Substituted pyrazolo-pyridine amides and their use as glun2b receptor modulators

Abstract

Substituted pyrazolo-pyridines as GluN2B receptor ligands. Such compounds can be used in modulating GluN2B receptors and in pharmaceutical compositions and methods for treating disease states, disorders, and conditions mediated by GluN2B receptor activity.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 62 / 861,656, filed June 14, 2019, and Argentine Patent Application No. P 20 01 01623, filed June 9, 2020, the contents of each of which are incorporated herein by reference in their entirety.

[0002] FIELD OF THE INVENTION The present invention relates to compounds having GluN2B modulating properties, pharmaceutical compositions containing these compounds, chemical processes for preparing these compounds, and their use in the treatment of diseases associated with GluN2B receptor activity in animals, particularly humans. [Background technology]

[0003] Glutamate is one of the major excitatory neurotransmitters widely distributed in the brain. Its role as an excitatory messenger was first demonstrated in the 1950s, when intravenous administration of glutamate was observed to induce seizures. However, it was not until the 1970s and 1980s, when numerous antagonists were developed or identified as antagonists, as in the cases of PCP and ketamine, that the entire glutamatergic neurotransmitter system, along with its various receptors, was identified. Finally, in the 1990s, molecular biology provided the tools to classify glutamatergic receptors.

[0004] N-methyl-D-aspartate (NMDA) receptors are a subtype of ionotropic glutamate receptors that mediate excitatory synaptic transmission in the brain. NMDA receptors are ubiquitously distributed throughout the brain and play important roles in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition, and learning. NMDA receptors are involved in the regulation of Mg at resting membrane potentials. 2+ blocked by and highly Ca 2+They differ from the other major subtypes of ionotropic glutamate receptors (AMPA and kainate receptors) in that they are permeable to NMDA receptors and require simultaneous activation by two different neurotransmitters: glutamate and glycine (or D-serine) (Traynelis SF et al., Pharmacol Rev. 2010;62(3):405-96). 2+ The influx of ATP induces signaling cascades that regulate gene expression critical for different forms of synaptic plasticity, including both long-term potentiation (LTP) (Berberich S et al., Neuropharmacology 2007;52(1):77-86) and long-term depression (LTD) (Massey, PV et al., J Neurosci. 2004 Sep 8;24(36):7821-8).

[0005] Most mammalian NMDA receptors form heterotetramers composed of two essential GluN1 units and two variable GluN2 receptor subunits (encoded by the GRIN1 gene and one of four GRIN2 genes, respectively). One or both GluN2 subunits can potentially be replaced with a GluN3A or GluN3B subunit. While the GRIN1 gene product has eight splice variants, there are four distinct GRIN2 genes (GRIN2A-D) that encode four distinct GluN2 subunits. The glycine-binding site is located on the GluN1 subunit, and the glutamate-binding site is located on the GluN2 subunit.

[0006] The GluNR2 subunit plays a key role in determining the functional and pharmacological properties of NMDA receptor assemblies and exhibits specific distribution in different brain regions. For example, the GluN2B subunit is primarily expressed in the forebrain of adult mammalian brains (Paoletti P et al., Nat Rev Neurosci. 2013;14(6):383-400; Watanabe M et al., J Comp Neurol. 1993;338(3):377-90) and is involved in learning, memory processing, mood, attention, emotion, and pain perception (Cull-Candy S et al., Curr Opin Neurobiol. 2001;11(3):327-35).

[0007] Compounds that modulate GluN2B-containing NMDA receptor function have been shown to be effective in treating bipolar disorder (Martucci L et al., Schizophrenia Res, 2006;84(2-3):214-21), major depressive disorder (Miller OH et al., eLife. 2014;3:e03581; Li N et al., Biol Psychiatry. 2011;69(8):754-61), treatment-resistant depression (Preskorn SH et al. J Clin Psychopharmacol. 2008;28(6):631-7), and other mood disorders (schizophrenia (Grimwood S et al., Neuroreport. 1999;10(3):461-5; Weickert CS et al. Molecular Psychiatry (2013) 18, 1185-1192), prepartum and postpartum depression, seasonal affective disorder, etc.), Alzheimer's disease (Hanson JE et al., Neurobiol Dis. 2015; 74:254-62; Li S et al., J Neurosci. 2011; 31(18):6627-38) and other cognitive (Orgogozo JM et al. Stroke 2002, 33:1834-1839), Parkinson's disease (Duty S, CNS Drugs. 2012; 26(12):1017-32; Steece-Collier K et al., Exp Neurol. 2000; 163(1):239-43; Leaver KR et al. Clin Exp Pharmacol Physiol.2008;35(11):1388-94), Huntington's chorea (Tang TS et al.,Proc Natl Acad Sci USA.2005;102(7):2602-7;Li L et al.,J Neurophysiol.2004;92(5):2738-46), multiple sclerosis (Grasselli G et al.,Br J Pharmacol.2013;168(2):502-17;Farjam M et al.,Iran J Pharm Res.2014;13(2):695-705), cognitive impairment (Wang D et al.2014, Expert Opin Ther Targets Expert Opin Ther Targets.2014;18(10):1121-30), head trauma (Bullock MR et al., Ann NY Acad Sci.1999;890:51-8), spinal cord injury, stroke (Yang Y et al., J Neurosurg.2003;98(2):397-403), epilepsy (Naspolini AP et al., Epilepsy Res.2012 Jun;100:1-2):12-9), movement disorders (e.g., dyskinesia) (Morissette M et al., Mov Disord.2006;21(1):9-17), various neurodegenerative diseases (e.g., amyotrophic lateral sclerosis (Fuller PI et al., Neurosci Lett. 2006;399:1-2):157-61), or neurodegeneration associated with bacterial or chronic infection), glaucoma (Naskar R et al. Semin Ophthalmol. 1999 Sep;14(3):152-8), pain (e.g., chronic, cancer, post-operative and neuropathic pain (Wu LJ and Zhuo M, Neurotherapeutics. 2009;6(4):693-702), diabetic neuropathy, migraine (Peeters M et al., J Pharmacol Exp Ther. 2007;321(2):564-72), cerebral ischemia (Yuan H et al., Neuron. 2015;85(6):1305-18), encephalitis (Dalmau J. et al., Lancet Neurol. 2008;7(12):1091-8), autism and autism spectrum disorders (Won H. et al., Nature. 2012;486(7402):261-5), memory and learning disorders (Tang, YPet al., Nature. 1999;401(6748):63-9), obsessive-compulsive consolidation disorder (Arnold PD et al., Psychiatry Res. 2009;172(2):136-9), attention deficit hyperactivity disorder (ADHD) (Dorval KM et al., Genes Brain Behav. 2007;6(5):444-52), PTSD (Haller J et al., Behav Pharmacol.2011;22(2):113-21; Leaderbrand K et al. Neurobiol Learn Mem. 2014;113:35-40), tinnitus (Guitton MJ, and Dudai Y, Neural Plast. 2007;80904; Hu SS et al. 2016;273(2):325-332), sleep disorders (narcolepsy or excessive daytime sleepiness, WO 2009058261(A1)), dizziness and nystagmus (Straube A. et al., Curr Opin Neurol. 2005;18(1):11-4; Starck M et al. J Neurol. 1997 Jan;244(1):9-16), anxiety and autoimmune diseases such as neuropsychiatric systemic lupus erythematosus (Kowal C et al. al. Proc. Natl. Acad. SCi. USA 2006;103,19854-19859) and addictions (e.g., alcoholism, drug addiction) (Nagy J, 2004, Curr Drug Targets CNS Neurol Disord. 2004;3(3):169-79; Shen H et al., Proc Natl Acad Sci USA. 2011;108(48):19407-12). Summary of the Invention [Problem to be solved by the invention]

[0008] Given the clinical importance of GluN2B, the identification of compounds that modulate GluN2B receptor function represents an attractive avenue in the development of new therapeutic agents. Such compounds are provided herein. [Means for solving the problem]

[0009] The present invention is directed to general and preferred embodiments as defined respectively by the independent and dependent claims appended hereto, which are incorporated herein by reference. One aspect of the present invention is a compound of formula (I):

[0010] [ka] (In the formula, R 1 is H, halo, or CH3; Ar 1 teeth, (a) Halo, C 1-6 Alkyl, OC 1-6 Alkyl, C 1-6 Perhaloalkyl, OC 1-6 Perhaloalkyl, CN, and C 3-6 phenyl substituted with one member selected from the group consisting of cycloalkyl; (b) Halo, C 1-6 Alkyl, C 1-6 Perhaloalkyl, OC 1-6 Alkyl, OC 1-6 phenyl substituted with two or three members each independently selected from the group consisting of perhaloalkyl, and (C=O)CH3; and (c) Haro, C 1-6 Alkyl, and C 1-6 Thienyl substituted with one or two members selected from perhaloalkyl, and pyridine substituted with CF3. is selected from the group consisting of R 2 teeth, (d)

[0011] [ka] (In the formula, R a H, halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, CH2OH, CH(OH)(CH3), CH2OCH3, OC 1~6 Haloalkyl, OC 1~6alkyl, NH(CH3), NHCO2CH3, NHC(=O)CH3, NHC(=O)CF3, NHC(=O)cyclopropyl, N(CH3)C(=O)CH3, C(=O)N(CH3)2, C(=O)CH3, CN, NHSO2CH3, SO2CH3, 1H-imidazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidin-4-yl, and pyrrolidin-2-one, or two R a The members combine to form C 3~6 forming a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one or two F members; (e)

[0012] [ka] (In the formula, R b are each independently selected from the group consisting of H, OH, F, OCH3, CH2OCH3, and NHC(=O)CH3; or two R b The members together form =O. ); (f)

[0013] [ka] and, (g)

[0014] [ka] (In the formula, R d is C 1~6 Alkyl, C 2~6 Alkenyl C 1~6 Haloalkyl, CH2CH2OCH3, CH2CH2OH, CH2CN, NH2, NH-C(=O)CH3, C 3~6 Cycloalkyl, C substituted with two F members 3~6 selected from the group consisting of alkenyl, 1-methylazetidin-3-yl, and oxetan-3-yl; R e is H or CH3. selected from the group consisting of: n is 1 or 2; m is 1 or 2; as well as pharmaceutically acceptable salts, stereoisomers, isotopic variants, N-oxides, or solvates of compounds of formula (I).

[0015] Pharmaceutically acceptable salts of compounds of formula (I), pharmaceutically acceptable prodrugs of compounds of formula (I), and pharmaceutically active metabolites of compounds of formula (I) provide further embodiments.

[0016] In certain embodiments, the compound of formula (I) is a compound selected from the species described or exemplified in the Detailed Description below.

[0017] In a further aspect, the present invention relates to the enantiomers and diastereomers of the compounds of formula (I) and to pharmaceutically acceptable salts thereof.

[0018] In a further aspect, the present invention relates to a pharmaceutical composition for treating a disease, disorder, or medical condition mediated by GluN2B receptor activity, comprising an effective amount of at least one compound selected from a compound of formula (I), a pharmaceutically acceptable salt of a compound of formula (I), a pharmaceutically acceptable prodrug of a compound of formula (I), and a pharmaceutically active metabolite of formula (I).

[0019] Pharmaceutical compositions according to the invention may further comprise one or more pharmaceutically acceptable excipients.

[0020] In another aspect, chemical embodiments of the present invention are useful as GluN2B receptor modulators. Accordingly, the present invention is directed to a method for modulating GluN2B receptor activity, comprising exposing the GluN2B receptor, when present in a subject, to an effective amount of at least one compound selected from a compound of Formula (I), a pharmaceutically acceptable salt of a compound of Formula (I), a pharmaceutically acceptable prodrug of a compound of Formula (I), and a pharmaceutically active metabolite of a compound of Formula (I).

[0021] In another aspect, the present invention is directed to methods of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by GluN2B receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound selected from the compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically active metabolites of compounds of Formula (I). Further embodiments of the methods of treatment are described in the Detailed Description of the Invention.

[0022] In another embodiment, metabolic studies (preferably 14 C), reaction kinetics studies (e.g., 2 H or 3 H), detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)), including drug or substrate tissue distribution assays, or methods for testing isotopically labeled compounds in the radiotherapy of patients, for example: 18 F or 11 C-labeled compounds may be particularly preferred for PET or SPECT studies.

[0023] Further embodiments of the present invention include methods of preparing compounds of formula (I), pharmaceutically acceptable salts of compounds of formula (I), pharmaceutically acceptable prodrugs of compounds of formula (I), and pharmaceutically active metabolites of formula (I).

[0024] It is an object of the present invention to overcome or mitigate at least one of the disadvantages of conventional methodologies and / or the prior art, or to provide a useful alternative thereto.

[0025] Additional embodiments, features, and advantages of the invention will become apparent from the following detailed description as well as by practice of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0026] In one aspect, provided herein is a compound of formula (I):

[0027] [ka] (In the formula, R 1 is H, halo, or CH3; Ar 1 teeth, (a) Halo, C 1-6 Alkyl, OC 1-6 Alkyl, C 1-6 Perhaloalkyl, OC 1-6 Perhaloalkyl, CN, and C 3-6 phenyl substituted with one member selected from the group consisting of cycloalkyl; (b) Halo, C 1-6 Alkyl, C 1-6 Perhaloalkyl, OC 1-6 Alkyl, OC 1-6 phenyl substituted with two or three members each independently selected from the group consisting of perhaloalkyl, and (C=O)CH3; and (c) Haro, C 1-6 Alkyl, and C 1-6Thienyl substituted with one or two members selected from perhaloalkyl, and pyridine substituted with CF3. is selected from the group consisting of R 2 teeth: (d)

[0028] [ka] (In the formula, R a H, halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, CH2OH, CH(OH)(CH3), CH2OCH3, OC 1~6 Haloalkyl, OC 1~6 alkyl, NH(CH3), NHCO2CH3, NHC(=O)CH3, NHC(=O)CF3, NHC(=O)cyclopropyl, N(CH3)C(=O)CH3, C(=O)N(CH3)2, C(=O)CH3, CN, NHSO2CH3, SO2CH3, 1H-imidazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidin-4-yl, and pyrrolidin-2-one, or two R a The members combine to form C 3~6 forming a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one or two F members; (e)

[0029] [ka] (In the formula, R b are each independently selected from the group consisting of H, OH, F, OCH3, CH2OCH3, and NHC(=O)CH3; or two R b The members together form =O. ); (f)

[0030] [ka] and, (g)

[0031] [ka] (In the formula, R d is C 1~6 Alkyl, C 2~6 Alkenyl C 1~6 Haloalkyl, CH2CH2OCH3, CH2CH2OH, CH2CN, NH2, NH-C(=O)CH3, C 3~6 Cycloalkyl, C substituted with two F members 3~6 selected from the group consisting of alkenyl, 1-methylazetidin-3-yl, and oxetan-3-yl; R e is H or CH3. selected from the group consisting of: n is 1 or 2; m is 1 or 2. and pharmaceutically acceptable salts, stereoisomers, isotopic isomers, N-oxides, or solvates thereof.

[0032] A further embodiment of the present invention is 1 is H.

[0033] A further embodiment of the present invention is 1 is F.

[0034] A further embodiment of the present invention is 1 is CH3.

[0035] A further embodiment of the present invention is 1is phenyl substituted with one member selected from the group consisting of Cl, F, CH3, OCH3, CH2F, CHF2, CF3, CHF2CH3, OCHF2, CN, and cyclopropyl.

[0036] A further embodiment of the present invention is 1 but, is a compound of formula (I) selected from the group consisting of:

[0037] [ka]

[0038] A further embodiment of the present invention is 1 is phenyl substituted with two members each independently selected from the group consisting of Cl, F, CH, CHF, CF, CHFCH, OCH, OCHF, and (C=O)CH.

[0039] A further embodiment of the present invention is 1 but,

[0040] [ka] is a compound of formula (I) selected from the group consisting of:

[0041] A further embodiment of the present invention is 1 is phenyl substituted with three members each independently selected from the group consisting of halo and CH3.

