / z = 380.2 [M + H]+1.

[0504] Step C: To a solution of tert-butyl 4-(6-(pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)- piperazine-1 -carboxylate 185 (700 mg, 1.84 mmol) in DCM (5 mL) is added HCI / EtOAc (10mL). The mixture is stirred at 25 °C for 2 hr. The reaction mixture is extracted with H2O three times. The combined water layers are lyophilized to give the title compound 3- (6- pi perazin- 1- yl-2-pyridyl)pyrazolo[1 ,5-a]pyridine (Compound 37) (500 mg, 96.8% yield) as a yellow solid. LCMS (ESI MS) m / z = 280.1 [M + H]+1.

[0505] 1H NMR (400 MHz, methanol-d4) 6 = 8.72 (d, J = 7.2 Hz, 1 H), 8.59 (s, 1 H), 8.16 (d, J = 9.2 Hz, 1 H), 8.07 (dd, J = 8.8, 7.8 Hz, 1 H), 7.55 (ddd, J = 8.8, 6.9, 0.9 Hz, 1 H), 7.39 (d, J = 7.6 Hz, 1 H), 7.11 - 7.18 (m, 2 H), 4.01 - 4.05 (m, 4 H), 3.46 - 3.50 (m, 4 H).

[0506] Example 38 / V-methyl-3-(6-piperazin-1-yl-2-pyridyl)pyrazolo[1 ,5-a]pyridin-5-amine

[0507] Step A: To a solution of tert-butyl (3-bromopyrazolo[1 ,5-a]pyridin-5-yl)carbamate 186 (750.0 mg, 2.40 mmol) in THF (10 mL) is added dropwise t-BuOK (1.08 g, 9.61 mmol) at 0 °C. After addition, the mixture is stirred at this temperature for 0.5 hr, and then Mel (1.36 g,9.61 mmol) is added dropwise at 0 °C. The resulting mixture is stirred at 25 °C for 3.5 hrs. The reaction is quenched with aq. NH3H2O (5 mL) drop-wise. The resulting mixture is quenched with water and extracted with EtOAc twice. The combined organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-30% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl / \ / -(3- bromopyrazolo[1 ,5-a]pyridin-5-yl)- / \ / -methyl-carbamate 187 (680 mg) as a yellow oil.

[0508] 1H NMR (400 MHz, methanol-d4) 6 = 8.44 (d, J = 7.6 Hz, 1 H), 7.93 (s, 1 H), 7.35 (d, J = 2.4 Hz, 1 H), 6.99 (dd, J = 2.4, 7.6 Hz, 1 H), 3.32 (s, 3H), 1 .49 (s, 9H).

[0509] Step B: A mixture of 2,6-dibromopyridine 188 (953.9 mg, 4.03 mmol), tert-butyl piperazine-1 -carboxylate 189 (500 mg, 2.68 mmol) and K2CO3(742.0 mg, 5.37 mmol) in DMF (15 mL) is stirred at 100 °C for 16 hrs. The reaction mixture is diluted with H2O, and the mixture is extracted with EtOAc three times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-8% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 4-(6-bromo-2-pyridyl)piperazine-1-carboxylate 190 (650 mg) as a white solid. LCMS (ESI MS) m / z = 342.0 [M + H]+1.

[0510] Step C: A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-1 ,3,2-dioxaborolane (486.1 mg, 1.91 mmol), tert-butyl 4-(6-bromopyridin-2-yl)piperazine-1-carboxylate 190 (400 mg, 1.06 mmol), Pd(dppf)CI2*CH2CI2(86.8 mg, 106.36 pmol), and KOAc (156.5 mg, 1.60 mmol) in dioxane (10 mL) is purged with N2three times, and then the mixture is stirred at 80 °C for 16 hr under N2. The reaction mixture is concentrated directly to give the crude title compound tert-butyl4-[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2- pyridyl]-piperazine-1 -carboxylate 191 (414 mg) as a brown solid. LCMS (ESI MS) m / z = 308.1 [M + H]+1.

[0511] Step D: A mixture of tert-butyl (3-bromopyrazolo[1 ,5-a]pyridin-5- yl)(methyl)carbamate 187 (80 mg, 233 pmol), (6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)boronic acid 191 (272 mg, 699 pmol), K3PO4(98.9 mg, 466 pmol), and XPhos Pd G3 (19.7 mg, 23.3 pmol) in dioxane (2 mL) and H2O (0.5 mL) is purged with N2three times, and then the mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is concentrated directly to yield the title compound tert-butyl4-[6-[5-[tert-butoxycarbonyl(methyl)amino]pyrazolo[1 ,5- a]pyridin-3-yl]-2-pyridyl-]piperazine-1-carboxylate 192 (90 mg, crude) as a black solid.

[0512] Step E: To a solution of tert-butyl 4-(6-(5-((tert-butoxycarbonyl)(methyl)amino)- pyrazolo[1 ,5-a] pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxylate 192 (80 mg, 157.3 pmol) in H2O (0.5 mL) is added HCI (12 M, 13 pL). The mixture is stirred at 25 °C for 1 hr. The reactionmixture is concentrated directly to give a residue which is purified by prep-HPLC (column: Nano C18, 100x40 mm 10 urn; mobile phase: [water (HCI)-ACN]; gradient: 0%-26% B over 36 min) to yield the title compound / V-methyl-3-(6-piperazin-1-yl-2-pyridyl)pyrazolo[1 ,5-a]pyridin- 5-amine (Compound 38) (12.6 mg, 25% yield) as a yellow solid. LCMS (ESI MS) m / z = 309.1 [M + H]+1.

[0513] 1H NMR (400 MHz, methanol-d4) 6 = 8.42 (s, 1 H), 8.31 (d, J = 7.6 Hz, 1 H), 7.95 (t, J = 8.0 Hz, 1 H), 7.31 (d, J = 7.6 Hz, 1 H), 7.00 - 6.88 (m, 2H), 6.63 (d, J = 7.6 Hz, 1 H), 3.99 - 3.95 (m, 4H), 3.47 - 3.43 (m, 4H), 2.92 (s, 3H).

[0514] Example 393-(4-chloro-6-piperazin-1-yl-2-pyridyl)- / V-methyl-pyrazolo[1 ,5-a]pyridin-5-amineCompound 39

[0515] Step A: A mixture of (6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-chloropyridin-2- yl)boronic acid 193 (126 mg, 367.8 pmol), tert-butyl (3-bromopyrazolo[1 ,5-a]pyridin-5- yl)(methyl)carbamate 194 (60 mg, 183.9 pmol), Pd(dppf)Ch (30 mg, 36.8 pmol), and CS2CO3 (72 mg, 220.7 pmol) in dioxane (2 mL) and H2O (0.2 mL) is purged with N2 three times, and then the mixture is stirred at 80 °C for 2 hr under N2. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-50% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 4-[6-[5-[tert-butoxycarbonyl(methyl)amino]pyrazolo[1 ,5- a]pyridin-3-yl]-4-chloro-2-pyridyl]piperazine-1 -carboxylate 195 (40 mg) as a yellow oil. LCMS (ESI MS) m / z = 543.4 [M + H]+1.

[0516] Step B: To a solution of tert-butyl 4-(6-(5-((tert-butoxycarbonyl)(methyl)amino)- pyrazolo[1 ,5-a]pyridin-3-yl)-4-chloropyridin-2-yl)piperazine-1 -carboxylate 195 (20 mg, 36.8 pmol) in DCM (2 mL) is added HCI / dioxane (4 M, 1 mL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give the crude product which is purified by prep-HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA) - ACN]; gradient: 0%-34% B over 25 min]; gradient: 12%-52% B over 32 min) to yield the title compound 3-(4-chloro-6-piperazin-1-yl-2-pyridyl)- / V-methyl-pyrazolo[1 ,5-a]pyridin-5-amine (Compound 39) (5.6 mg, FA salt) as a white solid. LCMS (ESI MS) m / z = 343 [M +H]+1.

[0517] 1H NMR (400 MHz, methanol-d4) 6 = 8.51 (br s, 1 H), 8.25 (s, 1 H), 8.13 - 8.19 (m, 1 H), 7.20 (br s, 1 H), 7.12 (s, 1 H), 6.64 (s, 1 H), 6.42 - 6.49 (m, 1 H), 3.86 - 3.90 (m, 4 H), 3.28 (br s, 4 H), 2.87 (s, 3 H).

[0518] Example 403-(6-piperazin-1-yl-2-pyridyl)-5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine

[0519] Step A: A mixture of 2,6-dibromopyridine 196 (954 mg, 4.03 mmol), tert-butyl piperazine- 1 -carboxylate 197 (500 mg, 2.68 mmol) and K2CO3 (742.0 mg, 5.37 mmol) in DMF (15 mL) is stirred at 100 °C for 16 hr. The reaction mixture is diluted with H2O, and the mixture is extracted with EtOAc three times. The combined organic layers are washed with brine, driedover Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-8% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 4-(6-bromo-2-pyridyl)piperazine-1-carboxylate 198 (650 mg) as a white solid. LCMS (ESI MS) m / z = 342.0 [M + H]+1.

[0520] Step B: A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-1 ,3,2- dioxaborolane 199 (486.1 mg, 1.91 mmol), 195 (400 mg, 1.06 mmol), Pd(dppf)Cl2’CH2Cl2 (86.8 mg, 106.36 pmol), and KOAc (156.5 mg, 1.60 mmol) in dioxane (10 mL) is purged with N2three times, and then the mixture is stirred at 80 °C for 16 hr under N2. The reaction mixture is concentrated directly to give the title compound tert-butyl 4-[6-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine-1-carboxylate 200 (414 mg, crude) as a brown solid. LCMS (ESI MS) m / z = 308.1 [M + H]+1.

[0521] Step C: A mixture of 3-bromo-5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine 201 (100 mg, 369.77 pmol), tert-butyl 4-[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2- pyridyl]piperazine-1-carboxylate 200 (287.9 mg, 739.5 pmol), XPhos Pd G3 (31 mg, 36.98 pmol), and K3PO4 (156.9 mg, 739.5 pmol) in dioxane (4 mL) and H2O (1 mL) is purged with N2three times, and then the mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is concentrated under reduced pressure to give the title compound tert-butyl 4-[6-[5- (trifluoromethyl)pyrazolo[1 ,5-a]pyridin-3-yl]-2-pyridyl]piperazine-1-carboxylate 202 (165 mg, crude) as a brown solid. LCMS (ESI MS) m / z = 448.1 [M + H]+1.

[0522] Step D: A solution of tert-butyl 4-[6-[5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-3-yl] - 2-pyridyl]piperazine-1-carboxylate 202 (100 mg, 223.5 pmol) in HCI / dioxane (4 M, 2 mL) is stirred at 25 °C for 2 hr. The reaction mixture is concentrated to give a residue which is purified by prep-HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA)-ACN]; gradient: 0%-34% B over 25 min) to yield the title compound 3-(6-piperazin-1-yl-2-pyridyl)-5- (trifluoromethyl)pyrazolo[1 ,5-a]pyridine (Compound 40) (32.0 mg, 36%, FA salt) as a white solid. LCMS (ESI MS) m / z = 348.1 [M + H]+1.

[0523] 1H NMR (400 MHz, methanol-d4) 6 = 8.84 (br s, 1 H), 8.71 (d, J = 7.2 Hz, 1 H), 8.56 (d, J = 0.8 Hz, 1 H), 8.53 (s, 1 H), 7.65 (t, J = 8.0 Hz, 1 H), 7.21 - 7.26 (m, 1 H), 7.11 (br d, J = 7.2 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 1 H), 3.85 - 3.89 (m, 4 H), 3.32 - 3.36 (m, 4 H).

[0524] Example 413-(4-chloro-6-piperazin-1-yl-2-pyridyl)-5-(trifluoromethyl) pyrazolo[1 ,5-a]pyridineCompound 41

[0525] Step A: A mixture of (6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-chloropyridin-2- yl)boronic acid 203 (60 mg, 226.4 pmol), 3-bromo-5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine 204 (116 mg, 339.6 pmol), CS2CO3 (147 mg, 452.8 pmol), and Pd(dppf)CI2(36.9 mg, 45.3 pmol) in toluene (2 mL) and H2O (0.5 mL) is purged with N2three times, and then the mixture is stirred at 80 °C for 2 hr under N2. The reaction is diluted with water and extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-5% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 4-[4-chloro-6-[5-(trifluoromethyl) pyrazolo[1 ,5-a]pyridin-3-yl]-2- pyridyl]piperazine-1 -carboxylate 205 (40 mg) as a white solid. LCMS (ESI MS) m / z = 482.0 [M + H]+1.

[0526] Step B: To a solution of tert-butyl 4-(4-chloro-6-(5-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-3-yl) pyridin-2-yl)piperazine-1-carboxylate 205 (10 mg, 20.76 pmol) in DCM (1 mL) is added HCI / dioxane (4M, 0.5 mL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give the crude product which is purified by prep-HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA)-ACN]; gradient: 0%-38% B over 25 min) to yield the title compound 3-(4-chloro-6-piperazin-1-yl-2-pyridyl)-5- (trifluoromethyl) pyrazolo[1 ,5-a]pyridine (Compound 41) (2.0 mg, FA salt) as a white solid. LCMS (ESI MS) m / z = 382.1 [M + H]+1.

[0527] 1H NMR (400 MHz, DMSO-cfe) 6 = 8.99 (d, J = 7.25 Hz, 1 H), 8.91 (s, 1 H), 8.88 (s, 1 H), 8.21 (s, 1 H), 7.38 (d, J = 1.38 Hz, 1 H), 7.27 (dd, J = 7.32, 2.06 Hz, 1 H), 6.83 (d, J =1.13 Hz, 1 H), 3.61 (br s, 4 H), 2.92 (br s, 4 H).

[0528] Example 425-chloro-3-(6-piperazin-1-yl-2-pyridyl)pyrazolo[1 ,5-a]pyridine

[0529] Step A: A mixture of 2,6-dibromopyridine 206 (954 mg, 4.03 mmol), tert-butyl piperazine- 1 -carboxylate 207 (500 mg, 2.68 mmol) and K2CO3 (742 mg, 5.37 mmol) in DMF (15 mL) is stirred at 100 °C for 16 hrs. Water is added to the reaction mixture, and the mixture is extracted with EtOAc three times. The combined organic layers are washed with brine, dried, filtered and concentrated under reduced pressure to give a residue. The residue is purified by flash silica gel chromatography (eluent of 0-8% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 4-(6-bromo-2-pyridyl)piperazine-1 -carboxylate 208 (650 mg, 65%) as a white solid. LCMS (ESI MS) m / z = 341 .9 [M + H]+1 .

[0530] Step B: A mixture of tert-butyl 4-(6-bromopyridin-2-yl)piperazine-1-carboxylate 208 (150 mg, 438.3 pmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 ,3,2-dioxaborolane (200 mg, 788.9 pmol), Pd(dppf)Cl2’CH2Cl2 (35.7 mg, 43.8 pmol), and KOAc (64.5 mg, 657.4 pmol) in dioxane (4 mL) is degassed and purged with N2three times. The mixture is stirred at 80 °C for 16 hr under a N2atmosphere. The reaction mixture is concentrated directly to yield the title compound [6-(4-tert-butoxycarbonylpiperazin-1-yl)-2-pyridyl]boronic acid 209 (134.6 mg, crude) as a brown solid. LCMS (ESI MS) m / z =308.1 [M + H]+1.

[0531] Step C: A mixture of (6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)boronic acid 209 (130 mg, 423.2 pmol), 3-bromo-5-chloropyrazolo[1 ,5-a]pyridine 210 (107.7 mg, 465.6 pmol), Pd(dppf)Ch (30.9 mg, 42.3 pmol), and CS2CO3 (275.8 mg, 846.49 pmol) in toluene (4 mL) and H2O (1 mL) is degassed and purged with N2 three times. The mixture is stirred at 80 °C for 16 hr under N2. The reaction mixture is concentrated under vacuum. The residue is purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 4-[6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)-2- pyridyl]piperazine-1 -carboxylate 211 (90 mg, 20%) as a yellow solid. LCMS (ESI MS) m / z =414.1 [M + H]+1.

[0532] Step D: To a solution of tert-butyl 4-(6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)piperazine-1 -carboxylate 211 (80 mg, 193.3 pmol) in DCM (2 mL) is added TFA (0.4 mL). The mixture is stirred at 20 °C for 2 hrs. The reaction mixture is extracted with H2O three times. The combined water layers are concentrated under reduced pressure to give a residue. The residue is purified by prep-HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA)-ACN]; gradient: 0%-32% B over 25 min) to yield the title compound 5- ch I oro-3- (6- piperazin-1-yl-2-pyridyl)pyrazolo[1 ,5-a]pyridine (Compound 42) (12.8 mg, 21 %) as a white solid. LCMS (ESI MS) m / z = 314.1 [M + H]+1.

[0533] 1H NMR (400 MHz, methanol-d4) 6 = 8.57 (d, J = 7.2 Hz, 1 H), 8.50 (s, 1 H), 8.46 (d, J = 2.4 Hz, 1 H), 7.62 - 7.69 (m, 1 H), 7.23 (d, J = 7.6 Hz, 1 H), 6.97 (dd, J = 7.2, 2.4 Hz, 1 H), 6.78 (d, J = 8.4 Hz, 1 H), 3.84 - 3.90 (m, 4 H), 3.33 - 3.39 (m, 4 H).

[0534] Example 435-chloro-3-(4-chloro-6-piperazin-1-yl-2-pyridyl)pyrazolo[1 ,5-a]pyridine212 214

[0535] Step A: To a solution of 2.6-dibromo-4-chloropyridine 212 (503 mg, 1.85 mmol) and tert-butyl piperazine-1 -carboxylate 213 (230 mg, 1.23 mmol) in DMF (5 mL) is added K2CO3 (340 mg, 2.47 mmol). The mixture is stirred at 80 °C for 12 hrs. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-11 % ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 4-(6-bromo-4-chloro-2- pyridyl)piperazine-1-carboxylate 214 (270 mg) as a white solid. LCMS (ESI MS) m / z = 321.9 [M -56]+ 1.