[0042] A further embodiment of the present invention is 1 but,

[0043] [ka] is a compound of formula (I) selected from the group consisting of:

[0044] A further embodiment of the present invention is 1 is thienyl independently substituted with one or two members selected from Cl, CH3, CF3, and CHF2.

[0045] A further embodiment of the present invention is 1 but,

[0046] [ka] is a compound of formula (I) selected from the group consisting of:

[0047] A further embodiment of the present invention is 1 but,

[0048] [ka] is a compound of formula (I) selected from the group consisting of:

[0049] A further embodiment of the present invention comprises: R 2 but,

[0050] [ka] (In the formula, Ra is H, Cl, F, OH, CH3, CH2CH3, CH2F, CHF2, CF3, =CH2, CH=CH2, CH=CH(CH3), CH=CH(F), CH=CF(F), C =each independently selected from the group consisting of CH, CH2OH, CH(OH)(CH3), CHOCH3, OCHF2, OCF3, OCH3, OCH2CH3, NH(CH3), NHCO2CH3, NHC(=O)CH3, NHC(=O)CF3, NHC(=O)cyclopropyl, N(CH3)C(=O)CH3, C(=O)N(CH3)2, C(=O)CH3, CN, NHSO2CH3, SO2CH3, 1H-imidazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidin-4-yl, and pyrrolidin-2-one, or two R a the members join to form cyclopropyl, cyclobutyl, or oxetanyl; cyclopropyl is optionally substituted with one or two F members; n is 1 or 2. is a compound of formula (I)

[0051] A further embodiment of the present invention is 2 but,

[0052] [ka] is a compound of formula (I) selected from the group consisting of:

[0053] A further embodiment of the present invention is 2 but,

[0054] [ka] is a compound of formula (I) selected from the group consisting of:

[0055] A further embodiment of the present invention is 2 but,

[0056] [ka] is a compound of formula (I) selected from the group consisting of:

[0057] A further embodiment of the present invention is2 but,

[0058] [ka] is a compound of formula (I) selected from the group consisting of:

[0059] A further embodiment of the present invention is 2 but,

[0060] [ka] is a compound of formula (I) selected from the group consisting of:

[0061] A further embodiment of the present invention is 2 but,

[0062] [ka]

[0063] A further embodiment of the present invention is 2 but,

[0064] [ka] is a compound of formula (I) selected from the group consisting of:

[0065] A further embodiment of the present invention is 2 but,

[0066] [ka] is a compound of formula (I) selected from the group consisting of:

[0067] A further embodiment of the invention are compounds of formula (I) wherein n is 1.

[0068] A further embodiment of the invention are compounds of formula (I) wherein n is 2.

[0069] A further embodiment of the invention are compounds of formula (I) wherein n is 1.

[0070] A further embodiment of the invention are compounds of formula (I) wherein n is 2.

[0071] A further embodiment of the present invention is a compound of formula (IA):

[0072] [ka] (In the formula, R 1 is H, F, or CH3; Ar 1 but, (a) Halo, C 1-6 Alkyl, OC 1-6 Alkyl, C 1-6 Perhaloalkyl, OC 1-6 Perhaloalkyl, CN, and C 3-6 phenyl substituted with one member selected from the group consisting of cycloalkyl; (b) Halo, C 1-6 Alkyl, C 1-6 Perhaloalkyl, OC 1-6 Alkyl, OC 1-6 phenyl substituted with two or three members each independently selected from the group consisting of perhaloalkyl, and (C=O)CH3; and (c) Haro, C 1-6 Alkyl, and C 1-6 Thienyl substituted with one or two members selected from perhaloalkyl, and pyridine substituted with CF3. is selected from the group consisting of R a But, H, halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, CH2OH, CH(OH)(CH3), CH2OCH3, OC 1~6Haloalkyl, OC 1~6 alkyl, NH(CH3), NHCO2CH3, NHC(=O)CH3, NHC(=O)CF3, NHC(=O)cyclopropyl, N(CH3)C(=O)CH3, C(=O)N(CH3)2, C(=O)CH3, CN, NHSO2CH3, SO2CH3, 1H-imidazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidin-4-yl, and pyrrolidin-2-one, or two R a The members are combined to form C 3~6 forming a cycloalkyl or heterocycloalkyl, C 3~6 cycloalkyl and heterocycloalkyl are optionally substituted with one or two F members; n is 1 or 2. The compound of formula (I) has the structure:

[0073] A further embodiment of the present invention is a compound comprising: R 1 is H, F, or CH3; Ar 1 But, Halo, C 1~4 Alkyl, C 1~4 Perhaloalkyl, OC 1~4 Alkyl and OC 1~4 phenyl substituted with two or three members each independently selected from the group consisting of perhaloalkyl; R a is H, Cl, F, OH, CH3, CH2CH3, CH2F, CHF2, CF3, =CH2, CH=CH2, CH=CH(CH3), CH=CH(F), CH=CF(F), C = or two R are each independently selected from the group consisting of CH, CHOH, CH(OH)(CH), CHOCH, OCHF, OCF, OCH, OCHCH, NH(CH), NHCOCH, NHC(=O)CH, NHC(=O)CF, NHC(=O)cyclopropyl, N(CH)C(=O)CH, C(=O)CH, N,NHSOCH, 1H-imidazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidin-4-yl, and pyrrolidin-2-one; or two Ra the members join to form cyclopropyl, cyclobutyl, or oxetanyl; cyclopropyl is optionally substituted with one or two F members; Compounds of formula (IA) wherein n is 1 or 2.

[0074] A further embodiment of the present invention is a compound of formula (I) wherein R 1 is H.

[0075] A further embodiment of the present invention is a compound of formula (IB):

[0076] [ka] (In the formula, Ar 1 but, (a) Halo and C 1~6 phenyl substituted with one member each independently selected from the group consisting of perhaloalkyl; (b) Halo, C 1~6 Alkyl, C 1~6 Perhaloalkyl, OC 1~6 phenyl substituted with two or three members each independently selected from the group consisting of perhaloalkyl; and (c) Haro, C 1~6 Alkyl, and C 1~6 thienyl independently substituted with one or two members selected from perhaloalkyl; and pyridine substituted with CF3. is selected from the group consisting of ring

[0077] [ka] but,

[0078] [ka] Selected from the group consisting of: R bare each independently selected from the group consisting of H, OH, F, OCH3, CH2OCH3, and NHC(=O)CH3; or two R b The members together form =O; n is 1 or 2; m is 1 or 2. is a compound of formula (I) having the formula:

[0079] A further embodiment of the present invention is a compound of the formula

[0080] [ka] but,

[0081] [ka] is a compound of formula (IB),

[0082] A further embodiment of the present invention is a compound of formula (IC):

[0083] [ka] (In the formula, R 1 is H, F, or CH3; Ar 1 but, (a) Halo and C 1-6 phenyl substituted with one member each independently selected from the group consisting of perhaloalkyl; (b) Halo, C 1-6 Alkyl, C 1-6 Perhaloalkyl, OC 1-6 phenyl substituted with two or three members each independently selected from the group consisting of perhaloalkyl; and (c) Haro, C 1-6 Alkyl, and C 1-6 Thienyl substituted with one or two members selected from perhaloalkyl, and pyridine substituted with CF3. is selected from the group consisting of R d But C 1~6 Alkyl, CH2CH=CH2, C 1~6 selected from the group consisting of haloalkyl, CH2CH2OCH3, CH2CH2OH, CH2CN, NH2, NH—C(═O)CH3, cyclopropyl, cyclobutyl, 3-bicyclo[1.1.1]pentanyl, 3,3-difluorocyclobutyl, 1-methylazetidin-3-yl, and oxetan-3-yl; R e is H or CH3. is a compound of formula (I) having the formula:

[0084] A further embodiment of the present invention is 1 but,

[0085] [ka] is a compound of formula (IC)

[0086] A further embodiment of the present invention is as follows:

[0087] [Table 1-1]

[0088] [Table 1-2]

[0089] [Table 1-3]

[0090] [Table 1-4]

[0091] [Table 1-5]

[0092] [Table 1-6]

[0093] [Table 1-7]

[0094] [Table 1-8]

[0095] [Table 1-9]

[0096] [Table 1-10] and pharmaceutically acceptable salts, N-oxides, or solvates thereof.

[0097] A further embodiment of the present invention comprises: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-[4-chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 1-(Azetidin-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(Azetidin-1-yl)-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[4-chloro-3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; and 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoro-3-methyl-azetidin-1-yl)ethanone and pharmaceutically acceptable salts, solvates, stereoisomers, isotopic variants, or N-oxides thereof.

[0098] A further embodiment of the present invention comprises: (A) an effective amount of a compound of formula (I):

[0099] [ka] (In the formula, R 1 is H, halo, or CH3; Ar 1 teeth, (a) Halo, C 1-6 Alkyl, OC 1-6 Alkyl, C 1-6 Perhaloalkyl, OC 1-6 Perhaloalkyl, CN, and C 3-6 phenyl substituted with one member selected from the group consisting of cycloalkyl; (b) Halo, C 1-6 Alkyl, C 1-6Perhaloalkyl, OC 1-6 Alkyl, OC 1-6 phenyl substituted with two or three members each independently selected from the group consisting of perhaloalkyl, and (C=O)CH3; and (c) Haro, C 1-6 Alkyl, and C 1-6 Thienyl substituted with one or two members selected from perhaloalkyl, and pyridine substituted with CF3. is selected from the group consisting of R 2 teeth, (d)

[0100] [ka] (In the formula, R a H, halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, CH2OH, CH(OH)(CH3), CH2OCH3, OC 1~6 Haloalkyl, OC 1~6 alkyl, NH(CH3), NHCO2CH3, NHC(=O)CH3, NHC(=O)CF3, NHC(=O)cyclopropyl, N(CH3)C(=O)CH3, C(=O)N(CH3)2, C(=O)CH3, CN, NHSO2CH3, SO2CH3, 1H-imidazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidin-4-yl, and pyrrolidin-2-one, or two R a The members combine to form C 3~6 forming a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one or two F members; (e)

[0101] [ka] (In the formula, R b are each independently selected from the group consisting of H, OH, F, OCH3, CH2OCH3, and NHC(=O)CH3; or two R b The members together form =O. ); (f)

[0102] [ka] and, (g)

[0103] [ka] (In the formula, R d is C 1~6 Alkyl, C 2~6 Alkenyl C 1~6 Haloalkyl, CH2CH2OCH3, CH2CH2OH, CH2CN, NH2, NH-C(=O)CH3, C 3~6 Cycloalkyl, C substituted with two F members 3~6 selected from the group consisting of alkenyl, 1-methylazetidin-3-yl, and oxetan-3-yl; R e is H or CH3. selected from the group consisting of: n is 1 or 2; m is 1 or 2; and a pharmaceutically acceptable salt, stereoisomer, isotopic variant, N-oxide, or solvate of a compound of formula (I), (B) at least one pharmaceutically acceptable excipient.

[0104] A further embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one compound of formula (IA), as well as pharmaceutically acceptable salts, N-oxides, or solvates of compounds of formula (IA), pharmaceutically acceptable prodrugs of compounds of formula (IA), and pharmaceutically active metabolites of compounds of formula (IA), and at least one pharmaceutically acceptable excipient.

[0105] A further embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one compound of formula (IB), as well as pharmaceutically acceptable salts, N-oxides, or solvates of compounds of formula (IB), pharmaceutically acceptable prodrugs of compounds of formula (IB), and pharmaceutically active metabolites of formula (IB), and at least one pharmaceutically acceptable excipient.

[0106] A further embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one compound of formula (IC), as well as pharmaceutically acceptable salts, N-oxides, or solvates of compounds of formula (IC), pharmaceutically acceptable prodrugs of compounds of formula (IC), and pharmaceutically active metabolites of formula (IC), and at least one pharmaceutically acceptable excipient.

[0107] A further embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one compound of Table 1, and pharmaceutically acceptable salts, N-oxides, or solvates of the compounds of Table 1, pharmaceutically acceptable prodrugs of the compounds of Table 1, and pharmaceutically active metabolites of the compounds of Table 1, and at least one pharmaceutically acceptable excipient.

[0108] Also within the scope of the present invention are enantiomers and diastereomers of the compounds of formula (I) (and formulas (IA), (IB), and (IC)). Also within the scope of the present invention are pharmaceutically acceptable salts, N-oxides, or solvates of the compounds of formula (I) (and formulas (IA), (IB), and (IC)). Also within the scope of the present invention are pharmaceutically acceptable prodrugs of the compounds of formula (I) (and formulas (IA), (IB), and (IC)), and pharmaceutically active metabolites of the compounds of formula (I) (and formulas (IA), (IB), and (IC)).

[0109] Also within the scope of the present invention are isotopic variants of the compounds of formula (I) (and formulae (IA), (IB), and (IC)), such as deuterated compounds of formula (I). Also within the scope of the present invention are pharmaceutically acceptable salts, N-oxides, or solvates of isotopic variants of the compounds of formula (I) (and formulae (IA), (IB), and (IC)). Also within the scope of the present invention are pharmaceutically acceptable prodrugs of isotopic variants of the compounds of formula (I) (and formulae (IA), (IB), and (IC)), and pharmaceutically active metabolites of isotopic variants of the compounds of formula (I) (and formulae (IA), (IB), and (IC)).

[0110] A further embodiment of the present invention is a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by GluN2B receptor activity, comprising administering to a subject in need of such treatment an effective amount of a compound of formula (I):

[0111] [ka] (In the formula, R 1 is H, halo, or CH3; Ar 1 teeth, (a) Halo, C 1-6 Alkyl, OC 1-6 Alkyl, C 1-6 Perhaloalkyl, OC 1-6 Perhaloalkyl, CN, and C 3-6phenyl substituted with one member selected from the group consisting of cycloalkyl; (b) Halo, C 1-6 Alkyl, C 1-6 Perhaloalkyl, OC 1-6 Alkyl, OC 1-6 phenyl substituted with two or three members each independently selected from the group consisting of perhaloalkyl, and (C=O)CH3; and (c) Haro, C 1-6 Alkyl, and C 1-6 Thienyl substituted with one or two members selected from perhaloalkyl, and pyridine substituted with CF3. is selected from the group consisting of R 2 teeth: (d)

[0112] [ka] (In the formula, R a H, halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, CH2OH, CH(OH)(CH3), CH2OCH3, OC 1~6 Haloalkyl, OC 1~6 alkyl, NH(CH3), NHCO2CH3, NHC(=O)CH3, NHC(=O)CF3, NHC(=O)cyclopropyl, N(CH3)C(=O)CH3, C(=O)N(CH3)2, C(=O)CH3, CN, NHSO2CH3, SO2CH3, 1H-imidazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidin-4-yl, and pyrrolidin-2-one, or two R a The members combine to form C 3~6 forming a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one or two F members; (e)

[0113] [ka] (In the formula, R b are each independently selected from the group consisting of H, OH, F, OCH3, CH2OCH3, and NHC(=O)CH3; or two R b The members together form =O. ); (f)

[0114] [ka] and, (g)

[0115] [ka] (In the formula, R d is C 1~6 Alkyl, C 2~6 Alkenyl C 1~6 Haloalkyl, CH2CH2OCH3, CH2CH2OH, CH2CN, NH2, NH-C(=O)CH3, C 3~6 Cycloalkyl, C substituted with two F members 3~6 selected from the group consisting of alkenyl, 1-methylazetidin-3-yl, and oxetan-3-yl; R e is H or CH3. selected from the group consisting of: n is 1 or 2; m is 1 or 2. and a pharmaceutically acceptable salt, stereoisomer, isotopic variant, N-oxide, or solvate thereof.