[0536] 1H NMR (400 MHz, DMSO-cfe) 6 = 6.95 (d, J = 1.38 Hz, 2 H), 3.48 - 3.55 (m, 4 H), 3.40 (br d, J = 5.13 Hz, 4 H), 1.42 (s, 9 H).

[0537] Step B: A mixture of tert-butyl 4-(6-bromo-4-chloropyridin-2-yl)piperazine-1- carboxylate 214 (100 mg, 265.5 pmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (135 mg, 530.9 pmol), Pd(dppf)Cl2*CH2Cl2 (44 mg, 53.1 pmol), and KOAc (31 mg, 318.6 pmol) in dioxane (1 mL) is degassed and purged with N2three times. The mixture is stirred at 80 °C for 40 min under a N2atmosphere. The reaction is filtered to remove the insoluble, and the filtrate is concentrated under vacuum to give the title compound [6-(4-tert-butoxycarbonylpiperazin-1-yl)-4-chloro-2-pyridyl]boronic acid 215 (220 mg, crude) as a brown oil. LCMS (ESI MS) m / z = 342.1 [M + H]+1.

[0538] Step C: A mixture of(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-chloropyridin-2- yl)boronic acid 215 (206 mg, 362.9 pmol), 3-bromo-5-chloropyrazolo[1 ,5-a]pyridine 216 (70 mg, 302.4 pmol), CS2CO3 (197 mg, 604.8 pmol), and Pd(dppf)Cl2*CH2Cl2 (50 mg, 60.5 pmol) in toluene (2 mL) and H2O (0.5 mL) is degassed and purged with N2three times. The mixtureis stirred at 80 °C for 40 min under N2. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-15% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 4-[4-chloro-6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)-2-pyridyl]piperazine-1- carboxylate 217 (45 mg) as a yellow solid. LCMS (ESI MS) m / z = 448.1 [M + H]+1.

[0539] Step D: To a solution of tert-butyl 4-(4-chloro-6-(5-chloropyrazolo[1 ,5-a]pyridin-3- yl)pyridin-2-yl)piperazine-1-carboxylate 217 (40 mg, 66.9 pmol) in DCM (1 mL) is added HCI / dioxane (4 M, 133 pL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give the crude product which is purified by prep-HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA)-ACN]; gradient: 0%-36% B over 25 min) to yield the title compound 5-chloro-3-(4-chloro-6-piperazin-1-yl-2- pyridyl)pyrazolo[1 ,5-a]pyridine (Compound 43) (20.6 mg, 58%) as a white solid. LCMS (ESI MS) m / z = 348.0 [M +H]+1.

[0540] 1H NMR (400 MHz, DMSO-cfe) 6 = 8.81 (d, J = 7.38 Hz, 1 H), 8.76 (s, 1 H), 8.41 (br s, 1 H), 8.26 (br d, J = 8.88 Hz, 1 H), 7.29 (s, 1 H), 7.08 (dd, J = 7.32, 1 .94 Hz, 1 H), 6.77 (s, 1 H), 3.63 - 3.73 (m, 4 H), 2.94 (br s, 4 H).

[0541] Example 445-chloro-3-(4-fluoro-6-piperazin-1-yl-2-pyridyl)pyrazolo[1 ,5-a]pyridine

[0542] Step A: A mixture of 2,6-dibromo-4-fluoropyridine 218 (460 mg, 1.80 mmol), tert-butyl piperazine-1 -carboxylate 219 (672.2 mg, 3.61 mmol), Pd2(dba)3(165.2 mg, 180.48 pmol), Xantphos (522.1 mg, 902.38 pmol), and NaHCO3(151.6 mg, 1.80 mmol) in toluene (5 mL) is purged with N2three times, and then the mixture is stirred at 80 °C for 2 hours under N2. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure to give a residue. The residue is purified by flash silica gel chromatography (eluent of 9-10% ethyl acetate / petroleum ether gradient) to give a crude product, which is further purified by prep- HPLC (Neutral condition; column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 46%-86% B over 32 min) to yield the title compound tert-butyl 4- (6-bromo-4-fluoropyridin-2-yl)piperazine-1 -carboxylate 220 (100 mg) as a white solid. LCMS (ESI MS) m / z = 304.0 [M-55],

[0543] Step B: A mixture of tert-butyl 4-(6-bromo-4-fluoropyridin-2-yl)piperazine-1- carboxylate 220 (20 mg, 55.52 pmol), 5-chloro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyrazolo[1 ,5-a]pyridine 221 (30.9 mg, 111.04 pmol), Cs2CO3(27.1 mg, 83.28 pmol), and Pd(dppf)CI2*CH2CI2(9.1 mg, 11.10 pmol) in toluene (1 mL) and H2O (1 mL) is purged with N2three times, and then the mixture is stirred at 80 °C for 2 hr under N2. The reaction is diluted with H2O and extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 15-20% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl4-[6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)-4- fluoro-2-pyridyl]-piperazine-1 -carboxylate 222 (30 mg) as a yellow solid. LCMS (ESI MS) m / z = 432.2 [M + H]+1.

[0544] Step C: To a solution of tert-butyl 4-(6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)-4- fluoropyridin-2-yl) piperazine-1 -carboxylate 222 (30 mg, 69.46 pmol) in DCM (1 mL) is added HCI / dioxane (4 M, 70 pL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give the crude product which is purified by prep-HPLC (HCI condition; column: Xtimate C18 150x40mmxl0um; mobile phase: [water (HCI)-ACN]; gradient: 0%-40% B over 36 min) to yield the title compound 5-chloro-3-(4-fluoro-6-piperazin-1-yl-2- pyridyl)pyrazolo[1 ,5-a]pyridine (Compound 44) (14.9 mg, 64%) as a white solid. LCMS (ESI MS) m / z = 332.1 [M + H]+1.

[0545] 1H NMR (400 MHz, methanol-d4) 6 = 8.61 (d, J = 7.2 Hz, 1 H), 8.55 (s, 1 H), 8.45 (d, J = 1.6 Hz, 1 H), 8.42 - 8.49 (m, 1 H), 7.08 (dd, J = 9.6, 1.6 Hz, 1 H), 7.03 (dd, J = 7.6, 2.4 Hz, 1 H), 6.59 (dd, J = 12.0, 1.6 Hz, 1 H), 3.92 - 3.99 (m, 4 H), 3.40 - 3.44 (m, 4 H).

[0546] 19F NMR (377 MHz, methanol-d4) 6 = -104.39 (s, 1 F).

[0547] Example 453-[6-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine227 Compound 45

[0548] Step A: To a solution of 2,6-dibromopyridine 223 (716.9 mg, 3.03 mmol) in DMF (10 mL) are added tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate 224 (500 mg, 2.52 mmol), K2CO3(1.05 g, 7.57 mmol) and KI (209.3 mg, 1.26 mmol). The mixture is stirred at 90 °C for 16 hr. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are washed with brine twice, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3-(6-bromo-2-pyridyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate 225 (600 mg, 67% yield) as a white solid. LCMS (ESI MS) m / z = 354.0 [M + H]+1.

[0549] 1H NMR (400 MHz, chloroform-d) 5 = 7.30 (t, J = 8.0 Hz, 1H), 6.77 (d, J = 7.2 Hz,1H), 6.41 (d, J = 8.4 Hz, 1 H), 4.28 (br d, J = 5.2 Hz, 2H), 4.10 - 3.98 (m, 2H), 3.55 - 3.34 (m,2H), 2.70 - 2.61 (m, 1H), 1.47 (d, J = 8.4 Hz, 1 H), 1.38 (s, 9H).

[0550] Step B: A mixture of tert-butyl 3-(6-bromopyridin-2-yl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate 225 (217.7 mg, 0.61 mmol), 3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine 226 (150 mg, 0.61 mmol), KsPO4(260.9 mg, 1.23 mmol), and XPhos Pd G3 (52.0 mg, 61.45 pmol) in dioxane (4 mL) and H2O (1 mL) is degassed and purged with N2 three times. The mixture is stirred at 80 °C for 2 hr under a N2 atmosphere. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleumether gradient) to yield the title compound tert-butyl3-(6-pyrazolo[1 ,5-a]pyridin-3-yl-2-pyridyl)- 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate 227 (200 mg, 83.1% yield) as a yellow oil. LCMS (ESI MS) m / z = 392.0 [M + H]+1.

[0551] 1H NMR (400 MHz, chloroform-d) 5 = 8.60 (d, J = 8.8 Hz, 1 H), 8.49 (d, J = 6.8 Hz, 1 H), 8.38 (s, 1 H), 7.53 (dd, J = 8.4, 7.6 Hz, 1 H), 7.26 - 7.21 (m, 1 H), 7.04 (d, J = 7.6 Hz, 1 H), 6.83 (td, J = 6.8, 1 .2 Hz, 1 H), 6.35 (d, J = 8.4 Hz, 1 H), 4.36 (br s, 2H), 4.22 (br s, 2H), 3.61 (br d, J = 10.8 Hz, 2H), 2.73 - 2.64 (m, 1 H), 1.40 - 1.35 (m, 10H).

[0552] Step C: To a solution of tert-butyl 3-(6-(pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate 227 (50 mg, 0.13 mmol) in DCM (1 mL) is added 4M HCI / EtOAc (1 mL). The mixture is stirred at 20 °C for 2 hr. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by prep-HPLC (column: Welch Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA) - ACN]; gradient: 18%-56% B over 25 min) to yield the title compound 3-[6-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)-2- pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 45) (29.1 mg, 77.5% yield) as a white solid. LCMS (ESI MS) m / z = 292.1 [M + H]+1.

[0553] 1H NMR (400 MHz, methanol-d4) 6 = 8.64 - 8.53 (m, 2H), 8.47 (s, 1 H), 7.64 (t, J = 8.0 Hz, 1 H), 7.35 (dd, J = 8.4, 7.2 Hz, 1 H), 7.22 (d, J = 7.6 Hz, 1 H), 6.97 (td, J = 6.8, 0.8 Hz, 1 H), 6.55 (d, J = 8.4 Hz, 1 H), 4.57 (br d, J = 6.0 Hz, 2H), 4.21-4.13 (m, 2H), 4.11-4.04 (m, 2H), 3.08 (dt, J = 10.0, 6.4 Hz, 1 H), 2.03 (d, J = 10.4 Hz, 1 H).

[0554] Example 463-(6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptanediazabicyclo[3.1.1]heptane-6-carboxylate 228 (100 mg, 0.28 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (143.4 mg, 0.56 mmol), KOAc (41.6 mg, 0.42 mmol), and Pd(dppf)Cl2*CH2Cl2 (23.1 mg, 28.23 pmol) in dioxane (2 mL) is purged with N2 three times. The mixture is stirred at 80 °C for 16 hr under N2. The reaction mixture is concentrated under reduced pressure to afford the title compound (6-(6-(tert- butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-yl)boronic acid 229 (90 mg, crude) as a brown oil, which is used in the next step without further purification.

[0556] Step B: A mixture of (6-(6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)pyridin-2-yl)boronic acid 229 (90 mg, 0.28 mmol), 3-bromo-5-chloropyrazolo[1 ,5-a]pyridine 230 (65.3 mg, 0.28 mmol), CS2CO3 (183.8 mg, 0.56 mmol), and Pd(dppf)Cl2*CH2Cl2 (46.1 mg, 56.4 pmol) in toluene (4 mL) and H2O (1 mL) is purged with N2 three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is concentrated under vacuum to afford the title compound tert-butyl 3-(6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)-3,6- diazabicvclo-[3.1.11heptane-6-carboxvlate 231 (120 mg, crude) as a brown solid, which is used directly without further purification.

[0557] Step C: To a solution of tert-butyl 3-(6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)pyridin- 2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate 231 (120 mg, 0.28 mmol) in DCM (4 mL) is added TFA (1 mL). The mixture is stirred at 25 °C for 2 hrs. The reaction mixture is diluted with DCM and extracted with H2O three times. The combined water layers are concentrated under reduced pressure. The residue is purified by prep-HPLC (column: Xtimate C18, 150x40 mmxlOum; mobile phase: [water (FA) - MeOH]; gradient: 12%-52% B over 25 min] to yield the title compound 3-(6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)-3,6- diazabicyclo[3.1.1]heptane (Compound 46) (12.4 mg, 11%, FA salt) as a white solid. LCMS (ESI MS) m / z = 326.1 [M + H]+1.

[0558] 1H NMR (400 MHz, methanol-d4) 6 = 8.62 (d, J = 2.0 Hz, 1 H), 8.56 - 8.53 (m, 1 H), 8.53 - 8.51 (m, 1 H), 8.49 (s, 1 H), 7.65 (t, J = 8.0 Hz, 1 H), 7.20 (d, J = 7.6 Hz, 1 H), 6.95 (dd, J = 2.4, 7.2 Hz, 1 H), 6.57 (d, J = 8.4 Hz, 1 H), 4.56 (br d, J = 6.0 Hz, 2H), 4.19 - 4.03 (m, 4H), 3.08 (td, J = 6.4, 10.4 Hz, 1 H), 2.03 (d, J = 10.4 Hz, 1 H).

[0559] Example 475-chloro-3-[4-chloro-6-(3,6-diazabicyclo[3.1 .1 ]heptan-3-yl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine

[0560] Step A: A mixture of tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate 233 (0.7 g, 3.53 mmol), 2,6-dibromo-4-chloropyridine 232 (1.4 g, 5.30 mmol), and K2CO3 (975.9 mg, 7.06 mmol) in DMF (2 mL) is degassed and purged with N2 three times. The mixture is stirred at 80 °C for 16 hr under a N2 atmosphere. The reaction mixture is extracted with EtOAc (3x). The combined organic layers are washed with brine three times, dried over Na2SC>4, filtered and concentrated under reduced pressure to give a crude product which is purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3-(6-bromo-4-chloro-2-pyridyl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate 234 (600 mg) as an orange solid.

[0561] 1H N MR (400 MHz, DMSO-cfe) 6 = 6.97 (d, J = 0.8 Hz, 1 H), 6.77 (d, J = 0.8 Hz, 1 H), 4.18 (br d, J = 6.0 Hz, 2H), 4.01 - 3.76 (m, 2H), 3.39 (br d, J = 11.6 Hz, 2H), 2.58 - 2.53 (m, 1 H), 1.45 (d, J = 8.8 Hz, 1 H), 1.28 (s, 9H).

[0562] Step B: A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-1 ,3,2- dioxaborolane (391.9 mg, 1.54 mmol), tert-butyl 3-(6-bromo-4-chloropyridin-2-yl)- 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate 234 (200 mg, 514.5 pmol), KOAc (60.6 mg,617.5 pmol), and Pd(dppf)Cl2*CH2Cl2 (84 mg, 102.91 pmol) in dioxane (2 mL) is degassed and purged with N2three times. The mixture is stirred at 80 °C for 40 min under N2. The reaction mixture is filtered, and the filtrate is concentrated under vacuum to yield the title compound [6- (6-tert-butoxycarbonyl-3,6-diazabicyclo[3.1 .1]heptan-3-yl)-4-chloro-2-pyridyl]boronic acid 235 (185 mg, crude) as a black solid.

[0563] Step C: A mixture of 3-bromo-5-chloropyrazolo[1 ,5-a]pyridine 236 (110 mg, 475.2 pmol), (6-(6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-4-chloropyridin-2- yl)boronic acid 235 (184.8 mg, 522.7 pmol), CS2CO3 (309.6 mg, 950.4 pmol), and Pd(dppf)Cl2’CH2Cl2 (77.6 mg, 95 pmol) in toluene (1 mL) and H2O (0.25 mL) is degassed and purged with N2 three times. The mixture is stirred at 80 °C for 40 min under N2. The reaction mixture is filtered, and the filtrate is concentrated to yield the title compound tert-butyl 3-[4- chloro-6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)-2-pyridyl]-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate 237 (185 mg, crude) as a black solid.

[0564] Step D: To a solution of tert-butyl 3-(4-chloro-6-(5-chloropyrazolo[1 ,5-a]pyridin-3- vl)pvridin-2-vl)-3.6-diazabicvclo[3.1.11heptane-6-carboxvlate 237 (180 mg, 391.0 pmol) in H2O (1 mL) is added HCI (12 M, 32 pL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give the crude product which is purified by prep-HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (HCI)-ACN]; gradient: 4%- 44% B over 36 min) to yield the title compound 5-chloro-3-[4-chloro-6-(3,6- diazabicyclo[3.1.1]heptan-3-yl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 47) (5.1 mg, 3%) as a white solid. LCMS (ESI MS) m / z =360.1 [M + H]+1.

[0565] 1H NMR (400 MHz, methanol-d4) 6 = 8.62 - 8.53 (m, 3H), 7.29 (s, 1 H), 7.06 - 6.94 (m, 1 H), 6.63 (s, 1 H), 4.64 (br d, J = 6.4 Hz, 2H), 4.26 - 4.02 (m, 4H), 3.18 - 3.07 (m, 1 H), 2.07 (d, J = 10.4 Hz, 1 H).

[0566] Example 483-[6-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine

[0567] Step A: To a solution of tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate 239 (89.6 mg, 422.1 pmol) and 2,6-dibromopyridine 238 (0.1 g, 422.1 pmol) in DMF (2 mL) are added KI (35 mg, 211.1 pmol) and K2CO3 (175 mg, 1.27 mmol). The mixture is stirred at 80 °C for 16 hr. The reaction mixture is partitioned between EtOAc and H2O. The organic phase is separated, washed with brine twice, dried over Na2SC>4, filtered and concentrated under reduced pressure to give a crude product which is purified by flash silica gel chromatography (eluent of 20-30% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 5-(6-bromo-2-pyridyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate 240 (0.1 g, 28%) as a yellow oil. LCMS (ESI MS) m / z = 311.9 [M - 55]+ 1.

[0568] Step B: A mixture of 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazolo[1 ,5- a]pyridine 241 (25.4 mg, 104.2 pmol), tert-butyl 5-(6-bromopyridin-2-yl)-2,5- diazabicyclo[2.2.2]octane-2-carboxylate 240 (43 mg, 104.2 pmol), K3PO4 (44.2 mg, 208.4 pmol), and XPhos Pd G3 (8.8 mg, 10.4 pmol) in dioxane (1 mL) and H2O (0.1 mL) is purged with N2three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 20-40% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 5-(6-pyrazolo[1 ,5-a]pyridin-3-yl-2-pyridyl)-2,5-diazabicyclo[2.2.2]octane- 2- carboxylate 242 (0.08 g, 80%) as a white solid. LCMS (ESI MS) m / z = 406.5 [M + H]+1.

[0569] Step C: To a solution of tert-butyl 5-(6-(pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate 242 (0.04 g, 98.6 pmol) in DCM (1 mL) is added HCI / dioxane (1 mL, 4M). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is partitioned between DCM and H2O. The organic phase is separated, and the water phase is lyophilized to yield the title compound 3-[6-(2,5-diazabicyclo[2.2.2]octan-2-yl)-2- pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 48) (15.1 mg, 46%) as a white solid. LCMS (ESI MS) m / z = 306.1 [M + H]+1.

[0570] 1H NMR (400 MHz, methanol-d4) 6 = 8.66 (br t, J = 6.4 Hz, 1 H), 8.56 - 8.46 (m, 1 H), 8.30 - 8.14 (m, 1 H), 7.95 - 7.84 (m, 1 H), 7.47 (br d, J = 6.0 Hz, 1 H), 7.31 - 7.18 (m, 1 H), 7.07 (br d, J = 5.6 Hz, 1 H), 6.82 (br d, J = 8.8 Hz, 1 H), 4.11 - 3.99 (m, 2H), 3.91 (br dd, J = 5.2, 12.4 Hz, 1 H), 3.67 - 3.55 (m, 2H), 2.33 - 2.04 (m, 5H).

[0571] Example 493-[6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-pyridyl]pyrazolo[1 ,5-a]pyridine

[0572] Step A: A mixture of 2,6-dibromopyridine 243 (106 mg, 447.9 pmol), tert-butyl (2S,6R)-2,6-dimethylpiperazine-1 -carboxylate 244 (80 mg, 373.3 pmol), and K2CO3 (103 mg, 746.6 pmol) in DMSO (2 mL) is degassed and purged with N2 three times. The mixture is stirred at 100 °C for 16 hr under a N2 atmosphere. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl (2S,6R)-4-(6-bromo-2-pyridyl)-2,6-dimethyl-piperazine-1 -carboxylate245 (113 mg) as a white solid. LCMS (ESI MS) m / z = 316.0 [M - 55J+1.

[0573] 1H NMR (400 MHz, DMSO-cfe) 6 = 7.43 (dd, J = 8.38, 7.50 Hz, 1 H), 6.87 (d, J = 8.50 Hz, 1 H), 6.76 (d, J = 7.38 Hz, 1 H), 4.07 - 4.15 (m, 4 H), 3.01 (dd, J = 13.26, 4.75 Hz, 2 H), 1.42 (s, 9 H), 1.12 (d, J = 6.75 Hz, 6 H).

[0574] Step B: A mixture of tert-butyl (2S,6R)-4-(6-bromopyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate 245 (73 mg, 196.6 pmol), 3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyrazolo[1 ,5-a]pyridine 246 (40 mg, 163.9 pmol), K3PO4 (70 mg, 327.7 pmol), and XPhos Pd G3 (14 mg, 16.4 pmol) in dioxane (2 mL) and H2O (0.5 mL) is purged with N2 three times. The mixture is stirred at 80 °C for 2 hours under N2. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-25% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl (2S,6R)-2,6-dimethyl- 4-(6-pyrazolo[1 ,5-a]pyridin-3-yl-2-pyridyl)-piperazine-1- carboxylate 247 (65 mg) as a yellow oil. LCMS (ESI MS) m / z = 408.3 [M + H]+1.

[0575] Step C: To a solution of tert-butyl (2S,6R)-2,6-dimethyl-4-(6-(pyrazolo[1 ,5-a]pyridin- 3-yl)pyridin-2-yl)piperazine-1-carboxylate 247 (50 mg, 122.7 pmol) in DCM (1.5 mL) is added TFA (112 mg, 981 .6 pmol, 75 pL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by prep-HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA)-ACN]; gradient: 0%-30% B over 25 min) to yield the title compound 3-[6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2- pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 49) (25.8 mg, 66%) as a white solid. LCMS (ESI MS) m / z = 308.2 [M + H]+1.

[0576] 1H NMR (400 MHz, methanol-d4) 6 = 8.52 - 8.57 (m, 2 H), 8.41 - 8.45 (m, 1 H), 8.32 - 8.38 (m, 1 H), 7.58 - 7.64 (m, 1 H), 7.31 - 7.39 (m, 1 H), 7.14 - 7.20 (m, 1 H), 6.92 - 6.99 (m, 1 H), 6.74 (dd, J = 8.32, 2.56 Hz, 1 H), 4.56 (br d, J = 13.63 Hz, 2 H), 3.37 - 3.48 (m, 2 H), 2.90 (dd, J = 14.01 , 11 .38 Hz, 2 H), 1.42 (d, J = 6.50 Hz, 6 H).

[0577] Example 503-[6-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-2-pyridyl]pyrazolo[1 ,5-a]pyridine252 Compound 50

[0578] Step A: A mixture of tert-butyl (2S,6S)-2,6-dimethylpiperazine-1-carboxylate 249 (500 mg, 2.33 mmol), 2,6-dibromopyridine 248 (663.2 mg, 2.80 mmol), and K2CO3 (644.9 mg, 4.67 mmol) in DMF (6 mL) is degassed and purged with N2three times. The mixture is stirred at 80 °C for 16 hours under N2. The reaction mixture is quenched with H2O, and the mixture is extracted with EtOAc three times. The combined organic layers are washed with brine three times, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-2% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl (2R,6R)-4-(6-bromo-2- pyridyl)-2,6-dimethyl-piperazine-1 -carboxylate 250 (400 mg) as a white solid. LCMS (ESI MS) m / z = 372.1 [M + H]+1.

[0579] Step B: A mixture of 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazolo[1 ,5- a]pyridine 251 (145 mg, 594.1 pmol), tert-butyl (2R,6R)-4-(6-bromopyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate 250 (200 mg, 540.1 pmol), K3PO4 (229.3mg, 1.08 mmol), and XPhos Pd G3 (45.7 mg, 54 pmol) in dioxane (1 mL) and H2O (0.25 mL) is degassed and purged with N2three times. The mixture is stirred at 80 °C for 2 hours under N2. The reaction mixture is concentrated under vacuum to give the crude product which is purified by flash silica gel chromatography (eluent of 0-15% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl (2R,6R)-2,6-dimethyl-4-(6-pyrazolo[1 ,5-a]pyridin-3-yl-2-pyridyl)piperazine-1- carboxylate 252 (120 mg, 50 %) as a yellow solid. LCMS (ESI MS) m / z =408.3 [M + H]+1.

[0580] 1H NMR (400 MHz, methanol-d4) 6 = 8.60 - 8.50 (m, 2H), 8.44 (d, J = 4.4 Hz, 1 H), 7.61 - 7.51 (m, 1 H), 7.42 - 7.31 (m, 1 H), 7.09 (dd, J = 4.4, 7.2 Hz, 1 H), 6.96 (dt, J = 2.8, 6.8 Hz, 1 H), 6.44 (dd, J = 4.0, 8.4 Hz, 1 H), 4.32 - 4.20 (m, 2H), 3.98 (br d, J = 12.4 Hz, 2H), 3.84 - 3.74 (m, 2H), 1.52 (d, J = 4.4 Hz, 9H), 1.30 (dd, J = 4.4, 6.4 Hz, 6H), 1 .20 (d, J = 4.4 Hz, 2H).

[0581] Step C: To a solution of tert-butyl (2R,6R)-2,6-dimethyl-4-(6-(pyrazolo[1 ,5- a]pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxylate 252 (100 mg, 202 pmol) in DCM (2 mL) is added TFA (0.5 mL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give the crude product which is purified by prep-HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA)-ACN]; gradient: 0%-30% B over 25 min) to yield the title compound 3-[6-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-2- pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 50) (56 mg, 77%) as a yellow solid. LCMS (ESI MS) m / z =308.0 [M + H]+1.

[0582] 1H NMR (400 MHz, methanol-d4) 6 = 8.58 (d, J = 6.8 Hz, 1 H), 8.52 (s, 1 H), 8.47 (s, 1 H), 8.42 (d, J = 8.8 Hz, 1 H), 7.64 (t, J = 8.0 Hz, 1 H), 7.43 - 7.34 (m, 1 H), 7.21 (d, J = 7.6 Hz, 1 H), 7.03 - 6.94 (m, 1 H), 6.74 (d, J = 8.4 Hz, 1 H), 3.96 (dd, J = 3.2, 13.6 Hz, 2H), 3.82 - 3.72 (m, 2H), 3.71 - 3.63 (m, 2H), 1 .44 (d, J = 6.6 Hz, 6H).

[0583] Example 513-[4-chloro-6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-pyridyl]pyrazolo[1 ,5-a]pyridineCompound 51

[0584] Step A: To a solution of tert-butyl (2S,6R)-4-(6-bromo-4-chloropyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate 253 (50 mg, 123.54 pmol) in dioxane (1 mL) and H2O (1 mL) are added 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazolo[1 ,5-a]pyridine 254 (60.3 mg, 247.1 pmol), Pd(dppf)Cl2 (20 mg, 24.71 pmol), and CS2CO3 (60 mg, 185.3 pmol). The mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is quenched with H2O, and the mixture is extracted with EtOAc three times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 15% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl (2S,6R)-4-(4-chloro-6-pyrazolo[1 ,5- a]pyridin-3-yl-2-pyridyl)-2,6-dimethyl-piperazine-1-carboxylate crude 255 (30 mg) as a white solid. LCMS (ESI MS) m / z = 444.0 [M + H]+1.

[0585] Step B: To a solution of tert-butyl (2S,6R)-4-(4-chloro-6-(pyrazolo[1 ,5-a]pyridin-3- yl)pvridin-2-vl)-2.6-dimethvlpiperazine-1-carboxvlate 255 (30 mg, 67.88 pmol) in DCM (1 mL) is added HCI / dioxane (4 M, 67.9 pL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by prep- HPLC (HCI condition; column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (HCI)- ACN]; gradient: 2%-42% B over 36 min) to yield the title compound 3-[4-chloro-6-[(3S,5R)-3,5- dimethylpiperazin-1-yl]-2-pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 51) (8.3 mg, 34%) as a white solid. LCMS (ESI MS) m / z = 342.1 [M +H]+1.

[0586] 1H NMR (400 MHz, methanol-d4) 6 = 8.63 (d, J = 7.2 Hz, 1 H), 8.54 (s, 1 H), 8.40 (d, J = 9.2 Hz, 1 H), 7.42 - 7.51 (m, 1 H), 7.29 (d, J = 1.2 Hz, 1 H), 7.04 (td, J = 6.8, 1.2 Hz, 1 H), 6.88 (d, J = 1 .2 Hz, 1 H), 4.68 (dd, J = 14.0, 2.8 Hz, 2 H), 3.46 - 3.57 (m, 2 H), 2.96 (dd, J = 14.4, 11.6 Hz, 2 H), 1.46 (d, J = 6.8 Hz, 6 H).

[0587] Example 523-[6-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4-fluoro-2-pyridyl]pyrazolo[1 ,5-a]pyridine

[0588] Step A: A mixture of tert-butyl (2S,6R)-4-(6-bromo-4-fluoropyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate 256 (70 mg, 180.28 pmol), 3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyrazolo[1 ,5-a]pyridine 257 (88 mg, 360.57 pmol), Pd(dppf)Cl2 (29 mg, 36.06 pmol), and CS2CO3 (117 mg, 360.57 pmol) in toluene (2 mL) and H2O (0.5 mL) is purged with N2 three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is quenched with H2O, and the mixture is extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-32% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl (2S,6R)-4-(4- fluoro-6-pyrazolo[1 ,5-a]pyridin-3-yl-2-pyridyl)-2,6-dimethyl -piperazine- 1 -carboxylate 258 (60 mg) as a yellow oil. LCMS (ESI MS) m / z = 426.5 [M +H]+1.

[0589] Step B: To a solution of tert-butyl (2S,6R)-4-(4-fluoro-6-(pyrazolo[1 ,5-a]pyridin-3- yl)pvridin-2-vl)-2.6-dimethvlpiperazine-1-carboxvlate 258 (40 mg, 94.01 pmol) in DCM (1 mL)is added HCI / dioxane (4 M, 0.5 mL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give the crude product which is purified by prep- HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA)-ACN]; gradient: 0%-34% B over 25 min) to yield the title compound 3-[6-[(3R,5S)-3,5-dimethylpiperazin-1-yl]- 4-fluoro-2-pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 52) (9 mg, 25%) as a white solid. LCMS (ESI MS) m / z = 326.2 [M + H]+1.

[0590] 1H NMR (400 MHz, methanol-d4) 6 = 8.58 (d, J = 7.00 Hz, 1 H), 8.51 (s, 1 H), 8.48 (s, 1 H), 8.37 (d, J = 8.88 Hz, 1 H), 7.38 - 7.44 (m, 1 H), 6.97 - 7.03 (m, 2 H), 6.54 (br d, J = 12.01 Hz, 1 H), 4.59 (br dd, J= 13.82, 1.81 Hz, 2 H), 3.41 (ddd, J = 10.19, 6.50, 3.44 Hz, 2 H), 2.86 - 2.97 (m, 2 H), 1.41 (d, J = 6.50 Hz, 6 H).

[0591] Example 533-[6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-pyridyl]- / \ / -methyl-pyrazolo[1 ,5-a]pyridin-5-aminePd(dppf)CI2, KOAc100 °C, 16 hrs dioxane, 100 °C, 16 hrsp3, 3 4262 dioxane / H2O, 100 °C, 16 hrs 264

[0592] Step A: To a solution of 2,6-dibromopyridine 259 (2.21 g, 9.33 mmol) and tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate 260 (1 g, 4.67 mmol) in DMF (30 mL) is added K2CO3 (1.29 g, 9.33 mmol). The mixture is stirred at 100 °C for 16 hr. The reaction mixture isdiluted with H20, and the mixture is extracted with EtOAc three times. The combined organic layers are washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl (2S,6R)- 4-(6-bromo-2-pyridyl)-2,6-dimethyl-piperazine-1 -carboxylate 261 (630 mg) as a white solid. LCMS (ESI MS) m / z = 370.1 [M + H]+1.

[0593] Step B: A mixture of tert-butyl (2S,6R)-4-(6-bromo-2-pyridyl)-2,6-dimethyl- piperazine-1 -carboxylate 261 (580 mg, 1.57 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (715.9 mg, 2.82 mmol), Pd(dppf)CI2(127.9 mg, 156.64 pmol), and KOAc (230.5 mg, 2.35 mmol) in dioxane (10 mL) is purged with N2three times. The mixture is then stirred at 100 °C for 16 hr under N2. The reaction mixture is concentrated under vacuum to give the title compound [6-[(3S,5R)-4-tert-butoxycarbonyl-3,5- dimethyl-piperazin-1-yl]-2-pyridyl]boronic acid 262 (400 mg, crude) as a white solid. LCMS (ESI MS) m / z = 336.2 [M + H]+1.

[0594] 1H NMR (400 MHz, methanol-d4) 6 = 7.90 (dd, J = 8.8, 7.1 Hz, 1 H), 7.13 (d, J = 8.8 Hz, 1 H), 7.03 (d, J = 6.8 Hz, 1 H), 4.32 - 4.41 (m, 2 H), 4.03 (br d, J = 14.2 Hz, 2 H), 3.49 (dd, J = 13.6, 4.6 Hz, 2 H), 1.50 (s, 9 H), 1.31 (s, 3 H), 1.29 (s, 3 H).

[0595] Step C: A mixture of [6-[(3S,5R)-4-tert-butoxycarbonyl-3,5-dimethyl-piperazin-1-yl]- 2-pyridyl]boronic acid 262 (92.4 mg, 275.9 pmol), tert-butyl (3-bromopyrazolo[1 ,5-a]pyridin-5- yl)(methyl)carbamate 263 (60 mg, 183.9 pmol), XPhos Pd G3 (31.1 mg, 36.79 pmol), and K3PO4 (78.0 mg, 367.8 pmol) in dioxane (1 mL) and H2O (0.25 mL) is purged with N2three times, and then the mixture is stirred at 100 °C for 16 hr under N2. The reaction mixture is diluted with H2O, and the mixture is extracted with EtOAc three times. The combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue is purified by flash silica gel chromatography (eluent of 25% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl (2S,6R)-4-[6-[5-[tert-butoxycarbonyl(methyl)amino]pyrazolo [1 ,5-a]pyridin-3-yl]-2 -pyridyl]-2,6- dimethyl-piperazine-1-carboxylate 264 (60 mg) as a white solid. LCMS (EB9118-326-P1 B1). LCMS (ESI MS) m / z = 537.3 [M +H]+1.