[0116] A further embodiment of the present invention is a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by GluN2B receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound selected from the compounds of Formula (I) (and Formulas (IA), (IB), (IC), and (IC)), enantiomers and diastereomers of compounds of Formula (I), isotopic variants of compounds of Formula (I), and pharmaceutically acceptable salts of all of the foregoing.

[0117] In a preferred embodiment of the method of the present invention, the disease, disorder, or medical condition is selected from neurological and psychiatric disorders, including, but not limited to, (1) mood disorders and mood-affective disorders; (2) neurological stress-related and somatoform disorders, including anxiety disorders; (3) disorders of psychological development; (4) physiological disorders and behavioral syndromes related to physical factors; (5) extrapyramidal and movement disorders; (6) epilepsy and seizure disorders; (7) pain; (8) forms of neurodegeneration; (9) acute and chronic cerebrovascular diseases; and any sequelae of cerebrovascular diseases.

[0118] Examples of mood and mood-affective disorders that may be treated according to the present invention include, but are not limited to, depression, hypomania, mania, and mixed forms of bipolar I disorder; bipolar II disorder; depressive disorders, such as single depressive episode or recurrent major depressive disorder, minor depressive disorder, treatment-resistant depression, postpartum-onset depressive disorder, and depressive disorder with psychotic symptoms; cyclothymia, dysthymia, manic-depressive remission; and persistent mood disorders such as premenstrual dysphoric disorder.

[0119] Examples of disorders belonging to neurological, stress-related, and somatoform disorders that can be treated in accordance with the present invention include, but are not limited to, anxiety disorders, generalized anxiety disorder, panic disorder with or without agoraphobia, specific phobias, social anxiety disorder, chronic anxiety disorder; obsessive-compulsive disorder; reaction and adjustment disorders to severe stress such as post-traumatic stress disorder (PTSD); and other neurological disorders, such as depersonalization-derealization syndrome.

[0120] Examples of psychological developmental disorders that may be treated in accordance with the present invention include, but are not limited to, Asperger's syndrome and Rett's syndrome, autistic disorders associated with mental retardation and stereotypic movements, childhood autism, and pervasive developmental disorders, including, but not limited to, hyperactivity disorder, specific motor developmental disorders, and specific learning skill developmental disorders.

[0121] Examples of physiological disorders and behavioral syndromes associated with physical factors according to the present invention include, but are not limited to, childbirth-related mental and behavioral disorders, including, but not limited to, postnatal (postpartum) depression and prenatal depression; eating disorders, including, but not limited to, anorexia nervosa, bulimia nervosa, pica, and binge eating disorder.

[0122] Examples of extrapyramidal disorders and movement disorders that can be treated in accordance with the present invention include Parkinson's disease; secondary parkinsonism such as postencephalitic parkinsonism; parkinsonism encompassed by other disorders; Lewy body disease; degenerative diseases of the basal ganglia; tremor, essential tremor and drug-induced tremor, myoclonic, chorea and drug-induced chorea, drug-induced tics and organic tics, drug-induced acute dystonia, drug-induced tardive dyskinesia, and eldopa-induced dyskinesia. , other extrapyramidal disorders and movement disorders, including but not limited to; neuroleptic malignant syndrome (NMS), neuroleptic-induced parkinsonism, neuroleptic-induced early or acute dyskinesia, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia, neuroleptic-induced tremor; restless legs syndrome, stiff man syndrome.

[0123] Further examples of movement disorders involving dysfunction and / or degeneration of the basal ganglia that can be treated according to the present invention include, but are not limited to, dystonia, including but not limited to focal dystonia, multiple focal or segmental dystonia; torsion dystonia, hemispheric, generalized, and tardive dystonia (induced by psychopharmacological drugs). Focal dystonias include cervical dystonia (torticollis), blepharospasm (eyelid spasms), limb dystonia (limb spasms such as writer's cramp), oromandibular dystonia, and spasmodic dysphonia (vocal cord spasms).

[0124] Examples of incident and seizure disorders that may be treated according to the present invention include, but are not limited to, epilepsy, including localization-related (focal) (partial) idiopathic epilepsies and epilepsy syndromes with localized onset seizures, localization-related (focal) (partial) symptomatic epilepsies and epilepsy syndromes with simple partial seizures, localization-related (focal) (partial) symptomatic epilepsies and epilepsy syndromes with complex partial seizures, myoclonic epilepsy of infancy, neonatal convulsions (familial), childhood absence epilepsy (pycnolepsy), epilepsy with grand mal seizures on awakening, absence epilepsy, myoclonic epilepsy (petit mal impulse), and generalized idiopathic epilepsies and epilepsy syndromes including, but not limited to, nonspecific atonic, clonic, myoclonic, tonic, and tonic-clonic epileptic seizures.

[0125] Further examples of epilepsies that may be treated in accordance with the present invention include, but are not limited to, myoclonic absence epilepsy, myoclonic astatic epilepsy, infantile spasms, Lennox-Gastaut syndrome, Salam seizures, symptomatic early myoclonic encephalopathy, West syndrome, petit mal and grand mal seizures, and status epilepticus.

[0126] Examples of pain include, but are not limited to, pain disorders associated with psychological factors, such as persistent somatoform disorders; acute, chronic, and chronic intractable pain, headache; acute and chronic pain associated with physiological processes and physical illnesses, including, but not limited to, back pain, toothache, abdominal pain, lower back pain, and joint pain; acute and chronic pain associated with diseases of the musculoskeletal system and connective tissue, including, but not limited to, rheumatism, myalgia, neuralgia, and fibromyalgia; acute and chronic pain associated with nerve, nerve root, and plexus disorders (e.g., trigeminal neuralgia, postherpetic neuralgia, painful phantom limb syndrome, carpal tunnel syndrome, sciatic nerve lesions, diabetic mononeuropathy); and acute and chronic pain associated with polyneuropathies and other disorders of the peripheral nervous system (e.g., hereditary and idiopathic neuropathies, inflammatory polyneuropathies, polyneuropathies induced by drugs, alcohol, or toxic agents, polyneuropathy in neoplastic disease, diabetic polyneuropathy).

[0127] Examples of diseases involving forms of neurodegeneration include, but are not limited to, acute neurodegeneration, such as stroke, diffuse and focal brain injury, intracranial brain injury such as epidural hemorrhage, subdural hemorrhage, and subarachnoid hemorrhage, and chronic neurodegeneration, such as Alzheimer's disease, Huntington's disease, multiple sclerosis, and ALS.

[0128] Examples of cerebrovascular diseases include, but are not limited to, subarachnoid hemorrhage, intracerebral hemorrhage, and other non-traumatic intracranial hemorrhage, cerebral infarction, stroke, occlusion and stenosis (not resulting in cerebral infarction) of the anterior cerebral artery and cerebral arteries, cerebral artery dissection, cerebral aneurysm, cerebral arteriosclerosis, progressive vascular leukoencephalopathy, hypertensive encephalopathy, non-suppurative thrombosis of the intracranial venous system, cerebral arteritis, cerebral amyloid angiopathy, and sequelae of cerebrovascular disease.

[0129] In some embodiments, administration of a compound of the invention or a pharmaceutically acceptable salt thereof is effective in preventing a disease, e.g., the prevention of a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder, but who has not yet experienced or manifested the pathology or symptoms of the disease.

[0130] Additional embodiments, features, and advantages of the invention will become apparent from the following detailed description as well as by practice of the invention.

[0131] The present invention may be more fully understood by reference to the following description, including the following glossary and concluding examples. For purposes of brevity, the disclosures of publications, including patents, cited in this specification are hereby incorporated by reference.

[0132] As used herein, the terms "including," "containing," and "comprising" are used herein in their open, non-limiting sense.

[0133] The term "alkyl" refers to a straight- or branched-chain alkyl group having 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me, which may also be depicted structurally with the symbol " / "), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that would be considered equivalent to any one of the above examples in light of ordinary skill in the art and the teachings provided herein. As used herein, the term C 1~6 Alkyl refers to a straight- or branched-chain alkyl group having 1 to 4 carbon atoms in the chain. As used herein, the term C 1~6 Alkyl refers to a straight- or branched-chain alkyl group having 1 to 6 carbon atoms in the chain.

[0134] The term "halo" refers to chloro, fluoro, bromo or iodo.

[0135] The term "perhaloalkyl" or "haloalkyl" refers to a straight- or branched-chain alkyl group having 1 to 6 carbon atoms in the chain, optionally with a hydrogen replaced with a halogen. 1~3 "Perhaloalkyl" refers to a straight or branched chain alkyl group having 1 to 3 carbon atoms in the chain, optionally with hydrogens replaced with halogens. As used herein, the term "C 1~6"Perhaloalkyl" refers to a straight- or branched-chain alkyl group having 1 to 6 carbon atoms in the chain, optionally replacing a hydrogen with a halogen. Examples of "perhaloalkyl" or "haloalkyl" groups include trifluoromethyl (CF), difluoromethyl (CFH), monofluoromethyl (CHF), pentafluoroethyl (CFCF), tetrafluoroethyl (CHFCF), monofluoroethyl (CHCHF), trifluoroethyl (CHCF), tetrafluorotrifluoromethylethyl (-CF(CF)), chloropropyl (CHCHCHCl), and groups that would be considered equivalent to any one of the above examples in light of ordinary skill in the art and the teachings provided herein.

[0136] The term "alkoxy" includes straight or branched chain alkyl groups with a terminal oxygen connecting the alkyl group to the remainder of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, and the like.

[0137] The term "cyano" refers to the group --CN.

[0138] The term "aryl" refers to a monocyclic aromatic carbocycle (a ring structure in which the ring atoms are all carbon) having six atoms per ring. (The carbon atoms in an aryl group are sp 2 It is a hybrid.)

[0139] The term "phenyl" refers to the following moiety:

[0140] [ka]

[0141] The term "thienyl" refers to the following moiety:

[0142] [ka]

[0143] The term "heteroaryl" refers to a monocyclic or fused bicyclic heterocycle (a ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having 3 to 9 ring atoms per heterocycle. Illustrative examples of heteroaryl groups include the following entities, in the form of appropriately bonded moieties:

[0144] [ka] Examples include:

[0145] Those of ordinary skill in the art will understand that the heteroaryl, cycloalkyl, aryl, and heterocycloalkyl species listed or exemplified above are not exhaustive and that additional species may be selected within the scope of these defined terms.

[0146] "Heterocycloalkyl" refers to saturated or partially saturated monocyclic, bicyclic ring systems (fused or spirocyclic) having from 4 to 7 ring atoms per ring system selected from carbon atoms and up to two heteroatoms selected from nitrogen, oxygen, and sulfur. Such ring systems may optionally contain up to two oxo groups on the sulfur ring members. Exemplary entities in the form of appropriately bonded moieties include:

[0147] [ka] Examples include:

[0148] The term "cycloalkyl" refers to a saturated or partially saturated monocyclic, fused polycyclic, or spiropolycyclic carbocycle having 3 to 12 ring atoms per carbocycle. Illustrative cycloalkyl groups include the following entities in the form of appropriately bonded moieties:

[0149] [ka] Examples include:

[0150] The term "pyridinyl" or "pyridyl" refers to the moiety:

[0151] [ka]

[0152] The pyridinyl or pyridyl moiety can be attached via any one of the 2-, 3-, 4-, 5-, or 6-carbon atoms.

[0153] The term "pyrimidinyl" refers to the moiety:

[0154] [ka]

[0155] The pyrimidinyl moiety can be attached via any one of the 2-, 4-, 5-, or 6-carbon atoms.

[0156] The term "imidazolyl" refers to the moiety:

[0157] [ka]

[0158] The imidazolyl moiety can be attached via any one of the 1, 2, 3, 4, or 5 carbon atoms.

[0159] The term "piperidinyl" refers to the moiety:

[0160] [ka]

[0161] The piperidinyl moiety may be attached via any one of atoms 1, 2, 3, 4, 5, or 6, where permitted.

[0162] The term "pyrrolidinyl" refers to the following moiety:

[0163] [ka]

[0164] When the piperidinyl moiety is a substituent, it may be attached via any one of the 1, 2, 3, 4, or 5 carbon atoms, where permitted.

[0165] The term "azetidinyl" refers to a 4-membered heterocycloalkyl moiety having one ring nitrogen. When the azetidinyl moiety is a substituent, it may be attached via any carbon or nitrogen atom, where permitted.

[0166] The term "morpholinyl" refers to the following moiety:

[0167] [ka]

[0168] When the morpholinyl moiety is a substituent, it may be attached via any one of atoms 2, 3, 4, 5, or 6, where permitted.

[0169] The term "substituted" means that the specified group or moiety has one or more substituents. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents. When the term "substituted" is used to describe a structural system, it means that the substitution occurs wherever valencies are allowed in that system. When a specified moiety or group is not expressly stated as being optionally substituted or substituted with any specified substituents, it is understood that such moiety or group is intended to be unsubstituted.

[0170] The terms "para," "meta," and "ortho" have their art-recognized meanings. Thus, for example, a fully substituted phenyl group has substituents at both "ortho" (o) positions adjacent to the point of attachment of the phenyl ring, both "meta" (m) positions, and one "para" (p) position opposite the point of attachment. To further clarify the location of substituents on the phenyl ring, the two different ortho positions are designated ortho and ortho', and the two different meta positions are designated meta and meta', as illustrated below.

[0171] [ka]

[0172] When referring to substituents on a pyridyl group, the terms "para," "meta," and "ortho" refer to the position of the substituent relative to the point of attachment to the pyridyl ring. For example, the following structure shows an X in the ortho position: 1 Substituent, X in meta position 2 Substituents and X in the para position 3 Described as substituted 3-pyridyl:

[0173] [ka]

[0174] In order to provide a more precise description, some of the quantitative expressions presented herein are not modified with the term "about." Regardless of whether the term "about" is explicitly used, all quantities presented herein are understood to refer to the actual given value, and also to refer to approximate values ​​of such given values ​​that can be reasonably inferred based on ordinary skill in the art, including equivalents and approximate values ​​based on experimental and / or measurement conditions for such given values. Whenever a yield is given as a percentage, such a yield refers to the mass of the entity for which the yield is given, relative to the maximum amount of the same entity that can be obtained under specific stoichiometric conditions. Concentrations given as percentages refer to mass ratios unless otherwise specified.

[0175] The terms "buffer" solution or "buffer" solution are used interchangeably herein in accordance with their standard meanings. Buffer solutions are used to control the pH of a medium, and their selection, use, and function are known to those skilled in the art. See, for example, GD Considine, ed., Van Nostrand's Encyclopedia of Chemistry, p. 261, 5th ed. (2005), which describes, among other things, buffer solutions and how the concentrations of buffer components relate to the pH of the buffer. For example, a buffer solution can be obtained by adding MgSO4 and NaHCO3 to a solution in a 10:1 weight ratio to maintain the pH of the solution at about 7.5.

[0176] Any formula given herein is intended to represent the compound having the structure depicted by that structural formula, as well as certain variations or forms. Specifically, compounds of any formula given herein may have asymmetric centers and therefore may exist in different enantiomeric forms. All optical isomers of a compound of a general formula and mixtures thereof are considered to be within the scope of the formula. Thus, any formula given herein is intended to represent its racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. Furthermore, a particular structure may exist as a geometric isomer (i.e., cis and trans isomers), as a tautomer, or as an atropisomer.

[0177] It is also understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are referred to as "isomers." Isomers that differ in the arrangement of their atoms in space are referred to as "."

[0178] Stereoisomers that are not mirror images of one another are called "diastereomers," while stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when the compound is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their chiral centers and described by the Cahn-Prelog R- and S-sequencing rules or by the way the molecule rotates the plane of polarized light, designated as dextrorotatory or levorotatory (i.e., (+) isomer or (-) isomer, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0179] "Tautomers" refer to interchangeable forms of a particular compound structure that differ in the substitution of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the shifting of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are similarly formed by treatment with acid or base.

[0180] Tautomeric forms may be relevant in achieving optimal chemical reactivity and biological activity of the subject compounds.

[0181] The compounds of the present invention may possess one or more asymmetric centers and therefore such compounds may occur as individual (R)- or (S)-stereoisomers or as mixtures thereof.

[0182] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both its individual enantiomers and mixtures, racemic or otherwise. Methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0183] Certain examples include chemical structures depicted as absolute enantiomers, but are intended to represent enantiomerically pure substances of unknown constitution. In these cases, (R * ) or (S * ) is used in the name to indicate that the absolute stereochemistry of the corresponding stereocenter is unknown. * A compound designated as (R) or (S) refers to an enantiomerically pure compound having the absolute configuration (R) or (S). When the absolute stereochemistry has been confirmed, the structure is named with (R) or (S).

[0184] symbol

[0185] [ka] are used to denote the same spatial arrangement in the chemical structures shown herein.

[0186] [ka] are used to refer to the same spatial arrangement in chemical structures shown herein.

[0187] Furthermore, any formula given herein is intended to refer to hydrates, solvates, and polymorphs of such compounds, and mixtures thereof, even if these forms are not explicitly stated. Certain compounds of Formula (I) (and Formulas (IA), (IB), and (IC)), or pharmaceutically acceptable salts of compounds of Formula (I) (and Formulas (IA), (IB), and (IC)), may be obtained as solvates. Solvates include those formed from the interaction or complexation of a compound of the invention with one or more solvents, either in solution or as a solid or crystalline form. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Furthermore, certain crystalline forms of compounds of Formula (I) (and Formulas (IA), (IB), and (IC)), or pharmaceutically acceptable salts of compounds of Formula (I) (and Formulas (IA), (IB), and (IC)), may be obtained as co-crystals. In certain embodiments of the present invention, the compound of Formula (I) is obtained in crystalline form. In other embodiments, the crystalline form of the compound of Formula (I) was cubic in nature. In other embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) was obtained in crystalline form. In still other embodiments, the compound of Formula (I) was obtained in one of several polymorphic forms, as a mixture of crystalline forms, as a polymorphic form, or as an amorphous form. In other embodiments, the compound of Formula (I) is convertible between one or more crystalline and / or polymorphic forms in solution.

[0188] Reference to a compound described herein represents a reference to either one of (a) the form of such compound actually described, and (b) the form of such compound in the medium in which such compound is believed to exist at the time of naming. For example, a reference herein to a compound such as R-COOH represents, for example, R-COOH (s) , R-COOH (sol) and R-COO - (sol) In this example, R-COOH (s) refers to a solid compound that may be found, for example, in a tablet or some other solid pharmaceutical composition or preparation, and R—COOH (sol)refers to the undissociated form of the compound in the solvent, and R-COO - (sol) represents the dissociated form of the compound in the solvent, for example, whether such dissociated form is derived from R-COOH, or a salt thereof, or R-COO when it is considered to have undergone dissociation in the medium. - The term "reacting an entity with a compound of formula R-COOH" refers to a dissociated form of a compound, such as a dissociated form of a compound in an aqueous environment, regardless of whether it originates from any other entity that gives rise to the compound R-COOH. In another example, a phrase such as "exposing an entity to a compound of formula R-COOH" refers to exposing such entity to the form(s) of the compound R-COOH that are present in the medium in which such exposure occurs. In yet another example, a phrase such as "reacting an entity with a compound of formula R-COOH" refers to (a) the entity in chemically relevant form(s) of such entity that are present in the medium in which such reaction occurs reacting with (b) chemically relevant form(s) of the compound R-COOH that are present in the medium in which such reaction occurs. In this context, when such entity is present, for example, in an aqueous environment, it is possible to avoid the possibility that the entity will react with the compound R-COOH because the compound R-COOH is also present in that same medium. (aq) and / or R-COO - (aq) (The subscript "(aq)" denotes "aqueous" according to its conventional meaning in chemistry and biochemistry.) In these nomenclature examples, a carboxylic acid functional group has been selected, but this selection is not intended to be limiting and is merely illustrative. It is understood that similar examples can be provided for other functional groups, including, but not limited to, hydroxyl, basic nitrogen members, such as the nitrogen members in amines, and any other groups that interact or transform in a known manner in a medium containing the compound. Such interactions and transformations include, but are not limited to, dissociation, association, tautomerization, solvolysis (including hydrolysis), solvation (including hydration), protonation, and deprotonation. Further examples are not provided in this context herein, since these interactions and transformations that occur in a given medium are known to those skilled in the art.

[0189] In another example, zwitterionic compounds are encompassed herein by reference to compounds known to form zwitterions, even if they are not specifically named in their zwitterionic form. Terms such as zwitterion(s) and their synonyms, zwitterionic compound(s), are standard names recognized by IUPAC that are part of a standard set of well-known and defined scientific names. In this context, the name zwitterion has been assigned the identifier CHEBI:27369 by the Chemical Entities of Biological Interest (ChEBI) dictionary of molecular entities. As is generally known, zwitterions or zwitterionic compounds are neutral compounds with formal unit charges of opposite signs. These compounds are sometimes referred to by the term "inner salts." While other sources refer to these compounds as "zwitterions," this latter term is a misnomer in still other sources. As a specific example, aminoethanoic acid (the amino acid glycine) has the formula H2NCH2COOH and forms a zwitterion in some media (in this case, a neutral medium). + H3NCH2COO - Zwitterions, zwitterionic compounds, inner salts, and zwitterions, in the known and well-established meanings of these terms, are within the scope of the present invention in all cases, as recognized by those skilled in the art. Since it is not necessary to name every embodiment that will be recognized by those skilled in the art, the structures of zwitterionic compounds related to the compounds of the present invention are not specified herein. However, they are also part of the embodiments of the present invention. Since the interactions and transformations in a given medium that lead to various forms of a given compound are known to those skilled in the art, further examples in this regard are not provided herein.

[0190] Also, any formula given herein is intended to represent unlabeled forms of the compound as well as isotopically labeled forms. Isotopically labeled compounds have the structure depicted in the formula given herein except that one or more atoms are replaced with an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 125 Such isotope-labeled compounds are useful in metabolic studies (preferably 14 C), reaction rate studies (e.g., using deuterium (i.e., D or 2 H); or tritium (i.e., T or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radiation treatment of patients. 18 F or 11 C-labeled compounds may be particularly suitable for PET or SPECT studies. Additionally, heavier isotopes, such as deuterium (i.e., 2 H), may result in greater metabolic stability and certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by practicing the schemes described below or the procedures disclosed in the Examples and Preparations, by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0191] When referring to any formula provided herein, the selection of a particular moiety from a list of possible species for a specified variable is not intended to define the same selection of that species for the variable elsewhere. In other words, when a variable appears more than once, the selection of a species from a specified list is independent of the selection of the species for the same variable elsewhere in the formula, unless otherwise indicated.

[0192] In accordance with the above interpretation of assignments and nomenclature, it is understood that express reference herein to a set means to refer independently to each embodiment of that set, as well as to all possible embodiments of any subset of the set that is expressly referred to, unless chemically meaningful and unless otherwise indicated.

[0193] As a first example of the term substituent, the substituent S 1 example is one of S1 and S2, and the substituent S 2 example If S is one of S3 and S4, then these assignments are 1 example is S1 and S 2 example is S3, S 1 example is S1 and S 2 example is S4, S 1 example is S2 and S 2 example is S3, S 1 example is S2 and S 2 example refers to the embodiment of the invention given by the alternative that "S" is S4, and the respective equivalents of such alternatives. 1 example is one of S1 and S2, and S 2 exampleThe term "is one of S3 and S4" is used herein for brevity and not as a limitation. The first example above of substituent terminology written in general terms is meant to illustrate the various substituent assignments described herein. The foregoing conventions for substituents shown herein are applied, where applicable, to R 1 , R 2 , R 3 , R a , R b , R d , R e Ar 1 , n, m, X, and ring A, as well as all other substituent symbols used herein.

[0194] Furthermore, when more than one assignment is given for any member or substituent, embodiments of the invention include the various groupings that can be made from the listed assignments and their equivalents when taken independently. As a second example of a substituent term, the substituent S example is described herein as being one of S1, S2, and S3, this enumeration is example is S1;S example is S2;S example is S3;S example is one of S1 and S2; S example is one of S1 and S3; S example is one of S2 and S3; S example is one of S1, S2 and S3; and S example is any equivalent of each of these alternatives. example The term "is one of S1, S2, and S3" is used herein for brevity and not as a limitation. The second example above of substituent terminology stated in general terms is intended to illustrate the assignment of the various substituents described herein. The foregoing convention for substituents set forth herein applies, where applicable, to R 1 , R 2 , Ra , R b , R d , R e Ar 1 , n, m, X, and ring A, as well as all other substituent symbols used herein.

[0195] Nomenclature “C i~j " (j>i)" is meant herein, when applied to a class of substituents, to refer to embodiments of the invention in which each and every number of carbon members from i to j, inclusive, is independently realized. For example, the term C 1~6 refers independently to embodiments having one carbon member (C1), two carbon members (C2), three carbon members (C3), and four carbon members (C4).

[0196] C n~m The term alkyl refers to an aliphatic chain, whether straight or branched, where the total number of carbon members in the chain, N, satisfies n≦N≦m, with m>n. Any disubstituent referred to herein is meant to encompass various bonding possibilities, where more than one of such possibilities is permitted. For example, reference to the disubstituent -AB- (where A≠B) herein refers to a disubstituent in which A is bonded to the first substituent and B is bonded to the second substituent, and also refers to a disubstituent in which A is bonded to the second substituent and B is bonded to the first substituent.

[0197] The present invention also includes pharmaceutically acceptable salts of compounds of formula (I) (and formulas (IA), (IB), and (IC)), preferably those described above and the specific compounds exemplified herein, and methods of treatment using such salts.

[0198] The term "pharmaceutically acceptable" means approved or approvable by a regulatory agency of the federal or state government, or a corresponding agency in countries outside the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, and more particularly in humans.

[0199] "Pharmaceutically acceptable salt" is intended to mean a free acid or free base salt of a compound represented by Formula (I) (and Formulas (IA), (IB), and (IC)) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. It should retain the desired pharmacological activity of the parent compound. See generally, G.S. Paulekuhn, et al., "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database," J. Med. Chem., 2007, 50:6665-72; S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm Sci., 1977, 66:1-19; and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are salts that are pharmacologically effective and suitable for contact with the tissues of a patient without undue toxicity, irritation, or allergic response. The compounds of formula (I) (and formulas (IA), (IB), and (IC)) have sufficiently acidic groups, sufficiently basic groups, or both types of functional groups, and therefore may react with many inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts.

[0200] Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1,4-dioate, hexyl phosphate ... Examples of suitable benzoates include benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

[0201] When the compound of formula (I) (and formulas (IA), (IB), and (IC)) contains a basic nitrogen, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art. For example, with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, etc.), or with organic acids (e.g., acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidyl acids (e.g., glucuronic acid or galacturonic acid), α-hydroxy acids (e.g., mandelic acid, citric acid), or tartaric acid), amino acids (e.g., aspartic, glutaric, or glutamic acid), aromatic acids (e.g., benzoic, 2-acetoxybenzoic, naphthoic, or cinnamic acids), sulfonic acids (e.g., lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid), any compatible mixture of acids such as those exemplified herein, and any other acids and mixtures thereof that are considered equivalents or acceptable substitutes given the level of ordinary skill in the art.

[0202] When the compound of Formula (I) (and Formulas (IA), (IB), and (IC)) is an acid, e.g., a carboxylic acid or a sulfonic acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, any compatible mixture of bases such as those exemplified herein, and any other base and mixture thereof that is considered equivalent or acceptable substitute in light of the level of ordinary skill in the art. Specific examples of suitable salts include organic salts made from amino acids such as N-methyl-D-glucamine, lysine, choline, glycine, and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines and cyclic amines such as tromethamine, benzylamine, pyrrolidine, piperidine, morpholine, and piperazine, and inorganic salts made from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0203] The present invention also relates to pharmaceutically acceptable prodrugs of compounds of Formula (I) (and Formulas (IA), (IB), and (IC)), and methods of treatment using such pharmaceutically acceptable prodrugs. The term "prodrug" means a precursor of the specified compound that, after administration to a subject, yields the compound in vivo by a chemical or physiological process, such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., the prodrug is converted to a compound of Formula (I) when brought to physiological pH). A "pharmaceutically acceptable prodrug" is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject. Exemplary procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," Ed. H. Bundgaard, Elsevier, 1985.

[0204] Exemplary prodrugs include compounds having an amino acid residue or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues covalently bonded through an amide or ester bond to a free amino, hydroxyl, or carboxylic acid group of a compound of Formula (I) (and Formulas (IA), (IB), and (IC)). Examples of amino acid residues include the 20 naturally occurring amino acids commonly represented by their three-letter symbols, as well as 4-hydroxyproline, hydroxylysine, demosin, isodesin, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone.

[0205] For example, the free carboxyl groups of the structures of Formula (I) (as well as Formulas (IA), (IB), and (IC)) may be derivatized as amides or alkyl esters to generate additional types of prodrugs. Examples of amides include ammonia, primary C 1~6 Alkylamines and secondary di(C 1~6 Secondary amines include those derived from 5- or 6-membered heterocycloalkyl or heteroaryl ring moieties. Examples of amides include ammonia, C 1~3 Alkyl primary amines and di(C 1~2 Examples of esters of the present invention include those derived from alkyl amines. 1~7 Alkyl, C 5~7 Cycloalkyl, phenyl, and phenyl(C 1~6Examples of suitable esters include (acyloxy)methyl and (acyloxy)ethyl ethers. Preferred esters include methyl esters. Prodrugs can also be prepared by derivatizing free hydroxy groups with groups including hemisuccinates, phosphates, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyl, following procedures such as those outlined in Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130. Carbamate derivatives of hydroxy and amino groups may also yield prodrugs. Carbonate derivatives, sulfonates, and sulfates of hydroxy groups may also provide prodrugs. Derivatizing hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers (the acyl group may be an alkyl ester optionally substituted with one or more ether, amine, or carboxylic acid functional groups, or the acyl group is an amino acid ester as described above) is also useful for generating prodrugs. Prodrugs of this type may be prepared as described by Robinson et al., J Med Chem. 1996, 39(1), 10-18. Free amines may also be derivatized as amides, sulfonamides, or phosphonamides. All of these prodrug moieties may incorporate groups including ether, amine, and carboxylic acid functionalities.

[0206] The present invention also relates to pharmaceutically active metabolites of the compounds of Formula (I) (and Formulas (IA), (IB), and (IC)) that may be used in the methods of the present invention. "Pharmaceutically active metabolite" means a pharmacologically active product of metabolism in the body of a compound of Formula (I) (and Formulas (IA), (IB), and (IC)D)) or a salt thereof. Prodrugs and active metabolites of a compound can be determined using routine methods known or available in the art. See, for example, Bertolini, et al., J Med Chem. 1997, 40, 2011-2016; Shan, et al., J Pharm Sci. 1997, 86(7), 765-767; Bagshawe, Drug Dev Res. 1995, 34, 220-230; Bodor, Adv Drug Res. 1984, 13, 224-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985), and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991).

[0207] The compounds of Formula (I) (as well as Formulas (IA), (IB), and (IC)) of the present invention, and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites thereof, are useful in the methods of the present invention as modulators of GluN2B receptors. As such modulators, the compounds can act as antagonists, agonists, or inverse agonists. The term "modulator" encompasses both inhibitors and activators, where an "inhibitor" refers to a compound that decreases, prevents, inactivates, desensitizes, or downregulates GluN2B receptor expression or activity, and an "activator" is a compound that increases, activates, promotes, sensitizes, or upregulates GluN2B receptor expression or activity.