[0596] Step D: A solution of tert-butyl (2S,6R)-4-[6-[5-[tert-butoxycarbonyl(methyl)amino]- pyrazolo [1 ,5-a]pyridin-3-yl]-2-pyridyl]-2,6-dimethyl-piperazine-1-carboxylate 264 (50 mg, 93.17 pmol) in HCI / dioxane (4 M, 2 mL) is stirred at 25 °C for 2 hr. The reaction mixture is concentrated under vacuum to give a residue which is purified by prep-HPLC (column: Xtimate C18, 150x40mmx10um; mobile phase: [water (FA)-ACN]; gradient: 0%-30% B over 25 min) to yield the title compound 3-[6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-pyridyl]- / \ / -methyl-pyrazolo[1 ,5-a]pyridin-5-amine (Compound 53) (5.0 mg, 15%) as a brown solid. LCMS (ESI MS) m / z = 337.2 [M +H]+1.

[0597] 1H NMR (400 MHz, methanol-d4) 6 = 8.51 (s, 1 H), 8.19 - 8.24 (m, 1 H), 8.11 - 8.16 (m, 1 H), 7.52 - 7.60 (m, 1 H), 7.16 (br d, J = 2.4 Hz, 1 H), 7.08 - 7.12 (m, 1 H), 6.64 (br d, J = 8.4 Hz, 1 H), 6.42 (dd, J = 7.6, 2.6 Hz, 1 H), 4.55 (br dd, J = 13.6, 2.7 Hz, 2 H), 3.43 (ddd, J = 10.8, 6.6, 3.3 Hz, 2 H), 2.86 - 2.89 (m, 3 H), 2.84 (br d, J = 2.4 Hz, 1 H), 2.81 (s, 1 H), 1 .40 (d, J = 6.4 Hz, 6 H).

[0598] Example 543-[4-chloro-6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-pyridyl]- / \ / -methyl-pyrazolo[1 ,5-a]pyridin-5-amine

[0599] Step A: A mixture of 2,6-dibromo-4-chloropyridine 265 (500 mg, 1.84 mmol), tertbutyl (2S.6R)-2.6-dimethvlpiperazine-1 -carboxylate 266 (592 mg, 2.76 mmol), and K2CO3 (509 mg, 3.69 mmol) in DMF (10 mL) is stirred at 80 °C for 2 hours. The reaction mixture is quenched with water and extracted with EtOAc three times. The combined organic layers are dried overanhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-5% ethyl acetate / petroleum ether gradient) to give the title compound tert-butyl (2S,6R)-4-(6-bromo-4-chloro-2-pyridyl)-2,6- dimethyl-piperazine-1 -carboxylate 267 (300 mg) as a white solid. LCMS (ESI MS) m / z = 405.9 [M + H]+1.

[0600] Step B: A mixture of tert-butyl (2S,6R)-4-(6-bromo-4-chloropyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate 267 (200 mg, 494.16 pmol), Sn2Mee (1.13 g, 3.45 mmol, 715.19 pL), and Pd(PPh3)4 (114 mg, 98.8 pmol) in toluene (4 mL) is purged with N2three times. The mixture is stirred at 110 °C for 2 hr under N2. The reaction is quenched with sat. KF and extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the title compound tert-butyl (2S,6R)-4-(4-chloro-6-(trimethylstannyl)pyridin-2-yl)-2,6-dimethylpiperazine-1- carboxylate 268 (160 mg) as a black solid. LCMS (ESI MS) m / z = 489.1 [M + H]+1.

[0601] Step C: To a solution of tert-butyl (2S,6R)-4-(4-chloro-6-(trimethylstannyl)pyridin-2- yl)-2,6-dimethylpiperazine-1-carboxylate 268 (157 mg, 321.9 pmol) and tert-butyl (3- bromopyrazolo[1 ,5-a]pyridin-5-yl)(methyl)carbamate 269 (70 mg, 214.6 pmol) in dioxane (3 mL) are added XPhos Pd G3 (36 mg, 42.9 pmol), Cui (82 mg, 429.2 pmol), and CsF (49 mg, 321.9 pmol). The mixture is stirred at 100 °C for 2 hr under N2. The reaction mixture is filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether gradient) to give the title compound tert-butyl (2S,6R)-4-[6-[5-[tert-butoxycarbonyl(methyl)amino]pyrazolo[1 ,5- a]pyridin-3-yl]-4- chloro-2-pyridyl]-2,6-dimethyl-piperazine-1-carboxylate 270 (30 mg) as a white solid. LCMS (ESI MS) m / z = 571.3 [M + H]+1 .

[0602] Step D: To a solution of tert-butyl (2S,6R)-4-(6-(5-((tert- butoxycarbonyl)(methyl)amino)pyrazolo[1 ,5-a]pyridin-3-yl)-4-chloropyridin-2-yl)-2,6-dimethyl- piperazine-1 -carboxylate 270 (30 mg, 52.5 pmol) in DCM (1 mL) is added HCI / dioxane (4 M, 169 pL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give the crude product which is purified by prep-HPLC (HCI condition; column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (HCI)-ACN]; gradient: 2%-42% B over 36 min) to yield the title compound 3-[4-chloro-6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2- pyridyl]- / V-methyl-pyrazolo[1 ,5-a]pyridin-5-amine (Compound 54) (5.0 mg, 24%) as an off- white solid. LCMS (ESI MS) m / z = 371.1 [M +H]+1 .

[0603] 1H NMR (400 MHz, methanol-d4) 6 = 8.30 - 8.38 (m, 1 H), 8.33 (s, 1 H), 8.18 - 8.24 (m, 1 H), 8.22 (d, J = 7.6 Hz, 1 H), 7.19 (s, 2 H), 6.78 (s, 1 H), 6.52 (d, J = 7.2 Hz, 1 H), 4.67 (br dd, J = 13.6, 2.0 Hz, 2 H), 3.48 - 3.54 (m, 2 H), 2.90 - 2.97 (m, 5 H), 1 .45 (d, J = 6.4 Hz, 6H).

[0604] Example 553-[6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-pyridyl]-5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridineCompound 55

[0605] Step A: A mixture of 3-bromo-5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine 272 (200 mg, 754.6 pmol), (6-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)boronic acid 271 (303.5 mg, 905.5 pmol), XPhos Pd G3 (63.8 mg, 75.4 pmol, 0.1 eq), and K3PO4 (320.3 mg, 1.51 mmol) in dioxane (5 mL) and H2O (1.25 mL) is purged with N2 three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is concentrated under reduced pressure to give a crude product which is purified by flash silica gel chromatography (eluent of 0-11 % ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl (2S,6R)-2,6-dimethyl-4-[6-[5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-3-yl]- 2-pyridyl] piperazine-1 -carboxylate 273 (110 mg, crude) as an off-white solid.

[0606] Step B: To a solution of tert-butyl (2S,6R)-2,6-dimethyl-4-(6-(5-(trifluoromethyl)- pyrazolo [1 ,5-a1pvridin-3-vl)pvridin-2-vl)piperazine-1-carboxvlate 273 (70 mg, 147.21 pmol) in H2O (1 mL) is added aqueous HCI (12 M, aq. 184 pL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated directly to give a crude product which is purified by prep- HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (HCI)-ACN]; gradient: 40 / 0-44% B over 36 min) to yield the title compound 3-[6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]- 2-pyridyl]-5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine (Compound 55) (12.5 mg, 22% yield) as a white solid. LCMS (ESI MS) m / z = 376.2 [M +H]+1.

[0607] 1H NMR (400 MHz, methanol-d4) 5 = 8.93 (s, 1 H), 8.76 (d, J = 7.2 Hz, 1 H), 8.62 (s, 1H), 7.69 (t, J = 8.0 Hz, 1 H), 7.31 (d, J = 7.Q Hz, 1 H), 7.15 (dd, J = 1.6, 7.2 Hz, 1 H), 6.87 (d, J = 8.4 Hz, 1 H), 4.61 (dd, J = 2.4, 13.6 Hz, 2H), 3.52 (ddd, J = 3.2, 6.8, 10.4 Hz, 2H), 2.92 (dd, J = 11.6, 13.6 Hz, 2H), 1.46 (d, J = 6.4 Hz, 6H).

[0608] Example 563-[4-chloro-6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-pyridyl]-5-(trifluoromethyl)pyrazolo[1 ,5- a]pyridine

[0609] Step A: A mixture of tert-butyl (2S,6R)-4-(6-bromo-4-chloropyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate 274 (50 mg, 123.5 pmol), 3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine 275 (77 mg, 247.08 pmol), Pd(dppf)Cl2 (20 mg, 24.71 pmol), and CS2CO3 (60 mg, 185.31 pmol) in dioxane (2 mL) and H2O (0.3 mL) is purged with N2 three times, and the mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is quenched with H2O, and the mixture is extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-8% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl (2S,6R)-4-[4-chloro-6-[5-(trifluoromethyl)pyrazolo [1 ,5-a]pyridin-3-yl]-2- pyridyl]-2,6-dimethyl-piperazine-1-carboxylate 276 (33 mg) as a yellow solid. LCMS (ESI MS) m / z = 510.2 [M + 1]+1.

[0610] Step B: To a solution of tert-butyl (2S,6R)-4-[4-chloro-6-[5-(trifluoromethyl)pyrazolo [1,5-a]pyridin-3-yl]-2-pyridyl]-2,6-dimethyl-piperazine-1-carboxylate 276 in DCM (1 mL) is added HCI / dioxane (4 M, 98 pL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give the crude product which is purified by prep-HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA)-ACN]; gradient: 2%-42% B over 25 min) to yield the title compound 3-[4-chloro-6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]- 2-pyridyl] -5-(trifluoromethyl)pyrazolo[1,5-a]pyridine (Compound 56) (4.5 mg, 21%) as a white solid. LCMS (ESI MS) m / z = 410.0 [M + H]+1.

[0611] 1H NMR (400 MHz, methanol-d4) 6 = 8.87 (s, 1 H), 8.76 (d, J = 7.38 Hz, 1 H), 8.62 (s, 1 H), 7.28 (s, 1 H), 7.16 (dd, J = 7.25, 1.75 Hz, 1 H), 6.84 (s, 1 H), 4.51 (br d, J = 2.25 Hz, 1 H), 4.48 (br d, J = 2.38 Hz, 1 H), 3.33 - 3.39 (m, 2 H), 2.78 - 2.85 (m, 2 H), 1.38 (d, J = 6.38 Hz, 6 H).

[0612] Example 575-chloro-3-[6-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-pyridyl]pyrazolo[1,5-a]pyridine

[0613] Step A: A mixture of 3-bromo-5-chloropyrazolo[1,5-a]pyridine 278 (165.7 mg, 716 pmol), (6-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)boronic acid 277 (200 mg, 596.6 pmol), Pd(dppf)CI2(44 mg, 59.7 pmol), and CS2CO3 (389 mg, 1.19 mmol) in dioxane (5 mL) and H2O (1.25 mL) is purged with N2three times. The mixture is stirred at 100 °C for 2 hr under N2. The reaction mixture is concentrated under reduced pressure to give a crude product which is purified by flash silica gel chromatography (eluent of 0-11% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl (2S,6R)-4-[6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)-2-pyridyl]-2,6-dimethyl-piperazine-1-carboxylate 279 (13.4 mg, crude) as a yellow solid.

[0614] Step B: To a solution of tert-butyl (2S,6R)-4-(6-(5-chloropyrazolo[1 ,5-a]pyridin-3- yl)pvridin-2-vl)-2.6-dimethvlpiperazine-1-carboxvlate 279 (13 mg, 29.41 pmol) in H2O (1 mL) is added aqueous HCI (12 M, 73 pL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under reduced pressure to give the crude product which is purified by prep- HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (HCI)-ACN]; gradient: 0%-40% B over 36 min) to yield the title compound 5-chloro-3-[6-[(3R,5S)-3,5- dimethylpiperazin-1-yl]-2-pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 57) (9.7 mg, 94% yield) as a white solid. LCMS (ESI MS) m / z = 342.2 [M + H]+1 .

[0615] 1H NMR (400 MHz, methanol-d4) 6 = 8.67 - 8.41 (m, 3H), 7.75 - 7.60 (m, 1 H), 7.32 - 7.17 (m, 1 H), 7.08 - 6.93 (m, 1 H), 6.89 - 6.74 (m, 1 H), 4.62 (br d, J = 13.2 Hz, 2H), 3.60 - 3.42 (m, 2H), 3.04 - 2.86 (m, 2H), 1.53 - 1.41 (m, 6H).

[0616] Example 585-chloro-3-[6-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4-fluoro-2-pyridyl]pyrazolo[1 ,5-a]pyridine

[0617] Step A: A mixture of tert-butyl (2S,6R)-2,6-dimethylpiperazine-1 -carboxylate 281 (100 mg, 466.6 pmol), 2,6-dibromo-4-fluoropyridine 280 (238 mg, 933.3 pmol), Pd(OAc)2 (21 mg, 93.33 pmol), BINAP (58 mg, 93.3 pmol), and t-BuONa (89 mg, 933.26 pmol) in toluene (2 mL) is purged with N2 three times. The mixture is stirred at 100 °C for 2 hr under N2. Thereaction mixture is quenched with H2O, and the mixture is extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-8% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl (2S,6R)-4-(6-bromo-4-fluoro-2-pyridyl)-2,6-dimethyl-piperazine-1-carboxylate 282 (480 mg) as a yellow solid. LCMS (ESI MS) m / z = 331.9 [M-55J+1.

[0618] Step B: A mixture of tert-butyl (2S,6R)-4-(6-bromo-4-fluoropyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate 282 (33 mg, 84.99 pmol), 5-chloro-3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyrazolo[1 ,5-a]pyridine 283 (36 mg, 127.5 pmol), Pd(dppf)CI2(14 mg, 17.00 pmol), and Cs2CC>3 (55 mg, 169.98 pmol) in toluene (2 mL) and H2O (0.5 mL) is purged with N2three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-18% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl (2S,6R)-4-[6-(5-chloropyrazolo[1 ,5-a]pyridin-3- yl)-4-fluoro-2-pyridyl]-2,6-dimethyl- piperazine-1 -carboxylate 284 (30 mg) as a white solid. LCMS (ESI MS) m / z = 462.0 [M + H]+1.

[0619] Step C: To a solution of tert-butyl (2S,6R)-4-(6-(5-chloropyrazolo[1 ,5-a]pyridin-3- yl)-4-fluoropyridin-2-yl)-2,6-dimethylpiperazine-1 -carboxylate 284 (25 mg, 54.35 pmol) in DCM (1 mL) is added HCI / dioxane (4 M, 108 pL). The mixture is stirred at 25 °C for 1 hr. The reaction is concentrated under vacuum to give the crude product which is purified by prep-HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (FA) - ACN]; gradient: 0%- 36% B over 25 min) to yield the title compound 5-chloro-3-[6-[(3R,5S)-3,5-dimethylpiperazin- 1-yl]-4-fluoro-2-pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 58) (12.5 mg, 56%) as a white solid. LCMS (ESI MS) m / z = 360.2 [M + H]+1.

[0620] 1H NMR (400 MHz, methanol-d4) 6 = 8.57 (br d, J = 7.38 Hz, 1 H), 8.51 (br s, 2 H), 8.46 (br s, 1 H), 6.99 (br s, 2 H), 6.55 (br d, J = 11.88 Hz, 1 H), 4.54 (br d, J = 13.88 Hz, 2 H), 3.36 - 3.44 (m, 2 H), 2.90 (br t, J = 12.51 Hz, 2 H), 1.42 (br d, J = 6.13 Hz, 6 H).

[0621] Example 595-chloro-3-[4-chloro-6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-pyridyl]pyrazolo[1 ,5-a]pyridine

[0622] Step A: A mixture of tert-butyl (2S,6R)-4-(6-bromo-4-chloropyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate 285 (50 mg, 123.54 pmol), 3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)- 5-chloropyrazolo[1 ,5-a]pyridine 286 (34.4 mg, 123.5 pmol), Pd(dppf)Ch (20.1 mg, 24.71 pmol), and CS2CO3 (80.5 mg, 247.08 pmol) in toluene (1 mL) and H2O (0.25 mL) is purged with N2 three times, and then the mixture is stirred at 100 °C for 2 hr under N2. The reaction mixture is concentrated under reduced pressure to give the title compound 287 (58.8 mg, crude) as a brown solid. LCMS (ESI MS) m / z = 476.1 [M + H]+1.

[0623] Step B: A solution of tert-butyl (2S,6R)-4-[4-chloro-6-(5-chloropyrazolo[1 ,5- a]pyridin-3-yl)-2-pyridyl]-2,6- dimethyl-piperazine-1-carboxylate 287 (50 mg, 104.9 pmol) in HCI / dioxane (4 M, 2 mL) is stirred at 25 °C for 2 hr. The reaction mixture is concentrated, and the residue is purified by prep-HPLC (column: Xtimate C18, 150x40mmxl0um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; gradient: 42%-82% B over 32 min) to yield the title compound 5-chloro-3-[4-chloro-6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-pyridyl]pyrazolo[1 ,5- a]pyridine (Compound 59) (1.5 mg, 3%) as a white solid. LCMS (ESI MS) m / z = 376.1 [M + H]+1.

[0624] 1H NMR (400 MHz, methanol-d4) 6 = 8.56 (s, 1 H), 8.54 (s, 1 H), 8.49 (s, 1 H), 7.12 (s, 1 H), 6.95 - 7.01 (m, 1 H), 6.66 (s, 1 H), 4.28 (dd, J = 12.4, 2.1 Hz, 2 H), 2.88 - 3.02 (m, 2 H), 2.55 (t, J = 11.8 Hz, 2 H), 1.22 (d, J = 6.4 Hz, 6 H).