[0208] As used herein, the terms "treat" or "treatment" are intended to refer to the administration of an active agent or composition of the invention to a subject for the purpose of providing a therapeutic or prophylactic benefit by modulating GluN2B receptor activity. Treatment includes ameliorating, alleviating, alleviating, inhibiting the progression of, reducing the severity of, or preventing a disease, disorder, or condition mediated by modulation of GluN2B receptor activity, or one or more symptoms of such a disease, disorder, or condition. The term "subject" refers to a mammalian patient, e.g., a human, in need of such treatment.

[0209] Accordingly, the present invention provides a method for the treatment of diseases, disorders, or conditions mediated by GluN2B receptor activity, such as, for example, depression, hypomania, mania, and mixed forms of bipolar I disorder; bipolar II disorder; depressive disorders, such as single depressive episode or recurrent major depressive disorder, minor depressive disorder, treatment-resistant depression, postpartum-onset depressive disorder, severe mood dysregulation disorder, depressive disorder with psychotic symptoms, and the like; cyclothymia, dysthymia, manic-depressive remission; and persistent conditions such as premenstrual dysphoric disorder. anxiety disorders, generalized anxiety disorder, panic disorder with or without agoraphobia, specific phobias, social anxiety disorder, chronic anxiety disorder; obsessive-compulsive disorder; severe stress response and adjustment disorders such as post-traumatic stress disorder (PTSD); other neurological disorders, e.g., depersonalization-derealization syndrome; Asperger's syndrome and Rett's syndrome, autistic disorder associated with mental retardation and stereotypic movements, childhood autism, and hyperactivity disorder, specific motor developmental disorder, and specific learning-skill developmental disorder. pervasive developmental disorders; postnatal (postpartum) depression and antenatal depression; eating disorders, including but not limited to anorexia nervosa, bulimia nervosa, pica, and binge eating disorder; Parkinson's disease; secondary parkinsonism such as postencephalitic parkinsonism; parkinsonism encompassed by other disorders; Lewy body disease; degenerative diseases of the basal ganglia; tremor, essential tremor and drug-induced tremor, myoclonic, chorea and drug-induced chorea, drug-induced tics and organic tics, drug-induced acute dystonia, drugs Other extrapyramidal disorders and movement disorders, including but not limited to drug-induced tardive dyskinesia, eldopa-induced dyskinesia; neuroleptic-induced movement disorders, including but not limited to neuroleptic malignant syndrome (NMS), neuroleptic-induced parkinsonism, neuroleptic-induced early or acute dyskinesia, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia, neuroleptic-induced tremor; restless legs syndrome, stiff-man syndrome;The present invention relates to methods of treating subjects diagnosed with or suffering from dystonia, including, but not limited to, focal dystonia, multiple focal or segmental dystonia, torsion dystonia, hemispheric, generalized, and tardive dystonia (induced by psychopharmacological drugs), including cervical dystonia (torticollis), blepharospasm (eyelid spasms), limb dystonia (limb spasms such as writer's cramp), oromandibular dystonia, and spasmodic dysphonia (vocal cord spasms); localization-related (focal) (partial) idiopathic epilepsies and epilepsy syndromes with localized onset seizures, localization-related (focal) (partial) symptomatic epilepsies and epilepsy syndromes with simple partial seizures, localization-related (focal) (partial) symptomatic epilepsies and epilepsy syndromes with complex partial seizures, breast Epilepsy, including generalized idiopathic epilepsy and epilepsy syndromes, including but not limited to myoclonic epilepsy of childhood, neonatal convulsions (familial), childhood absence epilepsy (pycnolepsy), epilepsy with awakening grand mal seizures, absence epilepsy, myoclonic epilepsy (petit mal impulse seizures), and nonspecific atonic, clonic, myoclonic, tonic, and tonic-clonic seizures; myoclonic absence epilepsy, myoclonic astatic epilepsy, infantile spasms epilepsy, Lennox-Gastaut syndrome, Salam seizures, symptomatic early myoclonic encephalopathy, West syndrome, petit mal and grand mal seizures; status epilepticus; persistent somatoform disorders; acute, chronic, and chronic intractable pain, headache; acute and chronic pain associated with physiological processes and physical illnesses, including but not limited to back pain, toothache, abdominal pain, lumbago, and joint pain; acute pain associated with diseases of the musculoskeletal system and connective tissue, including but not limited to rheumatism, myalgia, neuralgia, and fibromyalgia acute and chronic pain associated with nerve, nerve root and plexus disorders (e.g. trigeminal neuralgia, postherpetic neuralgia, painful phantom limb syndrome, carpal tunnel syndrome, sciatic nerve lesions, diabetic mononeuropathy); acute and chronic pain associated with polyneuropathies and other disorders of the peripheral nervous system (e.g. hereditary and idiopathic neuropathies, inflammatory polyneuropathies, polyneuropathies induced by drugs, alcohol or toxic agents, polyneuropathy in neoplastic diseases, diabetic polyneuropathy);and acute neurodegeneration, such as stroke, diffuse and focal brain injury, intracranial brain injury such as epidural hemorrhage, subdural hemorrhage, and subarachnoid hemorrhage, and chronic neurodegeneration, such as Alzheimer's disease, Huntington's disease, multiple sclerosis, and ALS; subarachnoid hemorrhage, intracerebral hemorrhage, and other non-traumatic intracranial hemorrhage, cerebral infarction, stroke, anterior cerebral artery and cerebral artery occlusion and stenosis (not resulting in cerebral infarction), cerebral artery dissection, cerebral aneurysm, cerebral arteriosclerosis, progressive vascular leukoencephalopathy, hypertensive encephalopathy, intracranial venous system non-suppurative thrombosis, cerebral arteritis, cerebral amyloid angiopathy, and sequelae of cerebrovascular disease; glaucoma and other neurological disorders; dementia, vascular dementia, dementia with Lewy bodies, frontotemporal dementia, and HIV dementia; dizziness and nystagmus; tinnitus; neuropsychiatric systemic lupus erythematosus; severe mood dysregulation disorder; schizophrenia spectrum disorder; and sleep / wake disorders;

[0210] In the treatment methods of the present invention, an effective amount of an agent of the present invention is administered to a subject suffering from or diagnosed with such a disease, disorder, or condition. An "effective amount" refers to an amount or dosage sufficient to generally produce the desired therapeutic or prophylactic effect in a patient in need of such treatment for the specified disease, disorder, or condition. Effective amounts or dosages of the compounds of the present invention may be determined by conventional methods, such as modeling, dose escalation studies, or clinical trials, and by considering routine factors, such as the form or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder, or condition, the subject's previous or current treatments, the subject's health status and response to the drug, and the judgment of the treating physician. Exemplary dosages range from about 0.001 to about 200 mg / kg of subject body weight per day, preferably about 0.05 to 100 mg / kg / day, or about 1 to 35 mg / kg / day, of the compound per kg of subject body weight, in single or divided dosage units (e.g., twice daily, three times daily, or four times daily). For a 70 kg human, an exemplary range of suitable dosages is about 0.05 to about 7 g / day or about 0.2 to about 2.5 g / day.

[0211] Once the patient's disease, disorder, or condition has improved, the dosage may be adjusted for preventive or maintenance treatment. For example, the dosage or administration frequency, or both, may be reduced as a function of symptoms to a level at which the desired therapeutic or preventive effect is maintained. Of course, once symptoms have been alleviated to an appropriate level, treatment may be stopped. However, if symptoms recur, the patient may require long-term intermittent treatment.

[0212] In addition, the active agents of the present invention can be used in combination with additional active ingredients in the treatment of the above conditions. The additional active ingredient can be co-administered separately with an active agent of Table 1 or can be included in a pharmaceutical composition according to the present invention together with such an agent. In an exemplary embodiment, the additional active ingredient is one known or discovered to be effective in treating a condition, disorder, or disease mediated by GluN2B activity, such as another GluN2B modulator or a compound active against another target associated with a particular condition, disorder, or disease. This combination can serve to increase efficacy (e.g., by including a compound in the combination that enhances the potency or effectiveness of an active agent according to the present invention), reduce one or more side effects, or reduce the required dosage of an active agent according to the present invention.

[0213] The active agents of the present invention are used alone or in combination with one or more additional active ingredients to formulate pharmaceutical compositions of the present invention, which comprise (a) an effective amount of at least one active agent according to the present invention, and (b) a pharmaceutically acceptable excipient.

[0214] A "pharmaceutically acceptable excipient" refers to a non-toxic, biologically tolerable, or otherwise biologically suitable substance for administration to a subject, such as an inert substance added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a drug, and which is compatible with the drug. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0215] A pharmaceutical composition delivery form containing one or more dosage units of an active agent can be prepared using suitable pharmaceutical excipients and formulation techniques known or available to those skilled in the art. The composition may be administered in the methods of the invention by a suitable delivery route, for example, oral, parenteral, rectal, topical, or ocular, or by inhalation.

[0216] The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. Preferably, the composition is formulated for intravenous injection, topical administration, or oral administration.

[0217] For oral administration, the compounds of the present invention can be provided in tablet or capsule form, or as a solution, emulsion, or suspension. To prepare an oral composition, the compound can be formulated to yield a dosage of, for example, about 0.05 to about 100 mg / kg per day, about 0.05 to about 35 mg / kg per day, or about 0.1 to about 10 mg / kg per day. For example, a total daily dosage of about 5 mg to 5 g per day can be achieved by administering the compound once, twice, three times, or four times per day.

[0218] Oral tablets may contain a compound according to the present invention mixed with pharmaceutically acceptable excipients, such as inert diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, coloring agents, and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary oral liquid excipients include ethanol, glycerol, water, and the like. Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrants. Binders may include starch and gelatin. Lubricants, if present, may be magnesium stearate, stearic acid, or talc. If desired, tablets may be coated with a substance such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0219] Capsules for oral administration include hard gelatin capsules and soft gelatin capsules.To prepare hard gelatin capsules, the compound of the present invention can be mixed with solid, semi-solid or liquid diluents.Soft gelatin capsules can be prepared by mixing the compound of the present invention with water, oil such as peanut oil or olive oil, liquid paraffin, a mixture of monoglycerides and diglycerides of short-chain fatty acids, polyethylene glycol 400 or propylene glycol.

[0220] Oral liquids may be in the form of suspensions, solutions, emulsions, or syrups, or may be freeze-dried or presented as a dry product for reconstitution with water or other suitable vehicles before use. Such liquid compositions may optionally contain pharmaceutically acceptable excipients, such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous vehicles, such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (e.g., methyl or propyl p-hydroxybenzoate, or sorbic acid); wetting agents such as lecithin; and, if necessary, flavorings or coloring agents.

[0221] The active agents of the present invention may also be administered parenterally. For example, the compositions described above may be formulated as suppositories for rectal administration. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the present invention may be provided in a sterile aqueous solution or suspension buffered to an appropriate pH and isotonicity, or in a parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose forms, such as ampoules or disposable injection devices, multi-dose forms, such as vials from which the appropriate dose can be withdrawn, or solid forms or pre-concentrates that can be used to prepare injectable formulations. Specific infusion doses may range from about 1 to 1,000 μg / kg / min of the compound mixed with a pharmaceutical carrier, infused over a period ranging from several minutes to several days.

[0222] For topical administration, the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another form of administration of the compounds of the present invention may utilize a patch formulation to effect transdermal delivery. Alternatively, compounds of the present invention may be administered in the methods of the present invention by inhalation via the nasal or oral routes, for example, in an aerosol formulation also containing a suitable carrier.

[0223] Exemplary compounds useful in the methods of the present invention will now be described by reference to the following exemplary synthetic schemes for their general preparation, followed by specific examples. To obtain the various compounds herein, those skilled in the art will understand that starting materials can be suitably selected so that the ultimately desired substituents are retained throughout the reaction scheme, with or without appropriate protection, to yield the desired product. Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituent, a suitable group that can be carried through the reaction scheme and optionally substituted with the desired substituent. Unless otherwise specified, variables are as defined above with reference to Formula (I). The reaction can be carried out between the melting point and the reflux temperature of the solvent, preferably between 0° C. and the reflux temperature of the solvent. The reaction can be carried out under heating using conventional or microwave heating. The reaction can also be carried out in a sealed pressure vessel at a temperature above the normal reflux temperature of the solvent.

[0224] Abbreviations and acronyms used herein are as follows:

[0225] [Table 2] * (Collingridge,GL,et al,Neuropharmacology,2009,56,2-5)

[0226] Preparation example Exemplary compounds useful in the methods of the present invention will now be described by reference to the following exemplary synthetic schemes for their general preparation and the following specific examples.

[0227] [ka]

[0228] According to Scheme 1, commercially available or synthetically available 6-bromo-1H-pyrazolo[4,3-b]pyridines can be halogenated under conditions known to those skilled in the art to give 6-bromo-1H-pyrazolo[4,3-b]pyridines of formula R 1 For example, 6-bromo-1H-pyrazolo[4,3-b]pyridine may be fluorinated using an electrophilic fluorine source such as N-fluorobenzenesulfonimide (NFSI), N-fluoro-o-benzenedisulfonimide (NFOBS), or 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectflor®), preferably Selectflor®, at a temperature ranging from 0 to 100° C. to give a compound of formula (V). R in the formula 1 is F.

[0229] [ka]

[0230] According to Scheme 2, 2-haloacetyl chlorides of formula (VI), such as 2-chloroacetyl chloride, 2-bromoacetyl chloride, where X is Cl or Br, can be prepared by reacting 2-haloacetyl chlorides of formula (VI), such as 2-chloroacetyl chloride, 2-bromoacetyl chloride, etc., with a 2-haloacetyl chloride of formula (VI), where X is Cl or Br, with a 2-haloacetyl chloride of formula (VI), such as 2-chloroacetyl chloride, 2-bromoacetyl chloride, etc., with a 2-haloacetyl chloride of formula (VI), where R a H, halo, or C 1~6 a commercially available or synthetically available suitably substituted azetidine of formula (VII) wherein ring A is as described in formula (IB) or a suitably substituted heterocycloalkylamine of formula (IX) wherein Rd is C 3-6 Cycloalkyl or C substituted with two F members 3-6 Reaction with a suitably substituted amine of formula (XI), where Re is cycloalkyl and Re is H or CH, in the presence of a suitable base such as triethylamine (TEA) or sodium bicarbonate in a solvent such as acetonitrile (ACN) or dichloromethane (DCM) at a temperature ranging from 0° C. to room temperature provides compounds of formula (VIII), formula (X) and formula (XII).

[0231] [ka]

[0232] According to Scheme 3, bromoarylcarbaldehyde (II) is difluorinated, for example, with diethylaminosulfur trifluoride (DAST) in a suitable solvent, such as DCM, to provide bromo(difluoromethyl)aryl (III). Bromo(difluoromethyl)aryl (III) can be boronated by methods known to those skilled in the art, for example, by treating bromo(difluoromethyl)aryl (III) with a transition metal catalyst, for example, 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl) in a solvent, such as dimethyl sulfoxide (DMSO) or 1,4-dioxane, and a base, such as KOAc, with bis(pinacolato)diboron to provide compounds of formula (IV).

[0233] Alternatively, a compound of formula (III), for example 2-bromo-5-(difluoromethyl)thiophene, can be borated via metal-halogen exchange of the bromide with an organolithium or magnesium reagent in a solvent such as ether or tetrahydrofuran (THF) at a temperature of about −78° C., with or without lithium chloride, followed by treatment with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to give a compound of formula (IV), for example 2-(5-(difluoromethyl)thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0234] [ka]

[0235] According to Scheme 4, in the formula, R 1is H, CH, or F, with a compound of formula (VIII), (X), or (XII), where X is Cl or Br, using a base such as CsCO, NaH, or the like, in a suitable solvent such as DMF, at a temperature ranging from about 0° C. to room temperature to form a compound of formula (VIII), (X), or (XII), where X is Cl or Br, 2 is as defined in Formula 1. The compound of formula (XIII) is reacted in a metal-mediated cross-coupling reaction to give a compound of formula (XIII), wherein Ar 1 is as defined in Formula 1. For example, a compound of formula (XIII), having H, CH, or F, can be reacted with a suitably substituted aryl or heteroaryl boronic acid, boronate ester, or the like, to form: In the presence of a palladium catalyst such as PdCl2(dtbpf), Pd(PPh3)4, bis(triphenylphosphine)palladium(II) chloride (PdCl2(PPh3)2), bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (RuPhos Pd G3), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), or a base such as KF, K3PO4, aqueous Na2CO3, or Cs2CO3, Reaction in a suitable solvent such as 1,4-dioxane, DMF, acetonitrile (ACN), water, or a mixture thereof at a temperature ranging from 60 to 120° C. for a period of about 16 to 48 hours provides a compound of formula (I).