[0625] Example 605-chloro-3-[5-chloro-6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-pyridyl]pyrazolo[1 ,5-a]pyridine

[0626] Step A: A mixture of tert-butyl (2S,6R)-4-(6-bromo-3-chloropyridin-2-yl)-2,6- dimethylpiperazine-1-carboxylate 288 (100 mg, 247.08 pmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1 ,3,2 -dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (126 mg, 494.16 pmol), KOAc (49 mg, 494.16 pmol), and Pd(dppf)Cl2 (36 mg, 49.42 pmol) in dioxane (2 mL) is purged with N2three times. The mixture is stirred at 80 °C for 1 hr under N2. The reaction mixture is filtered and concentrated under reduced pressure to yield the title compound [6-[(3S,5R)-4-tert- butoxycarbonyl-3,5-dimethyl-piperazin-1-yl]-5-chloro-2-pyridyl]boronic acid 289 (200 mg, crude) as a brown oil. LCMS (ESI MS) m / z = 370.1 [M +H]+1.

[0627] Step B: A mixture of 3-bromo-5-chloropyrazolo[1 ,5-a]pyridine 290 (56 mg, 243.47 pmol), (6-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-5-chloropyridin-2- yl)boronic acid 289 (90 mg, 243.47 pmol), Pd(dppf)CI2*CH2CI2(40 mg, 48.69 pmol), and Cs2CO3 (159 mg, 486.95 pmol) in dioxane (2 mL) is purged with N2three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether gradient) to yield the title compound (2S,6R)-4-[3-chloro-6-(5- chloropyrazolo[1 ,5-a]pyridin-3-yl)-2-pyridyl] -2,6-dimethyl- piperazine-1-carboxylate 291 (70 mg, 60%) as a white solid.

[0628] 1H NMR (400 MHz, methanol-d4) 6 = 8.82 (d, J = 7.6 Hz, 1 H), 8.76 (s, 1 H), 8.54 (d, J = 2.0 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.59 (d, J = 8.4 Hz, 1 H), 7.09 (dd, J = 2.4, 7.6 Hz, 1 H), 4.20 (br dd, J = 4.4, 6.0 Hz, 2H), 3.68 (br d, J = 12.0 Hz, 2H), 2.99 (br dd, J = 4.0, 12.0Hz, 2H), 1.45 (s, 9H), 1.38 (d, J = 6.8 Hz, 6H).

[0629] Step C: To a solution of tert-butyl (2S,6R)-4-(3-chloro-6-(5-chloropyrazolo[1 ,5- a]pyridin-3-yl)pyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate 291 (60 mg, 125.95 pmol) in DCM (1 mL) is added HCI / dioxane (4 M, 6.0 mL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is partitioned between DCM and H2O. The organic phase is discarded, and the aqueous phase is lyophilized to give the title compound 5-chloro-3-[5-chloro-6-[(3S,5R)- 3,5-dimethylpiperazin-1-yl]-2-pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 60) (28.3 mg, 56%) as a white solid. LCMS (ESI MS) m / z = 376.1 [M +H]+1.

[0630] 1H NMR (400 MHz, methanol-d4) 6 = 8.59 (d, J = 7.6 Hz, 1 H), 8.54 (s, 2H), 7.77 (d, J = 8.0 Hz, 1 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.01 (dd, J = 2.0, 7.2 Hz, 1 H), 4.12 (br d, J = 13.2 Hz, 2H), 3.69 - 3.60 (m, 2H), 3.02 (dd, J = 11 .6, 13.2 Hz, 2H), 1 .46 (d, J = 6.8 Hz, 6H).

[0631] Example 615-chloro-3-[6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-5-fluoro-2-pyridyl]pyrazolo[1 ,5-a]pyridine

[0632] Step A: A mixture of tert-butyl (2S,6R)-4-(6-bromo-3-fluoropyridin-2-yl)-2,6- dimethvlpiperazine-1-carboxvlate 292 (261 mg, 1.03 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1 ,3,2-dioxaborolane) (200 mg, 515.10 pmol), KOAc (101 mg, 1.03 mmol), and Pd(dppf)Cl2*CH2Cl2 (84 mg, 103.02 pmol) in dioxane (5 mL) is purged with N2 three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is quenched with H2O, and the mixture is extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound [6-[(3S,5R)-4-tert-butoxycarbonyl-3,5-dimethyl-piperazin-1-yl]-5-fluoro-2-pyridyl]boronic acid 293 (170 mg, crude) as a white solid. LCMS (ESI MS) m / z = 354.1 [M + H]+1.

[0633] Step B: A mixture of (6-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1- yl)-5-fluoropyridin-2-yl)boronic acid 293 (60 mg, 259.21 pmol), 3-bromo-5-chloropyrazolo[1 ,5- a]pyridine 294 (137 mg, 388.8 pmol), Cs2CC>3 (168 mg, 518.4 pmol), and Pd(dppf)Cl2’CH2Cl2 (42 mg, 51.84 pmol) in toluene (3 mL) and H2O (1 mL) is purged with N2 three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-25% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl (2S,6R)-4-[6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)-3-fluoro-2-pyridyl] - 2,6-dimethyl -piperazine-1-carboxylate 295 (50 mg) as a white solid. LCMS (ESI MS) m / z = 460.0 [M + H]+1.

[0634] Step C: To a solution of tert-butyl (2S,6R)-4-(6-(5-chloropyrazolo[1 ,5-a]pyridin-3- yl)-3-fluoropvridin-2-vl)-2.6-dimethvlpiperazine-1 -carboxylate 295 (40 mg, 86.97 pmol) in DCM (1 mL) is added HCI / dioxane (4 M, 1 mL). The mixture is stirred at 25 °C for 12 hrs. The reaction mixture is partitioned between DCM and H2O. The organic phase is discarded, and the aqueous phase is lyophilized to give the title compound 5-chloro-3-[6-[(3S,5R)-3,5- dimethylpiperazin-1-yl]-5-fluoro-2-pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 61) (19.0 mg, 58%) as a white solid. LCMS (ESI MS) m / z = 360.1 [M + H]+1.

[0635] 1H NMR (400 MHz, DMSO-cfe) 6 = 8.68 (d, J = 7.38 Hz, 1 H), 8.60 (s, 1 H), 8.34 (d, J = 2.13 Hz, 1 H), 7.57 (dd, J = 12.63, 8.25 Hz, 1 H), 7.42 (dd, J = 8.25, 2.38 Hz, 1 H), 7.03 (dd, J = 7.44, 2.19 Hz, 1 H), 4.10 (br d, J = 12.13 Hz, 2 H), 3.45 (ddd, J = 10.35, 6.79, 3.13 Hz, 2 H), 2.93 - 3.06 (m, 2 H), 1.31 (d, J = 6.50 Hz, 6 H).

[0636] Example 623-[4-chloro-6-(3-piperidyl)-2-pyridyl]- / V-methyl-pyrazolo[1 ,5-a]pyridin-5-amine299 Compound 62

[0637] Step A: A mixture of tert- butyl (3-bromopyrazolo[1 ,5-a]pyridine-5- yl)(methyl)carbamate 296 (100 mg, 306.6 pmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (155 mg, 613.1 pmol), KOAc (60 mg, 613.1 pmol), and XPhos Pd G3 (25 mg, 30.7 pmol) in DMSO (3 mL) is degassed and purged with N2 three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is quenched with H2O, and the mixture is extracted with EtOAc three times. The combined organic layers are washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl / V-methyl- / \ / -[3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl]carbamate 297 (70 mg) as a white solid. LCMS (ESI MS) m / z = 374.1

[0638] Step B: A mixture of tert-butyl / \ / -methyl- / \ / -[3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl]carbamate 297 (50 mg, 133.1 pmol), tert-butyl 3- (6-bromo-4-chloropyridin-2-yl)piperidine-1-carboxylate 298 (59 mg, 159.7 pmol), CS2CO3 (86 mg, 266.18 pmol), and Pd(dppf)Cl2.CH2Cl2 (10mg, 13.31 pmol) in dioxane (1 mL) and H2O (0.3 mL) is degassed and purged with N2 three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction is quenched with water and extracted with EtOAc three times. The combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl 5-(5-fluoro-6-pyrazolo[1 ,5-a]pyridin-3-yl-2-pyridyl)-3,6-dihydro-2H- pyridine-1 -carboxylate 299 (40 mg) as a white solid. LCMS (ESI MS) m / z = 542.3 [M + H]+1.

[0639] Step C: To a solution of 5-(5-fluoro-6-pyrazolo[1 ,5-a]pyridin-3-yl-2-pyridyl)-3,6-dihydro-2H-pyridine-1 -carboxylate 299 (40 mg, 73.8 pmol) in DCM (0.5 mL) is added HCI / dioxane (4M, 0.5 mL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give a crude product which is purified by prep-HPLC (column: Xtimate C18 150*40mm*10um; mobile phase: [water (FA)-ACN]; gradient: 0%-34% B over 25 min) to yield the title compound 3-[4-chloro-6-(3-piperidyl)-2-pyridyl]- / \ / -methyl-pyrazolo[1 ,5- a]pyridin-5-amine (Compound 62) (3 mg, 10%) as a brown oil. LCMS (ESI MS) m / z = 342.0 [M + H]+1.

[0640] 1H NMR (400 MHz, methanol-d4) 6 = 8.56 (br s, 1 H), 8.30 (s, 1 H), 8.19 (br d, J = 7.50 Hz, 1 H), 7.60 (s, 1 H), 7.30 (br s, 2H), 7.08 (s, 1 H), 6.49 (br dd, J = 7.38, 2.25 Hz, 2H), 3.69 (br d, J = 11.13 Hz, 2H), 3.40 - 3.50 (m, 2H), 3.37 (br s, 1 H), 3.33 (br s, 2H), 3.24 (br d, J = 9.88 Hz, 1 H), 2.94 - 3.08 (m, 3H), 2.25 (br d, J = 10.88 Hz, 1 H), 2.05 - 2.12 (m, 1 H), 1.98 (br d, J = 10.76 Hz, 1 H).

[0641] Example 635-chloro-3-[3-chloro-6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2- pyridyl]pyrazolo[1 ,5-a]pyridine

[0642] Step A: A mixture of 2,6-dibromopyridin-3-amine 300 (2.5 g, 9.92 mmol) and CuCI (2.46 g, 24.8 mmol) in ACN (30 mL) is stirred for 15 min at 25 °C. Isopentyl nitrite (2.33 g, 19.85 mmol) is added. The mixture is stirred for 2 hr at 70 °C. The reaction mixture isconcentrated under vacuum, and the residue is purified by flash silica gel chromatography (eluent of 5% ethyl acetate / petroleum ether gradient) to yield the title compound 5-chloro-3-[3- chloro-6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-pyridyl]pyrazolo[1 ,5-a]pyridine 301 (1 .7 g) as a white solid. LCMS (ESI MS) m / z = 269.8 [M + H]+1.

[0643] Step B: A mixture of 5-chloro-3-[3-chloro-6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2- pyridyl]pyrazolo[1 ,5-a]pyridine 301 (2 g, 7.37 mmol), 302 (1.11 g, 5.16 mmol) and K2CO3 (2.04 g, 14.74 mmol) in DMF (20 mL) is stirred at 90 °C for 16 hrs. The reaction mixture is diluted with H2O and extracted with EtOAc three times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 3-5% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl (2S,6R)-4-(6-bromo-5-chloro-2-pyridyl)- 2, 6-dimethyl-piperazine-1 -carboxylate 303 (430 mg) as a white solid. LCMS (ESI MS) m / z = 404.0 [M + H]+1.

[0644] 1H NMR (400 MHz, DMSO-cfe) 6 = 7.68 (d, J = 8.8 Hz, 1 H), 6.94 (d, J = 8.8 Hz, 1 H), 4.10 (br d, J = 12.4 Hz, 4H), 3.05 (br dd, J = 13.2, 4.4 Hz, 2H), 1.42 (s, 9H), 1.12 (d, J = 6.4 Hz, 6H).

[0645] Step C: A mixture of tert-butyl (2S,6R)-4-(6-bromo-5-chloro-2-pyridyl)-2,6-dimethyl- piperazine-1 -carboxylate 303 (250 mg, 617.7 pmol), trimethyl(trimethylstannyl)stannane (0.94 g, 2.9 mmol) and Pd(PPh3)4 (143 mg, 123.5 pmol) in toluene (3 mL) is purged with N2three times. The mixture is stirred at 110 °C for 2 hr under N2. The mixture is quenched with a saturated KF solution and stirred at 25 °C for 1 hr. The mixture is extracted with ethyl acetate three times. The combined organic layers are washed with brine, dried over Na2SO4 and evaporated under vacuum to give a residue which is purified by flash silica gel chromatography (eluent of 0-5% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl (2S,6R)-4-(5-chloro-6-trimethylstannyl-2-pyridyl)-2,6-dimethyl-piperazine-1 -carboxylate 304 (160 mg) as a white solid. LCMS (ESI MS) m / z = 490.1 [M + H]+1 .

[0646] Step D: A mixture of terf-butyl (2S,6R)-4-(5-chloro-6-trimethylstannyl-2-pyridyl)-2,6- dimethyl-piperazine-1-carboxylate 304 (160 mg, 327.4 pmol), 3-bromo-5-chloropyrazolo[1 ,5- alpyridine 305 (113.6 mg, 491.2 pmol), XPhos Pd G3 (55.4 mg, 65.5 pmol) and K3PO4 (139.0 mg, 654.9 pmol) in dioxane (3 mL) is purged with N2 three times. The mixture is stirred at 80 °C for 16 hr under N2. The reaction mixture is concentrated under vacuum to give a residue which is purified by flash silica gel chromatography (eluent of 13% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl (2S,6R)-4-[5-chloro-6-(5- chloropyrazolo[1 ,5-a]pyridin-3-yl)-2-pyridyl]-2,6-dimethyl-piperazine-1-carboxylate 306 (55 mg) as a yellow solid. LCMS (ESI MS) m / z = 476.1 [M + H]+1.

[0647] Step E: A solution of ferf-butyl (2S,6R)-4-[5-chloro-6-(5-chloropyrazolo[1 ,5- a]pyridin-3-yl)-2-pyridyl]-2,6-dimethyl-piperazine-1-carboxylate 306 (50 mg, 104.9 pmol) in HCI / dioxane (4 M, 7.5 mL) is stirred at 25 °C for 2 hr. The reaction mixture is filtered to give a residue which is purified by prep-HPLC (column: Xtimate C18 150*40mm*10um; mobile phase: [water (FA)-ACN]; gradient: 0%-38% B over 25 min) to yield the title compound 5-chloro-3-[3- chloro-6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2-pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 63) (9.7 mg, 24%) as a white solid. LCMS (ESI MS) m / z = 376.1 [M + H]+1.

[0648] 1H NMR (400 MHz, methanol-d4) 6 = 8.73 (s, 1 H), 8.59 (d, J = 7.2 Hz, 1 H), 8.51 (s, 1 H), 8.34 (d, J = 2.4 Hz, 1 H), 7.67 (d, J = 8.8 Hz, 1 H), 7.01 (dd, J = 7.2, 2.4 Hz, 1 H), 6.82 (d, J = 9.2 Hz, 1 H), 4.50 (dd, J = 13.6, 2.6 Hz, 2H), 3.36 - 3.46 (m, 2H), 2.87 (dd, J = 13.6, 11.4 Hz, 2H), 1.40 (d, J = 6.4 Hz, 6H).

[0649] Example 645-chloro-3-[6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-3-fluoro-2- pyridyl]pyrazolo[1 ,5-a]pyridine

[0650] Step A: A mixture of 5-chloro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyrazolo[1 ,5-a]pyridine 307 (36 mg, 128.8 pmol), terf-butyl (2S,6R)-4-(6-bromo-5- fluoropyridin-2-yl)-2,6-dimethylpiperazine-1-carboxylate 308 (50 mg, 128.8 pmol), Pd(dppf)Cl2’CH2Cl2 (21 mg, 25.7 pmol), and CS2CO3 (84 mg, 257.5 pmol) in H2O (0.1 mL) and dioxane (1 mL) is purged with N2 three times. The mixture is stirred at 80 °C for 16 hr under N2. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by flash silica gel chromatography (eluent of 20-30% ethyl acetate / petroleum ethergradient) to yield the title compound tert-butyl (2S,6R)-4-[6-(5-chloropyrazolo[1 ,5-a]pyridin-3- yl)-5-fluoro-2-pyridyl]-2,6-dimethyl-piperazine-1 -carboxylate 309 (40 mg, 67%) as a white solid. LCMS (ESI MS) m / z = 460.0 [M +H]+1.

[0651] Step B: To a solution of tert-butyl (2S,6R)-4-[6-(5-chloropyrazolo[1 ,5-a]pyridin-3- vl)-5-fluoro-2-pvridyl1-2.6-dimethvl-piperazine-1-carboxvlate 309 (30 mg, 65.2 pmol) in DOM (1 mL) is added HCI / dioxane (4M, 2.0 mL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is partitioned between DCM and H2O. The organic phase is discarded, and the water phase is lyophilized to yield the title compound 5-chloro-3-[6-[(3S,5R)-3,5-dimethylpiperazin- 1-yl]-3-fluoro-2-pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 64) (3.7 mg, 14%) as a white solid. LCMS (ESI MS) m / z = 360.1 [M + H]+1.

[0652] 1H NMR (400 MHz, DMSO-cfe) 6 = 8.87 (d, J = 7.2 Hz, 1 H), 8.55 - 8.48 (m, 2H), 7.67 (dd, J = 9.2, 10.8 Hz, 1 H), 7.15 (dd, J = 2.4, 7.2 Hz, 1 H), 6.90 (dd, J = 2.0, 9.2 Hz, 1 H), 4.49 - 4.44 (m, 1 H), 4.33 (br d, J = 11.2 Hz, 2H), 3.00 - 2.85 (m, 2H), 2.04 - 1 .93 (m, 1 H), 1 .33 (br d, J = 6.0 Hz, 6H).