[0236] [ka]

[0237] According to Scheme 5, in the formula, R 1 is H, CH, or F in a metal-mediated cross-coupling reaction with a suitably substituted aryl or heteroaryl boronic acid to give a compound of formula (V), wherein Ar1 is a group defined in formula (I). Subsequent alkylation with a compound of formula (VIII), or formula (X), or formula (XII), using the conditions previously described, provides a compound of formula (I).

[0238] [ka]

[0239] According to Scheme 6, in the formula, R 1 is H, CH3, or F, and Ar 1 A compound of formula (V) or a compound of formula (XV), wherein is as described in formula (I), is alkylated with an electrophile such as ethyl 2-bromoacetate, tert-butyl 2-bromoacetate, and a suitable base such as NaHCO, in a suitable solvent such as DMF at a temperature ranging from 0° C. to room temperature. Compounds of formula (XIV) are coupled, as previously described, with a suitably substituted phenyl or thienyl boronic acid or ester in a metal-mediated cross-coupling reaction using conditions as previously described to provide compounds of formula (XVI).

[0240] In the formula, Ar 1 is phenyl substituted with CHOH, is fluorinated with a fluorinating agent such as bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor®) in a suitable solvent such as DCM at 0° C. for a period of 1 to 4 hours to give a compound of formula (XVI), wherein Ar 1 is phenyl substituted with CHF.

[0241] The ester of formula (XVI) is saponified under basic conditions, such as NaOH, LiOH, KOH, etc., in a suitable solvent, such as methanol (MeOH), ethanol (EtOH), THF, ACN, HO, etc., or mixtures thereof, to provide the compound of formula (XVII). Alternatively, acidic hydrolysis of the ester of formula (XVI) is achieved using an acidic solvent, such as 6 N aqueous HCl, at a temperature ranging from room temperature to 80° C. to provide the compound of formula (XVII). It will be appreciated that in certain instances, in situ ester hydrolysis may occur without isolating the individual ester (XVI) to provide the compound of formula (XVII).

[0242] [ka]

[0243] According to Scheme 7, in the formula, R 1 is H, CH3, or F, and Ar 1 is suitably substituted phenyl or thienyl, R 2 The compound of formula (I), wherein R is as defined in claim 1, is prepared by conventional amide bond forming techniques such as coupling reactions well known to those skilled in the art (e.g., HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3 triazolo[4,5-b]pyridinium 3-hexafluorophosphate), BOP (benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate), or conversion of an acid to an acid chloride). For example, a compound of formula (I) can be prepared by coupling a suitably substituted heterocycloalkylamine of formula (IX) or a suitably substituted azetidine of formula (XVIII) or a compound of formula (XVIII) d is as defined in claim 1, and R eIn the case of the reaction of an amine of formula (XI) where is H or CH3 with an acid compound of formula (XVII), the acid may optionally be catalyzed by a catalyst such as hydroxybenzotriazole (HOBt) and / or 4-dimethylaminopyridine (DMAP); a halotrisaminophosphonium salt such as benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) or bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP®); a suitable pyridinium salt such as 2-chloro-1-methylpyridinium chloride; or N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), or a suitable pyridinium salt such as 2-chloro-1-methylpyridinium chloride. The hydroxybenzoates are activated with a suitable activating reagent, for example, a carbodiimide such as N,N'-dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC, or EDCI), in the presence of an activating reagent such as bis(dimethylamino)methylene-1H-triazol-1-yluronium hexafluorophosphate (HBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), or 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P®). The coupling reaction is carried out in a suitable solvent such as DCM, THF, DMF, and optionally in the presence of a tertiary amine such as N-methylmorpholine, N-ethyldiisopropylamine (DIEA, DIPEA), triethylamine (TEA), and the like, at a temperature ranging from about 0° C. to room temperature to provide compound a of formula (I).

[0244] The compound of formula (I) may be converted to its corresponding salt using methods known to those skilled in the art. For example, the amine of formula (I) may be treated with trifluoroacetic acid, HCl, or citric acid in a solvent such as EtO, CHCl, THF, MeOH, chloroform, or isopropanol to provide the corresponding salt form. Alternatively, reverse-phase HPLC purification conditions may result in the trifluoroacetate or formate salt. Crystalline forms of pharmaceutically acceptable salts of the compound of formula (I) may be obtained in crystalline form by recrystallization from a polar solvent (including a mixture of polar solvents and an aqueous mixture of polar solvents) or a nonpolar solvent (including a mixture of nonpolar solvents).

[0245] When the compounds according to the present invention have at least one chiral center, they may consequently exist as enantiomers. When the compounds have two or more chiral centers, they may additionally exist as diastereomers. It is understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0246] The compounds prepared according to the above-described schemes can be obtained in a single form, such as a single enantiomer, by form-specific synthesis or by resolution. Alternatively, the compounds prepared according to the above-described schemes can be obtained as a mixture of various forms, such as a racemic (1:1) or non-racemic (non-1:1) mixture. When racemic and non-racemic mixtures of enantiomers are obtained, single enantiomers can be isolated using conventional isolation methods known to those skilled in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization to diastereomeric adducts, biotransformation, or enzymatic conversion. When regioisomeric or diastereomeric mixtures are obtained, single isomers can be separated, if applicable, using conventional methods, such as chromatography or crystallization.

[0247] The following specific examples are provided to further illustrate the invention and various preferred embodiments. [Example]

[0248] In obtaining the compounds described in the Examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

[0249] Unless otherwise noted, reaction mixtures were magnetically stirred under a nitrogen atmosphere at room temperature (rt). Solutions were generally dried over a drying agent such as NaSO or MgSO. Mixtures, solutions, and extracts were typically concentrated under reduced pressure on a rotary evaporator. Reactions under microwave irradiation conditions were performed in a Biotage Initiator or CEM (Microwave Reactor) Discover instrument.

[0250] For reactions conducted under continuous flow conditions, "flowing through an LTF-VS mixer" refers to the use of a Chemyx Fusion 100 touch syringe pump in series with an LTF-VS mixer (Little Things Factory GmbH (http: / / www.ltf-gmbH.com)) via 1 / 16 inch PTFE tubing, unless otherwise specified.

[0251] Normal phase silica gel chromatography (FCC) was performed on silica gel (SiO2) using prepacked cartridges.

[0252] Preparative reverse-phase high performance liquid chromatography (RP HPLC) was performed by one of the following methods. Method A. Agilent HPLC using an Xterra Prep RP18 column (5 μM, 30 × 100 or 50 × 150 mm) or an XBridge C18 OBD column (5 μM, 30 × 100 or 50 × 150 mm) at a flow rate of 40 or 80 mL / min, with a mobile phase of 5% ACN in 20 mM NH4OH, held for 2 min, followed by a gradient change from 5 to 99% ACN over 15 min, followed by a 5 min hold at 99% ACN. or Method B. Shimadzu LC-8A series HPLC using an Inertsil ODS-3 column (3 μm, 30 × 100 mm, T = 45 °C) at a flow rate of 80 mL / min with a mobile phase of 5% ACN in HO (both containing 0.05% TFA) held for 1 min, followed by a gradient of 5 to 99% ACN over 6 min, followed by a 3 min hold at 99% ACN. or Method C. Shimadzu LC-8A series HPLC using an XBridge C18 OBD column (5 μm, 50 × 100 mm) at a flow rate of 80 mL / min with a mobile phase of 5% ACN in HO (both containing 0.05% TFA) held for 1 min, followed by a gradient change from 5 to 99% ACN over 14 min, followed by a 10 min hold at 99% ACN. or Method D. Gilson HPLC using an XBridge C18 column (5 μm, 100 × 50 mm) at a flow rate of 80 mL / min with a mobile phase of 5 to 99% ACN in 20 mM NH4OH over 10 min, followed by a 2 min hold at 99 ACN. or Method E. A Wufeng LC100 with a manual Rheodyne 3725i sampler was used with a Gemini-NX C18 column (5 μM, 30 × 100 mm) at a flow rate of 30 mL / min over 16 or 18 min using a mobile phase of 0–90% ACN:10 mM (NH4)HCO3 (9:1) in 10 mM aqueous (NH4)HCO3 containing 0.1% NH4OH. Method: F. Gilson HPLC using a C18 XBridge column (30 x 100 mm 5 um), mobile phase: 60% 0.1% NH4CO3H / NH4OH pH 9 in water, gradient from 40% CH3CN to 43% 0.1% NH4CO3H / NH4OH pH 9 in water, 57% CH3CN, flow rate of 80 mL / min.

[0253] Preparative supercritical fluid high-performance liquid chromatography (SFC) was performed on either a Jasco preparative SFC system, a Berger Instruments APS 1010 system, or an SFC-PICLAB-PREP 200 (PIC SOLUTION, Avignon, France). Separations were performed at 100–150 bar with flow rates ranging from 40–60 mL / min. The column was heated to 35–40 °C.

[0254] Mass spectra (MS) were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated masses correspond to exact masses.

[0255] Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker DRX spectrometer. Multiplicity definitions are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broadband. It will be understood that for compounds containing exchangeable protons, the protons may or may not be visible in the NMR spectrum, depending on the choice of solvent used to perform the NMR spectrum and the concentration of the compound in solution.

[0256] Compound names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0257] R * or S * Compounds designated as are enantiomerically pure compounds for which the absolute configuration has not been determined.

[0258] (Example) Intermediate 1: 2-chloro-1-(3-fluoroazetidin-1-yl)ethanone.

[0259] [ka]

[0260] Method A. To a mixture of chloroacetyl chloride (1.57 mL, 19.7 mmol, 1.42 g / mL) and sodium bicarbonate (NaHCO) (4.52 g, 53.8 mmol) in dichloromethane (DCM) (40 mL) under argon, 3-fluoroazetidine hydrochloride (2.0 g, 17.9 mmol) was added portionwise at 0 °C and stirred at 0 °C for 2 h. The reaction mixture was allowed to reach room temperature and stirred for 1 h. The mixture was filtered, and the precipitate was washed with DCM (3 × 4 mL). The combined filtrates were evaporated to give the title compound (2.70 g, 17.8 mmol, 99%) as a colorless liquid. MS (ESI): mass calculated for CHClFNO, 151.0; m / z found, 152.1 [M+H]. + .

[0261] Method B. Potassium carbonate (KCO) (46 g, 330 mmol) and 3-fluoroazetidine (16.7 g, 150 mmol) were stirred in 100 mL of distilled water until all solids were completely dissolved. To this solution was added 100 mL of DCM, and the biphasic reaction was cooled to 0 °C and vigorously stirred while chloroacetyl chloride (14.3 mL, 180 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h and then diluted with water until all solids were dissolved. The layers were separated, and the aqueous layer was extracted four times with DCM. The combined organics were concentrated to give the title compound (15.9 g, 105 mmol, 70%) as a pale yellow liquid, which was sufficiently pure to be used directly in the subsequent step. 1 H NMR (400MHz, CDCl3) δ 5.54-5.15(m,1H), 4.68-4.50(m,1H), 4.48-4.26(m,2H), 4.28-4.11(m,1H), 3.92(s,2H).

[0262] Intermediate 2: 2-chloro-N-(3,3-difluorocyclobutyl)acetamide.

[0263] [ka] The title compound was prepared in a manner similar to Method A for Intermediate 1, using 3,3-difluorocyclobutan-1-amine instead of 3-fluoroazetidine. MS (ESI): mass calculated for C6H8ClF2NO; observed 183.0 m / z, 182.1 [MH] - .

[0264] Intermediate 3: 2-chloro-1-(3,3-difluoropyrrolidin-1-yl)ethan-1-one.

[0265] [ka] The title compound was prepared in a manner similar to Method A for Intermediate 1, using 3,3-difluoropyrrolidine instead of 3-fluoroazetidine. MS (ESI): mass calculated for C6H8ClF2NO; observed m / z 183.0, 184.1 [MH] + .

[0266] Intermediate 4: (racemic) 2-chloro-1-(3-hydroxypyrrolidin-1-yl)ethan-1-one.

[0267] [ka] The title compound was prepared in a manner similar to Method A of Intermediate 1, using 3-hydroxypyrrolidine instead of 3-fluoroazetidine. MS(ESI): CH 10 Calculated mass of ClNO2: 163.0 m / z, observed mass: 164.1 [MH] + .

[0268] Intermediate 5: (racemic) 2-chloro-1-(3-fluoropyrrolidin-1-yl)ethan-1-one.

[0269] [ka] The title compound was prepared in a manner similar to Method A for Intermediate 1, using 3-fluoropyrrolidine instead of 3-fluoroazetidine. MS (ESI): mass calculated for C6H9ClFNO; observed m / z 165.0, 166.1 [M−H] + .

[0270] Intermediate 6: 2-chloro-1-(3-methylazetidin-1-yl)ethan-1-one.

[0271] [ka] To a solution of 3-methylazetidine hydrochloride (500 mg, 4.65 mmol) in DCM (7.75 mL) was added K2CO3 (1.93 g, 14.0 mmol) at 0 °C, and the reaction was stirred for 10 min. To the reaction mixture was added chloroacetyl chloride (407 μL, 5.11 mmol, 1.42 g / mL) dropwise at 0 °C. The reaction mixture was allowed to reach room temperature and stirred for 17 h. The suspension was filtered, and the precipitate was washed with DCM (2 × 10 mL). The combined filtrates were concentrated under reduced pressure. Purification (FCC, SiO2, 0-100% DCM / MeOH) afforded the title compound (580 mg, 3.93 mmol, 85%) as a yellow oil. MS (ESI): CH 10 Calculated mass of ClNO: 147.1 m / z, observed mass: 148.1 [MH] + .

[0272] Intermediate 7: 2-chloro-N-cyclobutylacetamide.

[0273] [ka] To a solution of cyclobutylamine (1.0 g, 14.1 mmol) in freshly distilled tetrahydrofuran (THF) (60 mL) was added triethylamine (EtN) (2.16 mL, 15.5 mmol, 0.726 g / mL) dropwise at room temperature. The mixture was cooled to 0 °C. Chloroacetyl chloride (1.23 mL, 15.5 mmol, 1.42 g / mL) was then added at 0 °C, and the reaction was stirred for 1 h. The reaction mixture was allowed to reach room temperature and stirred for 17 h. The reaction mixture was concentrated, and the residue was taken up in water (70 mL) and extracted with ethyl acetate (EtOAc) (1 × 70 mL). The organic layer was washed with 1 M hydrochloric acid (HCl) (1 × 35 mL), saturated NaHCO (1 × 35 mL), and saturated ammonium chloride (NH Cl) (1 × 35 mL), dried over sodium sulfate (Na SO ), filtered, and concentrated. Purification (FCC, SiO, 10-100% n-heptane / EtOAc) gave a residue that was triturated with n-heptane (10 mL) to give the title compound (1.37 g, 9.28 mmol, 66%) as a white crystalline solid. MS (ESI): CH 10 Calculated mass of ClNO: 147.1 m / z, observed mass: 148.1 [MH] + .