[0653] Example 653-[4-chloro-6-(3-piperidyl)-2-pyridyl]-5-isopropoxy-pyrazolo[1 ,5-a]pyridine

[0654] Step A: A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-1 ,3,2-dioxaborolane (995.4 mg, 3.92 mmol), 3-bromo-5-isopropoxypyrazolo[1 ,5- a]pyridine 310 (500 mg, 1.96 mmol), KOAc (384.7 mg, 3.92 mmol), and XPhos Pd G3 (165.9 mg, 196 pmol) in DMSO (8 mL) is purged with N2 three times. The mixture is stirred at 80 °C for 2 hr under N2 and then diluted with H2O (10 mL). The resulting mixture is extracted with EtOAc three times. The combined organic phase is washed with brine three times, dried overanhydrous Na2SC>4, filtered and concentrated to give a crude product which is purified by flash silica gel chromatography (eluent of 0-6% ethyl acetate / petroleum ether gradient) to give the title compound 5-isopropoxy-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazolo[1 ,5- a]pyridine 311 as a white solid.

[0655] 1H NMR (400 MHz, methanol-d4) 6 = 8.40 (d, J = 7.6 Hz, 1 H), 8.02 (s, 1 H), 7.20 (d, J = 2.4 Hz, 1 H), 6.62 (dd, J = 2.4, 7.6 Hz, 1 H), 4.69 (td, J = 6.0, 12.0 Hz, 1 H), 1 .39 (d, J = 6.0 Hz, 6H), 1.36 (s, 12H).

[0656] Step B: A mixture of 5-isopropoxy-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyrazolo[1 ,5-a]pyridine 311 (30 mg, 99.3 pmol), tert-butyl 3-(6-bromo-4-chloropyridin-2- yl)piperidine-1-carboxylate 312 (41 mg, 109.2 pmol), Pd(dppf)Cl2’CH2Cl2 (16 mg, 19.9 pmol), and CS2CC>3 (38 mg, 119.1 pmol) in dioxane (1 mL) and H2O (0.2 mL) is purged with N2three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is concentrated under vacuum to give a crude product which is purified by flash silica gel chromatography (eluent of 0-9% ethyl acetate / petroleum ether gradient) to yield the title compound tert-butyl 3- [4-chloro-6-(5-isopropoxypyrazolo[1 ,5-a]pyridin-3-yl)-2-pyridyl]piperidine- 1 -carboxylate 313 as brown oil. LCMS (ESI MS) m / z = 471.2 [M + H]+1.

[0657] Step C: To a solution of tert-butyl 3-[4-chloro-6-(5-isopropoxypyrazolo[1 ,5- a]pyridin-3-yl)-2-pyridyl]piperidine-1 -carboxylate 313 (20 mg, 42.5 pmol) in H2O (0.5 mL) is added HCI (12 M, 466 pL). The mixture is stirred at 25 °C for 1 hr. The reaction mixture is concentrated under vacuum to give a crude product which is purified by prep-HPLC (column: Xtimate C18 150*40mm*10um; mobile phase: [water (HCI)-ACN]; gradient: 10%-50% B over 25 min) to yield the title compound 3-[4-chloro-6-(3-piperidyl)-2-pyridyl]-5-isopropoxy- pyrazolo[1 ,5-a]pyridine (Compound 65) as a white solid. LCMS (ESI MS) m / z = 371.2 [M + H]+1.

[0658] 1H NMR (400 MHz, methanol-d4) 6 = 8.50 - 8.42 (m, 2H), 7.87 (d, J = 2.8 Hz, 1 H), 7.75 (d, J = 1 .6 Hz, 1 H), 7.19 (d, J = 1 .6 Hz, 1 H), 6.70 (dd, J = 2.8, 7.6 Hz, 1 H), 4.82 - 4.78 (m, 1 H), 3.69 (br d, J = 11.2 Hz, 1 H), 3.50 (br d, J = 12.4 Hz, 1 H), 3.37 - 3.32 (m, 1 H), 3.28 - 3.22 (m, 1 H), 3.09 - 2.95 (m, 1 H), 2.34 - 2.22 (m, 1 H), 2.17 - 2.08 (m, 1 H), 2.06 - 1.92 (m, 2H), 1.46 (dd, J = 4.0, 6.0 Hz, 6H).

[0659] Example 665-chloro-3-[6-(3,3,5,5-tetramethylpiperazin-1-yl)-2-pyridyl]pyrazolo[1 ,5-a]pyridine

[0660] A mixture of 1-(6-bromopyridin-2-yl)-3,3,5,5-tetramethylpiperazine 314 (70 mg, 234.73 pmol), 5-chloro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazolo[1 ,5-a]pyridine 315 (130 mg, 469.5 pmol), Pd(dppf)Ch (19 mg, 23.4 pmol), and Cs2CC>3 (152 mg, 469.4 pmol) in dioxane (3 mL) and H2O (1 mL) is purged with N2 three times. The mixture is stirred at 80 °C for 2 hr under N2. The reaction mixture is diluted with H2O, and the mixture is extracted with EtOAc three times. The combined organic layer is dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue which is purified by prep-HPLC (column: Xtimate C18 150*40mm*10um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; gradient: 38%-78% B over 25 min) to yield the title compound 5-chloro-3-[6-(3,3,5,5-tetramethylpiperazin-1-yl)-2- pyridyl]pyrazolo[1 ,5-a]pyridine (Compound 66) (25 mg, 26%) as a white solid. LCMS (ESI MS) m / z = 370.2 [M + H]+1.

[0661] 1H NMR (400 MHz, methanol-d4) 6 = 8.67 (s, 1 H), 8.56 (br d, J = 7.13 Hz, 1 H), 8.47 (s, 1 H), 7.56 (br t, J = 7.88 Hz, 1 H), 7.08 (br d, J = 7.38 Hz, 1 H), 6.97 (br d, J = 6.88 Hz, 1 H), 6.65 (br d, J = 8.63 Hz, 1 H), 3.53 (s, 4H), 1.31 (s, 12H).

[0662] Example 672-(methylsulfonyl)- / V-(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl)acetamide320 Compound 67

[0663] Step A: To a mixture of 3-bromopyrazolo[1 ,5-a]pyridin-5-amine 316 (200.0 mg, 0.94 mmol) and 2-(methylsulfonyl)acetic acid 317 (143.3 mg, 1.04 mmol) in DMF (5.0 mL) is added HATLI (430.4 mg, 1.13 mmol) and DIPEA (487.6 mg, 3.77 mmol). The reaction mixture is stirred at room temperature for 1 hr. The reaction mixture is quenched with saturated NaCI solution and extracted with EtOAc. The combined organic phase is concentrated under reduced pressure, and the resulting residue is purified by column chromatography (silica gel, eluent of 0-30% ethyl acetate / petroleum ether gradient) to give the title compound / \ / -(3- bromopyrazolo[1 ,5-a]pyridin-5-yl)-2-(methylsulfonyl)acetamide 318 (165 mg, 53% yield) as a white solid. LCMS (ESI) m / z = 332 [M + H]+.

[0664] Step B: To a mixture of / V-(3-bromopyrazolo[1 ,5-a]pyridin-5-yl)-2-(methylsulfonyl)acetamide 318 (100.0 mg, 0.30 mmol) and tert-butyl 3-(6-(trimethylstannyl)pyridin-2-yl)piperidine-1-carboxylate 319 (256.5 mg, 0.60 mmol) in dioxane (2 mL) is added K3PO4 (127.8 mg, 0.60 mmol) and Xphos Pd G3 (50.9 mg, 0.06 mmol). The reaction mixture is stirred at 80 °C for 3 hrs under nitrogen. The reaction mixture is filtered and concentrated in vacuo. The residue is purified by column chromatography (silica gel, eluent of 0-20% ethyl acetate / petroleum ether gradient) to give the title compound tert-butyl 3-(6-(5-(2- (methylsulfonyl)acetamido)pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)piperidine-1 -carboxylate 320 (130.0 mg, 84% yield) as a yellow solid. LCMS (ESI) m / z = 514.3 [M + H]+.

[0665] Step C: To a solution of tert-butyl 3-(6-(5-(2-(methylsulfonyl)acetamido)pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)piperidine-1 -carboxylate 320 (140.0 mg, 0.27 mmol) in DCM (3.0 mL) is added HCI / dioxane (1.5 mL, 4M). The reactionmixture is stirred at room temperature for 1 hr under nitrogen. The reaction mixture is concentrated under reduced pressure. The residue is purified by prep-HPLC (YMC-ActusTriart C18, 20%-68% MeCN in water with 0.1% NH4OH) to give the title compound 2- (methylsulfonyl)- / \ / -(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl)acetamide (Compound 67) (39.1 mg, 35% yield) as a white solid. LCMS (ESI) m / z = 414.2 [M + H]+.

[0666] 1H NMR (400 MHz, DMSO-cfe) 6 = 11.58 (s, 1 H), 9.11 (s, 1 H), 8.71 (d, J = 7.5 Hz, 1 H), 8.66 (s, 1 H), 7.74 - 7.69 (m, 2H), 7.25 - 7.19 (m, 1 H), 7.06 (dd, J = 5.3, 3.2 Hz, 1 H), 4.42 (d, J = 2.5 Hz, 2H), 3.45 (d, J = 11.0 Hz, 2H), 3.28 - 3.19 (m, 3H), 3.12 - 2.97 (m, 3H), 2.12 - 1.64 (m, 5H).

[0667] Example 682-(methylsulfonamido)- / \ / -(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5- yl)acetamideComoound 68

[0668] Step A: To a mixture of / V-(3-bromopyrazolo[1 ,5-a]pyridin-5-yl)-2-(methylsulfonamido)acetamide 321 (60 mg, 0.17 mmol) and tert-butyl 3-(6-(trimethylstannyl)pyridin-2-yl)piperidine-1-carboxylate 322 (147.11 mg, 0.35 mmol) in dioxane (6.0 mL) is added K3PO4 (73.44 mg, 0.35 mmol) and Xphos Pd G3 (14.64 g, 0.017 mmol). The reaction mixture is stirred at room temperature at 80 °C for 2 hrs. The reaction mixture is poured into water and then extracted with ethyl acetate three times. The combined organic layers are washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue is purified by column chromatography (silica gel, eluent of 0-30% MeOH / DCM gradient) to give the title compound 3-(6-(5-(2- (methylsulfonamido)acetamido)pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)piperidine-1- carboxylate 323 (43 mg, 47.1% yield) as a white solid. LCMS (ESI) m / z = 529.2 [M + H]+.

[0669] Step B: A mixture of 3-(6-(5-(2-(methylsulfonamido)acetamido)pyrazolo[1 ,5- a]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate 323 (43.0 mg, 0.08 mmol) in HCI / 1 ,4- dioxane (1 mL, 4M) is stirred at 25 °C for 3 hrs. The reaction mixture is concentrated under reduced pressure. The residue is purified by prep-HPLC (YMC-ActusTriart C18, 5%-55% MeCN in water with 0.1% FA) to give the title compound 2-(methylsulfonamido)- / \ / -(3-(6- (piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl)acetamide (Compound 68) (20 mg, 57% yield) as a yellow oil. LCMS (ESI) m / z = 429.1 [M + H]+.

[0670] 1H NMR (400 MHz, CD3OD) 5 = 9.51 (d, J = 2.4 Hz, 1 H), 8.54 (s, 1 H), 8.47 - 8.37 (m, 2H), 7.72 - 7.65 (m, 1 H), 7.63 - 7.56 (m, 1 H), 7.06 (d, J = 7.6 Hz, 1 H), 6.78 (dd, J = 7.6, 2.4 Hz, 1 H), 4.02 (s, 2H), 3.90 (t, J = 12 Hz, 1 H), 3.64 (dd, J = 12.8, 3.6 Hz, 1 H), 3.54 - 3.40 (m, 2H), 3.27 - 3.14 (m, 1 H), 3.07 (s, 3H), 2.17 - 2.00 (m, 3H), 1.98 - 1.88 (m, 1 H).

[0671] Example 69(R)-3-(6-(3-methylpiperazin-1-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine formate327Compound 69

[0672] Step A: To a mixture of 2-bromo-6-fluoropyridine 324 (1 g, 5.68 mmol) in NMP (30 mL) is added tert-butyl (R)-2-methylpiperazine-1 -carboxylate 325 (1.14 g, 5.68 mmol) and K2CO3 (3.93 g, 28.41 mmol). The mixture is stirred at 100 °C for 16 hours. The reaction mixture is poured into water and then extracted with ethyl acetate twice. The combined organic layers are washed with brine, dried over anhydrous Na2SO4. The mixture is filtered and concentrated under reduced pressure to give a residue. The residue is purified by column chromatography (silica gel, eluent of 0-25% ethyl acetate / petroleum ether gradient) to afford the title compound tert-butyl (R)-4-(6-bromopyridin-2-yl)-2-methylpiperazine-1 -carboxylate 326 (1 g, 49%) as a yellow solid. LCMS (ESI) m / z = 356.09 [M + H]+.

[0673] Step B: To a stirred mixture of tert-butyl ( ?)-4-(6-bromopyridin-2-yl)-2- methylpiperazine-1 -carboxylate 326 (1 g, 2.81 mmol) in 1 ,4-dioxane (20 mL) is added Sn2Me6(0.76 mL, 3.65 mmol) and Pd(PPhs)4 (0.32 g, 0.28 mmol). The resulting mixture is stirred at 110°C for 2 hours. KF solution is added, and the mixture is stirred for 30 minutes. The mixture is filtered and concentrated under reduced pressure to give the title compound tert-butyl (F?)- 2-methyl-4-(6-(trimethylstannyl)pyridin-2-yl)piperazine-1-carboxylate 327 (1.53 g, crude) as a black oil which is used directly in the next step without further purification. LCMS (ESI) m / z = 442.14 [M + H]+.

[0674] Step C: To a mixture of tert-butyl (F?)-2-methyl-4-(6-(trimethylstannyl)pyridin-2- yl)piperazine-1-carboxylate 327 (1.53 g, 3.46 mmol) in 1 ,4-dioxane (60 mL) is added 3- bromopyrazolo[1 ,5-a] pyridine (432.2 mg, 2.19 mmol), K3PO4 (3.68 g, 17.32 mmol) and Xphos Pd G3 (0.29 g, 0.35 mmol). The resulting mixture is stirred at 80 °C for 2 hours under nitrogen. The reaction mixture is poured into water and then extracted with ethyl acetate three times. The combined organic layers are washed with brine, dried over anhydrous Na2SO4 , and the mixture is filtered and concentrated under reduced pressure to give a residue. The residue is purified by column chromatography (silica gel, eluent of 0-25% ethyl acetate / petroleum ether gradient) to afford the title compound tert-butyl (F?)-2-methyl-4-(6-(pyrazolo[1 ,5-a]pyridin-3- yl)pyridin-2-yl)piperazine-1 -carboxylate 328 (261 mg, 19%) as a yellow solid. LCMS (ESI) m / z = 394.22 [M + H]+.

[0675] Step D: A mixture of tert-butyl (F?)-2-methyl-4-(6-(pyrazolo[1 ,5-a]pyridin-3- yl)pvridin-2-yl)piperazine-1 -carboxylate 328 (261 mg, 0.66 mmol) in HCI / dioxane (3 mL, 4M) is stirred at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure to give a residue. The residue is purified by prep-HPLC (C18250*21.2 mm, 10 - 95% MeCN in water with 0.1 % FA) to give the title compound (F?)-3-(6-(3-methylpiperazin-1- yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine formate (Compound 69) (119.5 mg, 61% yield) as a white solid. LCMS (ESI) m / z = 294 [M + H]+.

[0676] 1H NMR (400 MHz, CD3OD) 5 = 8.60 (br s, 1 H), 8.53 - 8.46 (m, 1 H), 8.38 (s, 1 H), 8.29 (d, J = 8.8 Hz, 1 H), 7.61 - 7.51 (m, 1 H), 7.34 - 7.24 (m, 1 H), 7.10 (d, J = 7.6 Hz, 1 H), 6.94 - 6.85 (m, 1 H), 6.71 - 6.63 (m, 1 H), 4.47 - 4.35 (m, 2H), 3.51 (d, J = 11.2 Hz, 1 H), 3.47 - 3.37 (m, 1 H), 3.32 - 3.16 (m, 2H), 3.04 (dd, J = 13.6, 10.4 Hz, 1 H), 1.45 - 1.41 (m, 3H).

[0677] Example 70(S)-3-(6-(3-methylpiperazin-1-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine formateCompound 70

[0678] Step A: To a mixture of 2-bromo-6-fluoropyridine 329 (1 g, 5.68 mmol) in NMP (30 mL) is added tert-butyl (S)-2-methylpiperazine-1-carboxylate 330 (1.14 g, 5.68 mmol) and K2CO3 (3.93 g, 28.41 mmol). The mixture is stirred at 100 °C for 16 hours. The reaction mixture is poured into water and then extracted with ethyl acetate twice. The combined organic layers are washed with brine, dried over anhydrous Na2SC>4. The mixture is filtered and concentrated under reduced pressure to give a residue. The residue is purified by column chromatography (silica gel, eluent of 0-25% ethyl acetate / petroleum ether gradient) to afford the title compound tert-butyl (S)-4-(6-bromopyridin-2-yl)-2-methylpiperazine-1 -carboxylate 331 (1 g, 49%) as a yellow solid. LCMS (ESI) m / z = 356.09 [M + H]+.

[0679] Step B: To a stirred mixture of tert-butyl (S)-4-(6-bromopyridin-2-yl)-2- methylpiperazine-1 -carboxylate 331 (700 mg, 1.97 mmol) in 1 ,4-dioxane (15 mL) is added Sn2Me6 (0.5 mL, 2.40 mmol) and Pd(PPhs)4 (0.23 g, 0.20 mmol). The resulting mixture is stirred at 110°C for 2 hours. KF solution is added, and the mixture is stirred for 30 minutes. The mixture is filtered and concentrated under reduced pressure to give the title compound tert- butyl (S)-2-methyl-4-(6-(trimethylstannyl)pyridin-2-yl)piperazine-1 -carboxylate 332 (952.6 mg, crude) as a black oil which is used directly in the next step without further purification. LCMS (ESI) m / z = 442.14 [M + H]+.