[0274] Intermediate 8: 2-(5-(difluoromethyl)thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0275] [ka] Step A: 2-Bromo-5-(difluoromethyl)thiophene. To dimethylaminosulfur trifluoride (5.6 mL, 42.4 mmol, 1.22 g / mL) was added 5-bromothiophene-2-carbaldehyde (2.00 g, 10.5 mmol) dropwise at 0 °C under argon. The reaction mixture was then stirred at room temperature for 2 h. The reaction was quenched by the dropwise addition of 2 M sodium hydroxide (NaOH) (10 mL) at 0 °C. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organics were dried over NaSO, filtered, and concentrated under reduced pressure. Purification (FCC, SiO, n-heptane) afforded the title compound (1.07 g, 5.03 mmol, 48%) as a colorless liquid. No mass ion was found by MS.

[0276] Step B. 2-(5-(difluoromethyl)thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. To a solution of 2-bromo-5-(difluoromethyl)thiophene (930 mg, 4.37 mmol) in THF (17 mL) was added n-butyllithium (n-BuLi) (1.6 M in hexanes, 3 mL, 4.8 mmol) dropwise under argon at −78 °C, and the reaction mixture was stirred at −78 °C for 1 h. To the reaction mixture was added a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (980 μL, 4.8 mmol, 0.912 g / mL in THF (2 mL)), and the reaction was stirred at −78 °C for 1 h. The reaction mixture was allowed to reach room temperature and then stirred for 16 h. The reaction was diluted with saturated NH4Cl (30 mL) and EtOAc (40 mL). The layers were separated and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to give the title compound (1.00 g) as a brown oil, which was used without further purification. MS (ESI): mass calculated for C5H5BF2O2S; found 178.0 m / z, 177.1 [MH] + .

[0277] Intermediate 9: 6-Bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine.

[0278] [ka] To a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (2.5 g, 12.6 mmol) in acetonitrile (62.5 mL) was added N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (6.7 g, 18.9 mmol). The reaction mixture was stirred at 90 °C for 22 h. The reaction mixture was poured into water (120 mL) and diluted with EtOAc (80 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 60 mL). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by basic reverse-phase preparative HPLC (Method E) to give the title compound (641 mg, 2.97 mmol, 23%) as a brown powder. MS (ESI): mass calculated for CHBrFN; observed m / z 214.9, 216.0 [M+H].

[0279] Intermediate 10: 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-N,N-dimethylacetamide.

[0280] [ka] Method A. To a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (2.00 g, 10.1 mmol) in dry DMF (40 mL) was added NaH (60% in mineral oil, 444 mg, 11.1 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. To the reaction mixture was added 2-chloro-N,N-dimethylacetamide (1.14 mL, 11.1 mmol, 1.18 g / mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (EA, EtOAc) (3 × 40 mL). The combined organic layers were evaporated. Purification (FCC, SiO, 25-100% hexane / EtOAc) gave a solid, which was purified by E. coli. t Trituration with 20 (4 mL) gave the title compound (1.83 g, 6.47 mmol, 64%) as an off-white powder. MS (ESI): 10 H 11Calculated mass for BrNO: 282.0; observed m / z: 283.0 [M+H] +

[0281] Method B. A solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (15.0 g, 75.7 mmol) in DMF (250 mL) was treated with 2-chloro-N,N-dimethylacetamide (8.6 mL, 83 mmol) and K2CO3 (12.6 g, 90.9 mmol), and the reaction mixture was stirred at room temperature overnight. The DMF was removed under reduced pressure to a total volume of approximately 50 mL, then diluted with water (300 mL) and allowed to stand overnight. The resulting precipitate was collected by filtration to give the title compound (14.0 g, 49.5 mmol, 65%). MS (ESI): C 10 H 11 Calculated mass for BrNO: 282.0; observed m / z: 283.0 [M+H] + . 1 H NMR (400MHz, CHCl3-d)δ 8.60(d,J=1.9Hz,1H), 8.22(d,J=1.0Hz,1H), 8.00(dd,J=1.9,1.0Hz,1H), 5.20(s,2H), 3.15(s,3H), 2.99(s,3H).

[0282] Intermediate 11: 2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)-N,N-dimethylacetamide.

[0283] [ka] The title compound was prepared in a manner similar to Method A of Intermediate 10 using 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 9). MS (ESI): C 10 H 10 Calculated mass of BrFNO: 300.0; observed m / z: 301.0 [M+H] + .

[0284] Intermediate 12: 2-(6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one.

[0285] [ka] A solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (10.0 g, 50.5 mmol) in DMF (100 mL) was treated with 2-chloro-1-(3-fluoroazetidin-1-yl)ethan-1-one (8.42 g, 55.5 mmol) and K2CO3 (8.4 g, 61 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was partitioned between DCM and water, and the aqueous layer was extracted with DCM (twice). The combined organic layers were concentrated. Residual DMF was removed by azeotroping with heptane. Purification (FCC, SiO2, 0-10% DCM / MeOH) gave a solid, which was then recrystallized from EtOAc. 8.33 g (26.6 mmol, 53%) of the title compound was isolated. MS (ESI): C 11 H 10 Calculated mass for BrFNO: 312.0; observed m / z: 313.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 8.61(d, J=2.0Hz, 1H), 8.51(dd, J=2.0, 1.0Hz, 1H), 8.36(d, J=1.0Hz, 1H), 5.57-5.37( m, 1H), 5.28(d, J=4.1Hz, 2H), 4.65-4.45(m, 1H), 4.42-4.16(m, 2H), 4.06-3.92(m, 1H).

[0286] Intermediate 13: 1-(azetidin-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one.

[0287] [ka] The title compound was prepared in a similar manner to Method A of Intermediate 10, using 1-(azetidin-1-yl)-2-chloroethan-1-one instead of 2-chloro-N,N-dimethylacetamide. MS(ESI):C 11 H 11Calculated mass for BrNO, 294.0; observed m / z, 295.0 [M+H] + .

[0288] Intermediate 14: 1-(azetidin-1-yl)-2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one.

[0289] [ka] The title compound was prepared in a manner similar to Method A of Intermediate 10, using 1-(azetidin-1-yl)-2-chloroethan-1-one instead of 2-chloro-N,N-dimethylacetamide and 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 9) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine. MS (ESI): C 11 H 10 Calculated mass for BrFNO: 312.0; observed m / z: 313.0 [M+H] + .

[0290] Intermediate 15: 2-(6-Bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one.

[0291] [ka] The title compound was prepared in a manner similar to Intermediate 12, using 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 9) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine. MS (ESI): C 11 Calculated mass for HBrFNO: 329.9; observed m / z: 331.0 [M+H] + .

[0292] Intermediate 16: 6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine.

[0293] [ka] A mixture of 6-bromo-1H-pyrazolo[4,3-b]pyridine (1.40 g, 7.07 mmol), 2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.31 g, 8.49 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.673 g, 0.92 mmol), and Na2CO3 (2.25 g, 21.2 mmol) in degassed acetonitrile (24.4 mL) and water (3.76 mL) was stirred at 120 °C for 4 h under microwave irradiation. The reaction mixture was poured into water (30 mL), and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification (FCC, SiO2, 10-50% n-heptane / EtOAc) gave a solid, which was t Trituration with 20 (4 mL) gave the title compound (1.41 g, 5.36 mmol, 76%) as an off-white powder. MS (ESI): 13 Calculated mass of H8F3N3, 263.1; observed m / z, 264.2 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 13.48(brs, 1H), 8.84(d, J=2.0Hz, 1H), 8.41-8.30(m, 1H), 8.30-8.20(m, 1H), 8.13-7.99(m, 2H), 7.60-7.49(m, 1H), 7.27(t, J=54.1Hz, 1H).

[0294] Intermediate 17: 6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine.

[0295] [ka] The title compound was prepared in a similar manner to Intermediate 16, using 2-(3-(difluoromethoxy)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS(ESI):C 13 Calculated mass of H8F3N3O, 279.0; observed m / z, 280.2 [M+H] + .

[0296] Intermediate 18: 6-(4-chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine.

[0297] [ka] The title compound was prepared in a similar manner to Intermediate 16, using 2-(3-(difluoromethoxy)-4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS(ESI):C 13 Calculated mass for H8ClF2N3O: 295.0; observed m / z: 296.0 [M+H] + .

[0298] Intermediate 19: 6-(3-(1,1-difluoroethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine.

[0299] [ka] The title compound was prepared in a similar manner to Intermediate 16, using 2-(3-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS(ESI):C 14H 10 Calculated mass of F3N3, 277.1; observed m / z, 278.1 [M+H] + .

[0300] Intermediate 20: 6-(3-(1,1-difluoroethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine.

[0301] [ka] The title compound was prepared in a similar manner to Intermediate 16, using 2-(3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS(ESI):C 14 H 11 Calculated mass of F2N3, 259.1; observed m / z, 260.1 [M+H] + .

[0302] Intermediate 21: 6-(3-(difluoromethyl)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine.

[0303] [ka] The title compound was prepared in a similar manner to Intermediate 16, using 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 9) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine. MS (ESI): C 13 Calculated mass of H7F4N3, 281.1; observed m / z, 282.1 [M+H] + .

[0304] Intermediate 22: 6-(4-chloro-3-(difluoromethoxy)phenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine.

[0305] [ka] The title compound was prepared in a similar manner to Intermediate 16, using 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 9) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine and 2-(3-(difluoromethoxy)-4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS(ESI):C 13 Calculated mass for H7ClF3N3O: 313.0; observed m / z: 314.1 [M+H] + .

[0306] Intermediate 23: 6-(3-(difluoromethoxy)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine.

[0307] [ka] The title compound was prepared in a similar manner to Intermediate 16, using 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 9) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine and 2-(3-(difluoromethoxy)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS(ESI):C 13 Calculated mass of H7F4N3O: 297.1; observed m / z: 298.0 [M+H] + .

[0308] Intermediate 24: 6-(3-(1,1-difluoroethyl)phenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine.

[0309] [ka] The title compound was prepared in a similar manner to Intermediate 16, using 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 9) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine and 2-(3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS(ESI):C 14 H 10 Calculated mass of F3N3, 277.1; observed m / z, 278.1 [M+H] + .

[0310] Intermediate 25: 6-(4-fluoro-3-methylphenyl)-1H-pyrazolo[4,3-b]pyridine.

[0311] [ka] The title compound was prepared in a similar manner to Intermediate 16, using 2-(4-fluoro-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS(ESI):C 13 H 10 Calculated mass of FN3, 227.1; observed m / z, 228.1 [M+H] + .

[0312] Intermediate 26: 6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine.

[0313] [ka] The title compound was prepared in a similar manner to Intermediate 16, using 6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine. MS(ESI):C 14 H 10 Calculated mass of F3N3, 277.1; observed m / z, 278.1 [M+H] + .

[0314] Intermediate 27: 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid.

[0315] [ka] Step A. Ethyl 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetate. To a solution of 6-[3-(difluoromethyl)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine (Intermediate 16, 2.00 g, 7.6 mmol) in DMF (30 mL) 、 Cs2CO3 (2.72 g, 8.35 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Ethyl chloroacetate (895 μL, 8.36 mmol, 1.14 g / mL) was added to the reaction mixture at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was poured into water (50 mL), and the mixture was extracted with EtOAc (3 × 75 mL). The organic layers were combined and concentrated under reduced pressure. Purification (FCC, SiO2, 0-75% n-heptane / EtOAc) gave the title compound (1.60 g, 4.58 mmol, 60%) as a white powder. MS (ESI): C 17 H 14 Calculated mass of F3N3O2, 349.1; observed m / z, 350.1 [M+H] + .

[0316] Step B: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetic acid. To a solution of ethyl 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetate (1.60 g, 4.58 mmol) in 1,4-dioxane (14 mL) and water (9 mL), lithium hydroxide monohydrate (385 mg, 9.17 mmol) was added, and the mixture was stirred at room temperature for 1 h, concentrated to approximately 9 mL, and diluted with water (75 mL). The mixture was acidified to pH 4 with 1 M hydrochloric acid. The precipitate was collected and washed with water (2 × 10 mL) and EtO (3 × 10 mL) to give the title compound (1.74 g, 5.416 mmol, 118%) as a white powder, which was used without further purification. MS(ESI):C 15 H 10 Calculated mass of F3N3O2, 321.1; observed m / z, 322.1 [M+H] + .

[0317] Intermediate 28: 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid.

[0318] [ka] The title compound was prepared in a similar manner to Intermediate 27, using 6-(3-(difluoromethyl)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 21) instead of 6-[3-(difluoromethyl)-4-fluorophenyl]-1H-pyrazolo[4,3-b]pyridine. MS(ESI): C 15 Calculated mass of H9F4N3O2, 339.1; observed m / z, 340.1 [M+H] + .

[0319] Intermediate 29: 2-(6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid.

[0320] [ka] The title compound was prepared in a similar manner to Intermediate 27, using 6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate 17) instead of 6-[3-(difluoromethyl)-4-fluorophenyl]-1H-pyrazolo[4,3-b]pyridine. MS(ESI):C 15 H 10 Calculated mass of F3N3O3: 337.1; observed m / z: 338.1 [M+H] + .

[0321] Intermediate 30: 6-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine

[0322] [ka] 6-Bromo-1H-pyrazolo[4,3-b]pyridine (845 mg, 4.27 mmol), 4-fluorophenylboronic acid (896 mg, 6.40 mmol), and sodium carbonate (1.36 g, 12.8 mmol) were placed in dioxane (15 mL) and water (5 mL). A stream of nitrogen gas was bubbled through the reaction mixture for 10 minutes, then tetrakis(triphenylphosphine)palladium (247 mg, 0.21 mmol) was added, and the reaction mixture was stirred at 90 °C for 24 hours. The reaction mixture was cooled to room temperature, diluted with water and DCM, and the aqueous layer was extracted with DCM (2 times). The combined organic layers were dried (MgSO), concentrated, and adsorbed onto silica gel. Purification (FCC, SiO, 0-100% hexanes / EtOAc, then 3-8% MeOH / DCM) gave the title compound (530 mg, 58%). MS (ESI): C 12 Calculated mass of H8FN3, 213.1; observed m / z, 214.1 [M+H] + .

[0323] Intermediate 31: 2-(6-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid.

[0324] [ka] Step A: Ethyl 2-(6-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate. 6-(4-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate. 6-(4-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate 30, 470 mg, 2.20 mmol) was placed in DMF (7 mL) and heated to 50 °C. To this solution was added sodium hydride (60% dispersion in mineral oil, 106 mg, 2.65 mmol), and the reaction mixture was stirred at 50 °C for 15 min. The mixture was allowed to cool to room temperature, and ethyl bromoacetate (515 mg, 3.09 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, poured onto ice, and extracted with EtOAc (2×). The combined organic layers were dried (MgSO4) and concentrated. Purification (FCC, SiO2, 0–100% hexanes / EtOAc) yielded 422 mg (1.41 mmol, 64%). MS(ESI):C 16 H 14 Calculated mass of FN3O2, 299.1; observed m / z, 300.1 [M+H] + .

[0325] Step B: 2-(6-(4-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid. Ethyl 2-(6-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate (400 mg, 1.34 mmol) and sodium hydroxide (80 mg, 2.01 mmol) were dissolved in a 1:1 mixture of water and acetonitrile (10 mL). The reaction mixture was stirred at 50° C. overnight. The pH of the mixture was adjusted to pH 1 with aqueous HCl and then extracted with DCM (4×). The combined organic layers were dried over MgSO4 and concentrated to give the title compound (400 mg, 1.475 mmol, 110%). The title compound was carried on crude to the next step. MS (ESI): C 14 H 10 Calculated mass of FN3O2, 271.1; observed m / z, 272.1 [M+H] + .

[0326] Intermediate 32: 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid.

[0327] [ka] Step A. Ethyl 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate. To a solution of 6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine (Intermediate 26, 300 mg, 1.08 mmol) in DMF (6 mL) was added CsCO (1.06 g, 3.25 mmol), followed by ethyl acetate (240 mg, 1.41 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and EtO, and the aqueous layer was extracted with EtO (2×). The combined organics were washed with water, brine, dried over MgSO, and concentrated. Purification (FCC, SiO, 0-100% hexanes / EtOAc) gave the title compound (313 mg, 0.861 mmol, 80%). MS (ESI): C 18 H 16 Calculated mass of F3N3O2, 363.1; observed m / z, 364.1 [M+H] + .