[0680] Step C: To a stirred mixture of tert-butyl (S)-2-methyl-4-(6-(trimethylstannyl)pyridin- 2-yl)piperazine-1 -carboxylate 332 (952.6 mg, 2.16 mmol) in 1 ,4-dioxane (50 mL) is added 3- bromopyrazolo[1 ,5-a] pyridine (468 mg, 2.38 mmol), K3PO4 (2.29 g, 10.79 mmol) and Xphos Pd G3 (182.8 mg, 0.22 mmol). The resulting mixture is stirred at 80 °C for 2 hours under nitrogen. The reaction mixture is poured into water and then extracted with ethyl acetate threetimes. The combined organic layers are washed with brine, dried over anhydrous Na2SC>4 , and the mixture is filtered and concentrated under reduced pressure to give a residue. The residue is purified by column chromatography (silica gel, eluent of 0-25% ethyl acetate / petroleum ether gradient) to afford the title compound tert- butyl (S)-2-methyl-4-(6-(pyrazolo[1 ,5-a]pyridin-3- yl)pyridin-2-yl)piperazine-1 -carboxylate 333 (339 mg, 40%) as a yellow solid. LCMS (ESI) m / z = 393.22 [M + H]+.

[0681] Step D: A mixture of tert-butyl (S)-2-methyl-4-(6-(pyrazolo[1 ,5-a]pyridin-3- yl)pyridin-2-yl)piperazine-1 -carboxylate 333 (200 mg, 0.508 mmol) in HCI / dioxane (3 mL) is stirred at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by prep-HPLC (C18 / S-5um / 12nm, 10-95% MeCN in water with 0.1% FA) to give the title compound (S)-3-(6-(3-methylpiperazin-1-yl)pyridin-2- yl)pyrazolo[1 ,5-a]pyridine formate (Compound 70) (64.2 mg, 43% yield) as a white solid. LCMS (ESI) m / z = 294 [M + H]+.

[0682] 1H NMR (400 MHz, CD3OD) 5 = 8.58 (s, 1 H), 8.52 - 8.45 (m, 1 H), 8.39 - 8.33 (m, 1 H), 8.30 - 8.22 (m, 1 H), 7.59 - 7.49 (m, 1 H), 7.32 - 7.22 (m, 1 H), 7.12 - 7.04 (m, 1 H), 6.93 - 6.84 (m, 1 H), 6.70 - 6.62 (m, 1 H), 4.46 - 4.33 (m, 2H), 3.51 (dd, J= 12, 3.2 Hz, 1 H), 3.47 - 3.39 (m, 1 H), 3.36 - 3.16 (m, 2H), 3.10 - 2.99 (m, 1 H), 1.46 - 1.43 (m, 3H).

[0683] Example 715-chloro-3-(6-((3S,5F?)-3,4,5-trimethylpiperazin-1-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridineCompound 71

[0684] Step A: To a stirred mixture of 2-bromo-6-fluoropyridine 334 (1 g, 5.68 mmol) in DMF (25 mL) is added (2 ?,6S)-1 ,2,6-trimethylpiperazine 335 (0.73 g, 5.68 mmol) and K2CO3(3.93 g, 28.4 mmol). The resulting mixture is stirred at 1OO°C for 16 hours. The reaction mixture is poured into water and then extracted with ethyl acetate three times. The combined organic layers are washed with brine, dried over anhydrous Na2SO4, and the mixture is filtered and concentrated under reduced pressure to give a residue. The residue is purified by column chromatography (silica gel, eluent of 0-25% ethyl acetate / petroleum ether gradient) to afford the title compound (2S,6 ?)-4-(6-bromopyridin-2-yl)-1 ,2,6-trimethylpiperazine 336 (1.12 g, 69%) as a yellow solid. LCMS (ESI) m / z = 284.07 [M + H]+.

[0685] Step B: To a stirred mixture of (2S,6 ?)-4-(6-bromopyridin-2-yl)-1 ,2,6- trimethylpiperazine 336 (1.12 g, 3.94 mmol) in 1 ,4-dioxane (50 mL) is added Sn2Mee (1.68 g,5.12 mmol) and Pd(PPh3)4 (0.45 g, 0.39 mmol). The resulting mixture is stirred at 110 °C for 2 hours under nitrogen. KF solution is added, and the mixture is stirred for 30 minutes. The mixture is filtered and concentrated under reduced pressure to give the title compound (2S,6 ?)-1 ,2,6-trimethyl-4-(6-(trimethylstannyl)pyridin-2-yl)piperazine 337 (1.5 g, crude) as a black oil which is used directly in the next step without further purification. LCMS (ESI) m / z =370.12 [M + H]+.

[0686] Step C: To stirred mixture of (2S,6F?)-1 ,2,6-trimethyl-4-(6-(trimethylstannyl)pyridin- 2-yl)piperazine 337 (200 mg, 0.54 mmol) in 1 ,4-dioxane (5 mL) is added 3-bromo-5- chloropyrazolo[1 ,5-a]pyridine 338 (125.4 mg, 0.54 mmol), K3PO4 (575 mg, 2.71 mmol) and Xphos pd G3 (45.86 mg, 0.05 mmol). The resulting mixture is stirred at 80 °C for 2 hours. The reaction mixture is concentrated under reduced pressure to give a residue, and the residue is purified by prep-HPLC (C18 / S-5um / 12nm, 30-95% MeCN in water with 0.1% TFA) to give the title compound 5-chloro-3-(6-((3S,5 ?)-3,4,5-trimethylpiperazin-1-yl)pyridin-2-yl)pyrazolo[1 ,5- a]pyridine (Compound 71) (5.9 mg, 3% yield) as a yellow solid. LCMS (ESI) m / z = 356.16 [M + H]+.

[0687] 1H NMR (400 MHz, CD3OD) 5 = 8.57 (d, J = 7.2 Hz, 1 H), 8.55 - 8.47 (m, 2H), 7.72 - 7.62 (m, 1 H), 7.33 - 7.21 (m, 1 H), 7.01 - 6.88 (m, 1 H), 6.86 - 6.75 (m, 1 H), 4.65 - 4.60 (m, 2H), 3.53 - 3.50 (m, 2H), 3.18 - 3.06 (m, 2H), 3.01 - 2.97 (m, 2H), 1.59 - 1.43 (m, 7H).

[0688] Example 72 / V-(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl)picolinamide

[0689] Step A: To a mixture of 3-bromopyrazolo[1 ,5-a]pyridin-5-amine 339 (500 mg, 2.36 mmol) and picolinic acid 340 (348.3 mg, 2.83 mmol) in DMF (10.0 mL) is added HATLI (1075.9 mg, 2.83 mmol) and DI PEA (1219 mg, 9.43 mmol). The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into water and extracted with ethyl acetate three times. The combined organic phase is concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel, eluent of 0-30% ethyl acetate / petroleum ether gradient) to give the title compound / V-(3-bromopyrazolo[1 , 5-a]pyridin- 5-yl)picolinamide 341 (395 mg, 53% yield) as a white solid. LCMS (ESI) m / z = 317 [M + H]+.

[0690] Step B: To a mixture of / V-(3-bromopyrazolo[1 ,5-a]pyridin-5-yl)picolinamide 341 (80.0 mg, 0.25mmol) and tert-butyl 3-(6-(trimethylstannyl)pyridin-2-yl)piperidine-1-carboxylate 342 (128.69 mg, 0.30 mmol) in dioxane (4 mL) is added K3PO4 (267.71 mg, 1.26 mmol) and Xphos Pd G3 (21 .35 mg, 0.03 mmol). The reaction mixture is stirred at 80 °C for 5 hours under nitrogen. The mixture is concentrated under reduced pressure. The residue is purified by column chromatography (silica gel, eluent of 0-20% MeOH / DCM gradient) to give the title compound terf-butyl 3-(6-(5-(picolinamido)pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)piperidine-1- carboxylate 343 (50 mg, 40% yield) as a yellow solid. LCMS (ESI) m / z = 499.3 [M + H]+.

[0691] Step C: A mixture of terf-butyl 3-(6-(5-(picolinamido)pyrazolo[1 ,5-a]pyridin-3- yl)pyridin-2-yl)piperidine-1 -carboxylate 343 (50 mg, 0.10 mmol) in HCI / dioxane (2 mL, 4M) is stirred at room temperature for 1 hour under nitrogen. The reaction mixture is concentrated under reduced pressure. The residue is purified by prep-HPLC (YMC-ActusTriart C18, 20%- 68% MeCN in water with 0.1 % FA) to give the title compound A / -(3-(6-(piperidin-3-yl)pyridin-2- yl)pyrazolo[1 ,5-a]pyridin-5-yl)picolinamide (Compound 72) (2.6 mg, 6.5% yield) as a yellowsolid. LCMS (ESI) m / z = 399.4 [M + H]+.

[0692] 1H NMR (400 MHz, CD3OD) 5 = 9.90 (d, J = 2.0 Hz, 1 H), 8.76 (d, J = 4.4 Hz, 1 H), 8.59 - 8.52 (m, 2H), 8.50 (s, 1 H), 8.30 (d, J = 7.Q Hz, 1 H), 8.10 - 8.02 (m, 1 H), 7.77 - 7.71 (m, 1 H), 7.71 - 7.68 (m, 1 H), 7.67 - 7.61 (m, 1 H), 7.15 - 7.08 (m, 2H), 4.02 (t, J = 12.0 Hz, 1 H), 3.72 - 3.66 (m, 1 H), 3.66 - 3.58 (m, 1 H), 3.57 - 3.49 (m, 1 H), 3.29 - 3.23 (m, 1 H), 2.32 - 2.21 (m, 1 H), 2.20 - 2.10 (m, 2H), 2.03 - 1.91 (m, 1 H).

[0693] Example 73 / V-(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl)-2-(pyridin-2-yloxy)acetamide

[0694] Step A: To a mixture of tert-butyl 3-(6-(trimethylstannyl)pyridin-2-yl)piperidine-1- carboxylate 344 (79.6 mg, 0.19 mmol) in dioxane (2 mL) is added / V-(3-bromopyrazolo[1 ,5- a]pyridin-5-yl)-2-(pyridin-2-yloxy)acetamide 345 (50 mg, 0.14 mmol), XPhos Pd G3 (24.3 mg, 0.029 mmol) and K3PO4 (91.7 mg, 0.43 mmol). The resulting mixture is stirred at 80 °C for 2 hours under N2. The mixture is filtered and concentrated under reduced pressure to give a residue. The residue is purified by prep-TLC (DCM:MeOH = 10:1) to afford the title compound tert-butyl 3-(6-(5-(2-(pyridin-2-yloxy)acetamido)pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2- yl)piperidine-1 -carboxylate 346 (55 mg, 72% yield) as a yellow solid. LCMS (ESI MS) m / z = 529 [M + H]+.

[0695] Step B: A mixture of tert-butyl 3-(6-(5-(2-(pyridin-2-yloxy)acetamido)pyrazolo[1 ,5- a]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate 346 (55 mg, 0.10 mmol) in DCM (2 mL) and HCI / dioxane (3 mL) is stirred at room temperature for 0.5 hour. The reaction mixture is concentrated under reduced pressure to give a residue which is purified by prep-HPLC (C18 250*21 mm MeCN in water with 0.1% FA) to afford the title compound A / -(3-(6-(piperidin-3- yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl)-2-(pyridin-2-yloxy)acetamide (Compound 73) (9.4mg, 21 % yield) as a yellow solid. LCMS (ESI MS) m / z = 429 [M + H]+.

[0696] 1H NMR (400 MHz, CD3OD) 5 = 9.74 (d, J = 2.4 Hz, 1 H), 8.52 (d, J = 7.2 Hz, 1 H), 8.48 (d, J = 5.6 Hz, 7H), 7.72 - 7.67 (m, 2H), 7.67 -7.61 (m, 2H), 7.03 (dd, J = 7.2, 1.2 Hz, 1 H), 6.77 (dd, J = 7.6, 2.4 Hz, 1 H), 6.63 (d, J = 8.8 Hz, 1 H), 6.52 - 6.42 (m, 1 H), 5.00 (d, J = 16.0 Hz, 1 H), 4.90 (t, J = 10.0 Hz, 1 H), 3.72 (t, J = 12.0 Hz, 1 H), 3.39 (d, J = 10.4 Hz, 1 H), 3.12 (ddd, J = 11.6, 10.0, 3.6 Hz, 3H), 2.20 (d, J = 13.6 Hz, 1 H), 2.00 (d, J = 9.6 Hz, 1 H), 1.83 (d, J = 14.4 Hz, 2H).

[0697] Example 743-cyano- / V-(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl)propanamide

[0698] Step A: To a mixture of 3-bromopyrazolo[1 ,5-a]pyridin-5-amine 347 (300 mg, 1.42 mmol) and 3-cyanopropanoic acid 348 (140.2 mg, 1.42 mmol) in DMF (6.0 mL) is added HATLI (807.1 mg, 2.12 mmol) and DIPEA (731.5 mg, 5.66 mmol). The reaction mixture is stirred at 50 °C for 16 hours. The reaction mixture is poured into water and extracted with ethyl acetate three times. The combined organic layers are washed with brine, dried over anhydrous Na2SC>4, and the mixture is filtered and concentrated under reduced pressure to give a residue. The residue is purified by column chromatography (silica gel, eluent of 0-30% MeOH / DCM gradient) to give the title compound / V-(3-bromopyrazolo[1 ,5-a]pyridin-5-yl)-3- cyanopropanamide 349 (142 mg, 34% yield) as a solid. LCMS (ESI) m / z = 292.9 [M + H]+.

[0699] Step B: To a mixture of / V-(3-bromopyrazolo[1 ,5-a]pyridin-5-yl)-3- cyanopropanamide 349 (140 mg, 0.48 mmol) and tert-butyl 3-(6-(trimethylstannyl)pyridin-2- yl)piperidine-1-carboxylate 350 (243.7 mg, 0.57 mmol) in dioxane (5 mL) is added K3PO4 (506.9 mg, 2.39 mmol) and Xphos Pd G3 (40.4 mg, 0.05 mmol). The reaction mixture is stirredat 80 °C for 5 hours under nitrogen. The mixture is filtered and concentrated under reduced pressure. The residue is purified by column chromatography (silica gel, eluent of 0-20% MeOH / DCM gradient) to give the title compound tert-butyl 3-(6-(5-(3- cyanopropanamido)pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate 351 (37 mg, 16% yield) as a yellow solid. LCMS (ESI) m / z = 475.2 [M + H]+.

[0700] Step C: To a solution of tert-butyl 3-(6-(5-(3-cyanopropanamido)pyrazolo[1 ,5- a1pvridin-3-vl)pvridin-2-yl)piperidine-1-carboxvlate 351 (37 mg, 0.08 mmol) in DCM (1.0 mL) is added HCI / dioxane (1.0 mL, 4M). The reaction mixture is stirred at room temperature for 1 hour under nitrogen. The reaction mixture is concentrated under reduced pressure. The residue is purified by prep-HPLC (YMC-ActusTriart C18, 20%-68% MeCN in water with 0.1% TFA) to give the title compound 3-cyano- / V-(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5- a]pyridin-5-yl)propanamide (Compound 74) (8.3 mg, 28% yield) as a yellow solid. LCMS (ESI) m / z = 375.2 [M + H]+.

[0701] 1H NMR (400 MHz, CD3OD) 5 = 9.66 (d, J = 2.4 Hz, 1 H), 8.51 - 8.44 (m, 2H), 7.72 (t, J = 7.6 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.08 (d, J = 7.2 Hz, 1 H), 6.77 - 6.70 (m, 1 H), 3.91 (t, J = 12.0 Hz, 1 H), 3.65 - 3.53 (m, 2H), 3.51 - 3.41 (m, 1 H), 3.28 - 3.15 (m, 1 H), 2.90 - 2.84 (m, 2H), 2.84 - 2.78 (m, 2H), 2.30 - 2.15 (m, 1 H), 2.15 - 2.12 (m, 1 H), 2.12 - 2.04 (m, 1 H), 2.00 - 1.77 (m, 1 H).

[0702] Example 754-cyano- / V-(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl)butanamide

[0703] Step A: To a mixture of 3-bromopyrazolo[1 ,5-a]pyridin-5-amine 352 (400 mg, 1.40 mmol) and 4-cyanobutanoic acid 353 (158.7 mg, 1.40 mmol) in DMF (5.0 mL) is added HATLI (800.6 mg, 2.11 mmol) and DI PEA (1.08 mg, 8.42 mmol). The reaction mixture is stirred atroom temperature for 16 hours. The reaction mixture is poured into water and then extracted with ethyl acetate three times. The combined organic layers re washed with brine, dried over anhydrous Na2SC>4, and the mixture is filtered and concentrated under reduced pressure to give a residue. The residue is purified by column chromatography (silica gel, eluent of 0-30% MeOH / DCM gradient) to give the title compound / V-(3-bro...

Claims

What is claimed is:or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, wherein:R1is hydrogen, Ci-Ce alkyl, C3-C6 cycloalkyl, halogen, halo Ci-Ce alkyl, -OR6, cyano, -NR7R8, or -NHC(O)R9, whereinR6is hydrogen, Ci-Ce alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl Ci-Ce alkyl, 3-6 membered heterocyclyl, or 3-6 membered heterocyclyl Ci-Ce alkyl; each of R7and R8is independently hydrogen, Ci-Ce alkyl, or together with the nitrogen to which they are attached form a 3-8 membered monocyclic heterocyclyl group; andR9isCe-C aryl optionally substituted with Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, - OR9A, cyano, or -NR9BR9C, whereinR9Ais hydrogen or Ci-Ce alkyl, and each of R9Band R9Cis independently hydrogen or Ci-Ce alkyl;5- or 6-membered heteraryl comprising one nitrogen atom wherein the heteroaryl is optionally substituted with Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, -OR9A, cyano, or -NR9BR9C, orCi-Ce alkyl optionally substituted with halogen, -SO2CH3, cyano, 5- or 6-membered heteroaryl, -OR9D, or -NR9ER9F, whereinR9Dis hydrogen, Ci-Ce alkyl, or 5- or 6-membered heteroaryl comprising one nitrogen atom and optionally substituted with Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, -OR9A, cyano, or -NR9BR9C, and each of R9Eand R9Fis independently hydrogen, Ci-Ce alkyl, -SO2CH3, or 5- or 6-membered heteroaryl comprising one nitrogen atom;R2is hydrogen, -NHC(O)R10, or -C(O)NHR11, wherein each of R10and R11is independently hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3;R3is hydrogen or halogen;R4is hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy;R5is hydrogen or halogen; andQ is a 3-8 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom; the heterocyclyl group is optionally fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen, oxygen, or sulfur atoms and the remainder are carbons; the heterocyclyl group is optionally substituted with 1-4 R12groups, wherein each R12is independently Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy; and the heterocyclyl group is optionally substituted with one R13group, wherein R13is hydrogen, Ci-Ce alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or Ci-Ce alkyl, and R15is hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3.

2. A compound according to claim 1 , wherein R1is hydrogen.

3. A compound according to claim 1 , wherein R1is methyl.

4. A compound according to claim 1 , wherein R1is cyclopropyl.

5. A compound according to claim 1 , wherein R1is fluoro, chloro or bromo.

6. A compound according to claim 1 , wherein R1is trifluoromethyl.

7. A compound according to claim 1 , wherein R1is -OR6and R6is hydrogen.

8. A compound according to claim 1 , wherein R1is -OR6and R6is isopropyl.

9. A compound according to claim 1 , wherein R1is -OR6and R6is cyclopropyl methyl.

10. A compound according to claim 1 , wherein R1is -OR6and R6is methyloxetane.

11. A compound according to claim 1 , wherein R1is cyano.

12. A compound according to claim 1 , wherein R1is -NR7R8, and wherein each of R7and R8is independently hydrogen.

13. A compound according to claim 1 , wherein R1is -NR7R8, and wherein each of R7and R8is independently C1-C3 alkyl.

14. A compound according to claim 1 , wherein R1is -NR7R8, and wherein R7and R8together with the nitrogen to which they are attached form a 3-7 membered monocyclic heterocyclyl group.

15. A compound according to claim 1 , wherein R1is morpholine.

16. A compound according to claim 1 , wherein R1is -NHC(O)R9and R9is phenyl.

17. A compound according to claim 1 , wherein R1is -NHC(O)R9and R9is 5- or 6- membered heteroaryl.

18. A compound according to claim 17, wherein R9is 2-pyridyl.

19. A compound according to claim 1 , wherein R1is -NHC(O)R9and R9is C1-C3 alkyl substituted with -NHSO2CH3.

20. A compound according to claim 1 , wherein R1is -NHC(O)R9and R9is C1-C3 alkyl substituted with -SO2CH3.

21. A compound according to claim 1 , wherein R1is -NHC(O)R9and R9is C1-C3 alkyl substituted with cyano.

22. A compound according to claim 1 , wherein R1is -NHC(O)R9and R9is C1-C3 alkyl substituted with 5- or 6-membered heteroaryl.

23. A compound according to claim 22, wherein R9is 2-pyridyl methyl or 3-pyridyl methyl.

24. A compound according to claim 1 , wherein R1is -NHC(O)R9and R9is C1-C3 alkyl substituted with -OR9D, and wherein R9Dis hydrogen, Ci-Ce alkyl, or 5- or 6-membered heteroaryl.

25. A compound according to claim 24, wherein R9is methyl substituted with -OR9Dand R9Dis 5- or 6-membered heteroaryl.

26. A compound according to claim 25, wherein R9Dis pyridyl.

27. A compound according to claim 1 , wherein R1is -NHC(O)R9and R9is C1-C3 alkyl substituted with -NR9ER9F, wherein each of R9Eand R9Fis independently hydrogen, Ci-Ce alkyl, or 5- or 6-membered heteroaryl.

28. A compound according to claim 27, wherein R9is methyl substituted with -NR9ER9F, and wherein R9Eis hydrogen and R9Fis pyridyl.

29. A compound according to claim 27, wherein R9is methyl substituted with -NR9ER9F, and wherein R9Eis pyridyl and R9Fis hydrogen.

30. A compound according to any of claims 1-29, wherein R2is hydrogen.31 . A compound according to any of claims 1-29, wherein R2is -NHC(O)R10, and wherein R10is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

32. A compound according to any of claims 1-29, wherein R2is -C(O)NHR11, and wherein R11is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

33. A compound according to any of claims 1-32, wherein R3is hydrogen.

34. A compound according to any of claims 1-32, wherein R3is fluoro, chloro or bromo.

35. A compound according to any of claims 1-34, wherein R4is hydrogen.

36. A compound according to any of claims 1-34, wherein R4is fluoro, chloro or bromo.

37. A compound according to any of claims 1-34, wherein R4is C1-C3 alkoxy.

38. A compound according to any of claims 1-37, wherein R5is hydrogen.

39. A compound according to any of claims 1-37, wherein R5is fluoro, chloro or bromo.

40. A compound according to any of claims 1-39, wherein Q is a 3-7 membered heterocyclyl group including at least one nitrogen atom.

41. A compound according to any of claims 1-39, wherein Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen atoms and the remainder are carbons.

42. A compound according to any of claims 1-39, wherein Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one or two R12groups, wherein each R12is independently C1-C3 alkyl.

43. A compound according to any of claims 1-39, wherein Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one R13group, wherein R13is hydrogen, C1-C3 alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or C1-C3 alkyl, and R15is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

44. A compound according to any of claims 1-39, wherein Q is a 3-7 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom and is substituted with one or two R12groups and with one R13group, wherein each R12is independently C1-C3 alkyl; andR13is hydrogen, C1-C3 alkyl, -SO2R14, or -C(O)R15, wherein R14is hydrogen or Ci-Cs alkyl, and R15is hydrogen or C1-C3 alkyl substituted with -NHSO2CH3.

45. A compound of formula (II):(II) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, wherein:R1is fluoro, chloro, or bromo;R2is hydrogen, -NHC(O)R10, or -C(O)NHR11, wherein each of R10and R11is independently hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3;R3is hydrogen or halogen;R4is hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy;R5is hydrogen or halogen; andQ is a 3-8 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom; the heterocyclyl group is optionally fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen, oxygen or sulfur atoms and the remainder are carbons; the heterocyclyl group is optionally substituted with one to four R12groups, wherein each R12is independently Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy; and the heterocyclyl group is optionally substituted with one R13group, wherein R13is hydrogen, Ci-Ce alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or Ci-Ce alkyl, and R15is hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3.

46. A compound of formula (III):or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, wherein:R2is hydrogen, -NHC(O)R10, or -C(O)NHR11, wherein each of R10and R11is independently hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3;R3is hydrogen or halogen;R4is hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy;R5is hydrogen or halogen; andQ is a 3-8 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom;the heterocyclyl group is optionally fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen, oxygen or sulfur atoms and the remainder are carbons; the heterocyclyl group is optionally substituted with one to four R12groups, wherein each R12is independently Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy; and the heterocyclyl group is optionally substituted with one R13group, wherein R13is hydrogen, Ci-Ce alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or Ci-Ce alkyl, and R15is hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3.

47. A compound of formula (IV):or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, wherein:R2is hydrogen, -NHC(O)R10, or -C(O)NHR11, wherein each of R10and R11is independently hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3;R3is hydrogen or halogen;R4is hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy;R5is hydrogen or halogen;R6is hydrogen, Ci-Ce alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl Ci-Ce alkyl, 3-6 membered heterocyclyl, or 3-6 membered heterocyclyl Ci-Ce alkyl; andQ is a 3-8 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom; the heterocyclyl group is optionally fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen, oxygen or sulfur atoms and the remainder are carbons; the heterocyclyl group is optionally substituted with one to four R12groups, wherein each R12is independently Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy; and the heterocyclyl group is optionally substituted with one R13group, wherein R13is hydrogen, Ci-Ce alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or Ci-Ce alkyl, and R15is hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3.

48. A compound of formula (V):or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, wherein:R2is hydrogen, -NHC(O)R10, or -C(O)NHR11, wherein each of R10and R11is independently hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3;R3is hydrogen or halogen;R4is hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy;R5is hydrogen or halogen;R7and R8are independently hydrogen or Ci-Ce alkyl, or together with the nitrogen to which they are attached form a 3-8 membered monocyclic heterocyclyl group; andQ is a 3-8 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom; the heterocyclyl group is optionally fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen, oxygen or sulfur atoms and the remainder are carbons; the heterocyclyl group is optionally substituted with one to four R12groups, wherein each R12is independently Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy; and the heterocyclyl group is optionally substituted with one R13group, wherein R13is hydrogen, Ci-Ce alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or Ci-Ce alkyl, and R15is hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3.

49. A compound of formula (VI):or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, wherein:R2is hydrogen, -NHC(O)R10, or -C(O)NHR11, wherein each of R10and R11is independently hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3;R3is hydrogen or halogen;R4is hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy;R5is hydrogen or halogen;R9is Ce-C aryl, 5- or 6-membered heteroaryl, or Ci-Ce alkyl, wherein the Ce-Cw aryl is optionally substituted with Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, - OR9A, cyano, or -NR9BR9C, whereinR9Ais hydrogen or Ci-Ce alkyl, and each of R9Band R9Cis independently hydrogen or Ci-Ce alkyl; the 5- or 6-membered heteraryl comprises one nitrogen atom and is optionally substituted with Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, -OR9A, cyano, or -NR9BR9C, and the Ci-Ce alkyl is optionally substituted with halogen, -SO2CH3, cyano, 5- or 6- membered heteroaryl, -OR9D, or -NR9ER9F, whereinR9Dis hydrogen, Ci-Ce alkyl, or 5- or 6-membered heteroaryl comprising one nitrogen atom and optionally substituted with Ci-Ce alkyl, halogen, halo Ci- Ce alkyl, -OR9A, cyano, or -NR9BR9C, and each of R9Eand R9Fis independently hydrogen, Ci-Ce alkyl, -SO2CH3, or 5- or 6-membered heteroaryl comprising one nitrogen atom; andQ is a 3-8 membered heterocyclyl group, wherein the heterocyclyl group includes at least one nitrogen atom; the heterocyclyl group is optionally fused to a non-aromatic ring containing 3-6 ring members of which 1 or 2 are optionally nitrogen, oxygen or sulfur atoms and the remainder are carbons; the heterocyclyl group is optionally substituted with one to four R12groups, wherein each R12is independently Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy; and the heterocyclyl group is optionally substituted with one R13group, wherein R13is hydrogen, Ci-Ce alkyl, -SO2R14, or -C(O)R15, and wherein R14is hydrogen or Ci-Ce alkyl, and R15is hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3.

50. A compound according to any of claims 1-49, wherein Q is a group of the formula:wherein each v represents 0, 1 , 2, 3 or 4; each R12is independently hydrogen, Ci-Ce alkyl, halogen, halo Ci-Ce alkyl, or Ci-Ce alkoxy;R13is hydrogen, Ci-Ce alkyl, -SO2R14, or -C(O)R15, wherein R14is hydrogen or Ci-Ce alkyl, and R15is hydrogen or Ci-Ce alkyl substituted with -NHSO2CH3; andX is CR16or nitrogen, wherein R16is hydrogen or Ci-Ce alkyl.51 . A compound according to claim 1 , which is:3-(6-(piperidin-4-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;3-(6-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;3-(6-(pyrrolidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;5-chloro-3-(6-(pyrrolidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;Rac-5-chloro-3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;(+)-5-chloro-3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;(-)-5-chloro-3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;5-bromo-3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;5-methyl-3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;3-(6-(piperidin-3-yl)pyridin-2-yl)-5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine;5-methoxy-3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-ol;5-isopropoxy-3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;5-(cyclopropylmethoxy)-3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;5-(oxetan-3-ylmethoxy)-3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;4-(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl)morpholine;3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine-5-carbonitrile;5-cyclopropyl-3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-amine; / V-methyl-3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-amine; / V-ethyl-3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-amine;3-(methylsulfonamido)- / \ / -(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5- a]pyridin-5-yl)propanamide;3-(methylsulfonamido)- / \ / -(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5- a]pyridin-6-yl)propanamide; / V-(2-(methylsulfonamido)ethyl)-3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5- a] py ri di ne-6-carboxam i de ; / V-(2-oxo-2-(3-(6-(pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)piperidin-1- yl)ethyl)methanesulfonamide;3-(6-(1-(methylsulfonyl)piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;3-(4-methoxy-6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;3-(4-chloro-6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;3-(5-chloro-6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;3-(3-chloro-6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;3-(4-fluoro-6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;3-(3-fluoro-6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;3-(5-fluoro-6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;5-chloro-3-(4-chloro-6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;5-chloro-3-(4-fluoro-6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;3-(4-chloro-6-(piperidin-3-yl)pyridin-2-yl)-5-(trifluoromethyl)pyrazolo[1 ,5- a]pyridine;3-(6-(piperazin-1-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;N-methyl-3-(6-(piperazin-1-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-amine;3-(4-chloro-6-(piperazin-1-yl)pyridin-2-yl)- / \ / -methylpyrazolo[1 ,5-a]pyridin-5- amine;3-(6-(piperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine;3-(4-chloro-6-(piperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)pyrazolo[1 ,5- a]pyridine;5-chloro-3-(6-(piperazin-1-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;5-chloro-3-(4-chloro-6-(piperazin-1-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;5-chloro-3-(4-fluoro-6-(piperazin-1-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;3-(6-(pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane;3-(6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)-3,6- diazabicyclo[3.1 .1 ]heptane;3-(4-chloro-6-(5-chloropyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)-3,6- diazabicyclo[3.1 .1 ]heptane;2-(6-(pyrazolo[1 ,5-a]pyridin-3-yl)pyridin-2-yl)-2,5-diazabicyclo[2.2.2]octane;3-(6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;3-(6-((3R,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;3-(4-chloro-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)pyrazolo[1 ,5- a]pyridine;3-(6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-4-fluoropyridin-2-yl)pyrazolo[1 ,5- a]pyridine;3-(6-((3S,5R)-3,5-dimethylpiperazin-1 -yl)pyridin-2-yl)- / V-methylpyrazolo[1 ,5- a]pyridin-5-amine;3-(4-chloro-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)- / \ / - methylpyrazolo[1 ,5-a]pyridin-5-amine;3-(6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine;3-(4-chloro-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine;5-chloro-3-(6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)pyrazolo[1 ,5- a]pyridine;5-chloro-3-(6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-4-fluoropyridin-2- yl)pyrazolo[1 ,5-a]pyridine;5-chloro-3-(4-chloro-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)pyrazolo[1 ,5-a]pyridine;5-chloro-3-(5-chloro-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)pyrazolo[1 ,5-a]pyridine;5-chloro-3-(6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-5-fluoropyridin-2- yl)pyrazolo[1 ,5-a]pyridine;3-(4-chloro-6-(piperidin-3-yl)pyridin-2-yl)- / \ / -methylpyrazolo[1 ,5-a]pyridin-5- amine;5-chloro-3-(3-chloro-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2- yl)pyrazolo[1 ,5-a]pyridine;5-chloro-3-(6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-fluoropyridin-2- yl)pyrazolo[1 ,5-a]pyridine;3-(4-chloro-6-(piperidin-3-yl)pyridin-2-yl)-5-isopropoxypyrazolo[1 ,5-a]pyridine;5-chloro-3-(6-(3,3,5,5-tetramethylpiperazin-1-yl)pyridin-2-yl)pyrazolo[1 ,5- a]pyridine;2-(methylsulfonyl)- / V-(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5- yl)acetamide;2-(methylsulfonamido)- / \ / -(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5- a]pyridin-5-yl)acetamide;(R)-3-(6-(3-methylpiperazin-1-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;(S)-3-(6-(3-methylpiperazin-1-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridine;5-chloro-3-(6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridin-2-yl)pyrazolo[1 ,5- a]pyridine; / V-(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl)picolinamide;A / -(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl)-2-(pyridin-2- yloxy)acetamide;3-cyano- / V-(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5- yl)propanamide;4-cyano- / V-(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5- yl)butanamide;A / -(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl)-2-(pyridin-4- yloxy)acetamide;2-cyano- / V-(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5- yl)acetamide;A / -(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl)-2-(pyridin-3- yl)acetamide;A / -(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl)-2-(pyridin-4- ylamino)acetamide;A / -(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl)-2-(pyridin-3- ylamino)acetamide;A / -(3-(6-(piperidin-3-yl)pyridin-2-yl)pyrazolo[1 ,5-a]pyridin-5-yl)-2-(pyridin-2- yl)acetamide; or a pharmaceutically acceptable salt thereof.

52. A pharmaceutical composition comprising a compound or salt according to any of claims 1-51 together with a pharmaceutically acceptable carrier, excipient, or diluent.

53. A method of treating a disease or disorder associated with LRRK2 kinase activity, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-51 or a pharmaceutical composition of claim 52.

54. The method of claim 53, wherein the disease or disorder is Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, ischemic stroke, traumatic brain injury, or spinal cord injury.

55. A method of inhibiting LRRK2 kinase activity, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-51 or a pharmaceutical composition of claim 52.

56. A method of treating Parkinson’s disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-51 or a pharmaceutical composition of claim 52.

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