[0328] Step B. 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid. To a solution of ethyl 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate (313 mg, 0.861 mmol) in THF (15 mL) was added 4 N aqueous lithium hydroxide (5 mL). The biphasic mixture was stirred vigorously overnight. The solution was partitioned between water and EtO and the layers were separated. The organic layer was extracted with water (2×). The combined aqueous layers were acidified to pH 1 with 1 N HCl. The resulting precipitate was collected by filtration, washed with water and dried to afford the title compound (293 mg, 100%) as a white solid. This compound was sufficiently pure to be carried on to the next step without further purification. MS (ESI): C 16 H 12 Calculated mass of F3N3O2, 335.1; observed m / z, 336.1 [M+H] + .

[0329] Intermediate 33: 3-Ethynylazetidine·HCl salt.

[0330] [ka] Step A. tert-Butyl 3-ethynylazetidine-1-carboxylate. tert-Butyl 3-formylazetidine-1-carboxylate (500 mg, 2.70 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (10 wt%, 9.2 mL, 4.05 mmol), and potassium carbonate (1120 mg, 8.10 mmol) were placed in methanol (10 mL). The reaction mixture was stirred at room temperature for 3 hours and diluted with diethyl ether and water. The organic layer was separated, washed with water followed by saturated aqueous sodium carbonate, dried over MgSO, and concentrated. Purification (FCC, SiO, 0-25% ethyl acetate / hexanes gradient) afforded the title compound (356 mg, 1.96 mmol, 73%). 1H NMR (400MHz, CDCl3)δ 4.14(t, J=8.5Hz, 2H), 3.94(dd, J=8.2, 6.3Hz, 2H), 3.36-3.25(m, 1H), 2.28(d, J=2.4Hz, 1H), 1.44(s, 9H).

[0331] Step B: 3-Ethynylazetidine HCl salt. tert-Butyl 3-ethynylazetidine-1-carboxylate (50 mg, 0.28 mmol) was dissolved in 4 N HCl in dioxane (1 mL), and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated, and the hydrochloride salt of the title compound was used directly in the next step without further purification.

[0332] Intermediate 34: (Z)-3-(prop-1-en-1-yl)azetidine·HCl salt.

[0333] [ka] Step A. tert-Butyl (Z)-3-(prop-1-en-1-yl)azetidine-1-carboxylate. Ethyl(triphenylphenyl)phosphonium bromide (1.21 g, 3.24 mmol) was suspended in dry THF (15 mL). The suspension was cooled to 0 °C. n-BuLi (2.5 M in hexanes, 1.3 mL, 3.24 mmol) was added dropwise to the stirring reaction mixture, and the reaction mixture was stirred at 0 °C for 1 h. tert-Butyl 3-formylazetidine-1-carboxylate (500 mg, 2.70 mmol) was added slowly to the reaction mixture at 0 °C, and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated and partitioned between DCM and water. The aqueous layer was extracted with DCM (twice), and the combined organics were concentrated. The crude material was purified on silica gel (FCC, SiO 2 , 0-50% ethyl acetate / hexanes gradient) to afford the title compound as a 7:1 mixture of Z / E isomers (318 mg, 1.61 mmol, 60%). 1H NMR (400MHz, CDCl3)δ 5.69-5.56(m, 1H), 5.56-5.45(m, 1H), 4.12(t, J=8.4Hz, 2H), 3.67(dd, J=8.4, 6. 0Hz, 2H), 3.50-3.47(m, 1H), 1.58(dd, J=6.8, 1.6Hz, 3H), 1.44(d, J=1.5Hz, 9H).

[0334] Step B. (Z)-3-(prop-1-en-1-yl)azetidine HCl salt. tert-Butyl (Z)-3-(prop-1-en-1-yl)azetidine-1-carboxylate (50 mg, 0.28 mmol) was dissolved in 4 N HCl in dioxane (1 mL), and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated, and the hydrochloride salt of the title compound was used directly in the next step.

[0335] Intermediate 35: 3-(2,2-difluorovinyl)azetidine hydrochloride.

[0336] [ka] Step A. tert-Butyl 3-(2,2-difluorovinyl)azetidine-1-carboxylate. tert-Butyl 3-formylazetidine-1-carboxylate (1000 mg, 5.40 mmol) and triphenylphosphine (2.8 g, 10.8 mmol) were placed in dry DMF (10 mL) and heated to 100 °C with stirring. Sodium chlorodifluoroacetate (1.7 g, 10.8 mmol) was added portionwise over 30 min, and the reaction mixture was stirred at 100 °C for 15 min. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove DMF, diluted with DCM, and briefly shaken with 30% aqueous HO. The resulting biphasic mixture was further diluted with DCM and water. The aqueous layer was extracted with DCM (twice), and the combined organics were concentrated. Purification (FCC, SiO2, 0-50% ethyl acetate / hexanes gradient) gave the title compound (786 mg, 3.58 mmol, 66%). 1H NMR (400MHz, CDCl3)δ 4.51-4.37(m, 1H), 4.14(t, J=8.4Hz, 2H), 3.70(dd, J=8.6, 6.0Hz, 2H), 3.39-3.27(m, 1H), 1.44(d, J=0.7Hz, 9H).

[0337] Step B. 3-(2,2-Difluorovinyl)azetidine HCl salt. tert-Butyl 3-(2,2-difluorovinyl)azetidine-1-carboxylate (75 mg, 0.34 mmol) was dissolved in 4 N HCl in dioxane (1 mL), and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated, and the hydrochloride salt of the title compound was used directly in the next step.

[0338] Intermediate 36: (Z)-3-(2-fluorovinyl)azetidine·HCl salt.

[0339] [ka] Step A. tert-Butyl (Z)-3-(2-fluorovinyl)azetidine-1-carboxylate. tert-Butyl 3-(2,2-difluorovinyl)azetidine-1-carboxylate (500 mg, 2.28 mmol), bis(neopentylglycolato)diboron (1.6 g, 6.8 mmol), and water (120 μL, 6.8 mmol) were dissolved in dimethylacetamide (10 mL). The solution was degassed by sparging with N. Copper thiophene-2-carboxylate (43 mg, 0.23 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos®) (135 mg, 0.23 mmol), and lithium tert-butoxide (565 mg, 6.8 mmol) were added (a strong exotherm occurred upon addition of the base). The reaction mixture was stirred at 40 °C overnight and then partitioned between water and a 3:1 ethyl acetate / hexane mixture. The organic layer was extracted with DCM (2 times). The organic layer was concentrated. Purification (FCC, SiO, 0-50% ethyl acetate / hexane gradient) afforded the title compound (319 mg, 1.59 mmol, 70%) contaminated with approximately 20 mol % starting material and 7 mol % E isomer. The title compound was carried on directly to the next step. 1 H NMR (400MHz, CDCl3): δ 6.66-6.30(m, 1H), 5.17-4.86(m, 1H), 4.19-4.12(m, 2H), 3.74-3.67(m, 2H), 3.66-3.53(m, 1H), 1.44(s, 9H).

[0340] Step B. (Z)-3-(2-fluorovinyl)azetidine HCl salt. tert-Butyl (Z)-3-(2-fluorovinyl)azetidine-1-carboxylate (319 mg, 1.59 mmol) was dissolved in 4 N HCl in dioxane (5 mL), and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated, and the hydrochloride salt of the title compound was used directly without further purification.

[0341] Intermediate 37: 6-(5-chloro-2-thienyl)-1H-pyrazolo[4,3-b]pyridine.

[0342] [ka] To a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (500 mg, 2.52 mmol) in degassed 1,4-dioxane (39.4 mL) and water (9.55 mL) was added 5-chlorothiophene-2-boronic acid (431 mg, 2.654 mmol), potassium fluoride (440 mg, 7.57 mmol), and tetrakis(triphenylphosphine)palladium(0) (205 mg, 0.177 mmol). The reaction mixture was stirred under argon at 80° C. for 1 h. Additional 5-chlorothiophene-2-boronic acid (123 mg, 0.757 mmol) and tetrakis(triphenylphosphine)palladium(0) (87 mg, 0.075 mmol) were introduced, and the reaction mixture was stirred under argon at 80° C. for 2 h. The reaction mixture was diluted with water (40 mL) and DCM (30 mL). The layers were separated and the aqueous layer was extracted with DCM (3x40 mL). The combined organics were dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification (FCC, SiO2, 25-100% n-heptane / EtOAc) afforded the title compound (419 mg, 1.78 mmol, 70%) as a yellow powder after trituration with diethyl ether (7 mL). MS (ESI): C 10 Calculated mass of H6ClN3s, 235.0; observed m / z, 236.0 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ 13.42(s, 1H), 8.82(d, J=2.0Hz, 1H), 8.35-8.29(m, 1H), 8.17-8.09(m, 1H), 7.64(d, J=4.0Hz, 1H), 7.25(d, J=4.0Hz, 1H).

[0343] Intermediate 38: 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine.

[0344] [ka] A suspension of 6-bromo-1H-pyrazolo[4,3-b]pyridine (5.0 g, 25.3 mmol), 3-(trifluoromethyl)phenylboronic acid (5.8 g, 30.3 mmol), and palladium-tetrakis(triphenylphosphine) (1.5 g, 1.3 mmol) in aqueous sodium carbonate (2 M, 32.5 mL, 64.9 mmol) and 1,4-dioxane (96.9 mL) was stirred at 120 °C under a nitrogen atmosphere. After 48 h, EtOAc was added, and the mixture was washed with HO (twice). The organic layer was dried (NaSO) and concentrated in vacuo. The residue was purified (FCC, SiO in heptane, 0-50% EtOAc) to give a yellowish solid. The solid was triturated with EtO and collected by filtration to give the title compound (2.1 g, 8.0 mmol, 31.6%). MS (ESI): C 13 Calculated mass of H8F3N3, 263.1; observed m / z, 264.1 [M+H] + .

[0345] Intermediate 39: 2-(6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid.

[0346] [ka] Sodium hydride (60% dispersion in mineral oil, 387.5 mg, 9.7 mmol) was added to a stirred solution of 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate 38,850 mg, 3.2 mmol) in DMF (20 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes. Ethyl bromoacetate (0.54 mL, 4.8 mmol) was then added, and the reaction mixture was allowed to warm to room temperature. After 16 hours, aqueous potassium hydroxide (1 M, 16.1 mL, 16.1 mmol) was added to the reaction mixture and stirred for 1 hour. The mixture was concentrated in vacuo, and the residue was dissolved in water and washed with EtOAc. The aqueous layer was separated and acidified with 1 M HCl. The solid was filtered, washed with water, dried, and triturated from EtO to give the title product (630 mg, 2.0 mmol, 60.7%). MS(ESI):C 15 H10 Calculated mass of F3N3O2, 321.1; observed m / z, 322.2 [M+H] + .

[0347] Intermediate 40: ethyl 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate.

[0348] [ka] 6-Bromo-1H-pyrazolo[4,3-b]pyridine (639.5 mg, 3.2 mmol) was added to a suspension of NaH (60% dispersion in mineral oil, 180.8 mg, 4.5 mmol) in DMF (33.7 mL) at room temperature under a nitrogen atmosphere. After 10 min, ethyl bromoacetate (0.5 mL, 4.5 mmol) was added to the reaction mixture. After 16 h, water (80 mL) was added to induce slow precipitation. The solid was collected by filtration and purified (FCC, SiO, 0-90% EtOAc in hexanes) to give the title compound (917 mg, 3.2 mmol, 100%). MS (ESI): C 10 H 10 Calculated mass for BrNO, 283.0; observed m / z, 284.0 [M+H] + .

[0349] Intermediate 41: 2-(6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid.

[0350] [ka] Lithium hydroxide (4 M in water, 1.9 mL, 7.6 mmol) was added to a mixture of ethyl 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate (Intermediate 40, 1.54 g, 5.4 mmol) in THF (65.9 mL) at room temperature. After 16 h, complete conversion was observed and the precipitate was collected by filtration, rinsed with THF, and dried under vacuum to give the title compound (1.16 g, 4.5 mmol, 83.6%). MS (ESI): mass calculated for CHBrNO, 255.0; m / z found, 256.0 [M+H]+ . 1 H NMR (500Hz, DMSO-d6) δ 8.50 (d, J=2.0Hz, 1H), 8.26-8.24 (m, 1H), 8.17-8.15 (m, 1H), 4.66 (s, 2H).

[0351] Intermediate 42: 2-(6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3,3-difluoroazetidin-1-yl)ethan-1-one.

[0352] [ka] 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (Intermediate 41, 300 mg, 1.2 mmol), 3,3-difluoroazetidine hydrochloride (182 mg, 1.4 mmol) in DCM (11.7 mL) 、 A mixture of T3P® (50% solution in DMF, 2.1 mL, 3.5 mmol) and DIPEA (0.4 mL, 2.5 mmol) was stirred at room temperature. After 16 h, complete conversion was observed and water (20 mL) was added. The mixture was extracted with EtOAc (3×35 mL). The combined organics were dried (MgSO), filtered, and concentrated in vacuo to give the title compound (287 mg, 0.9 mmol, 74.0%). MS (ESI): C 11 Calculated mass for HBrFNO: 330.0; observed m / z: 331.0 [M+H] + .

[0353] Intermediate 43: 2-(6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one.

[0354] [ka] The title compound was prepared in a similar manner to Intermediate 42, using pyrrolidine instead of 3,3-difluoroazetidine hydrochloride. MS(ESI):C 12 H 13Calculated mass for BrNO, 308.0; observed m / z, 309.0 [M+H] + .

[0355] Intermediate 44: (S)-2-(6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoropyrrolidin-1-yl)ethan-1-one.

[0356] [ka] The title compound was prepared in a manner similar to Example 42, using (S)-3-fluoropyrrolidine hydrochloride instead of 3,3-difluoroazetidine hydrochloride. MS (ESI): C 12 H 12 Calculated mass for BrFNO: 326.0; observed m / z: 327.0 [M+H] + .

[0357] Intermediate 45: (R)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoropyrrolidin-1-yl)ethan-1-one.

[0358] [ka] The title compound was prepared in a similar manner to Intermediate 42, using (R)-3-fluoropyrrolidine hydrochloride instead of 3,3-difluoroazetidine hydrochloride. MS(ESI):C 12 H 12 Calculated mass for BrFNO: 326.0; observed m / z: 327.0 [M+H] + .

[0359] Intermediate 46: ethyl 2-(6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate.

[0360] [ka] The title compound was prepared in a similar manner to Intermediate 40, using 6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine. MS(ESI):C 11 H 12 Calculated mass for BrNO, 297.0; observed m / z, 298.1 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 8.57(d, J=1.9Hz, 1H), 8.53(d, J=1.9Hz, 1H), 5.33(s, 2H), 4.14(q, J=7.1Hz, 2H), 2.52(s, 3H), 1.20(t, J=7.1Hz, 3H).

[0361] Intermediate 47: 2-(6-Bromo-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid.

[0362] [ka] The title compound was prepared in a similar manner to Intermediate 41, using ethyl 2-(6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate (Intermediate 46) instead of ethyl 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate. MS (ESI): mass calculated for CHBrNO, 269.0; m / z found, 270.0 [M+H] + .

[0363] Intermediate 48: 1-(azetidin-1-yl)-2-(6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one.

[0364] [ka] The title compound was prepared in a similar manner to Intermediate 13, using 2-(6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (Intermediate 47) instead of 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid. MS (ESI): C 12 H 13 Calculated mass for BrNO, 308.0; observed m / z, 309.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.54-8.53(m, 1H), 8.42-8.41(m, 1H), 5.09(s, 2H), 4.19(t, J=7.7Hz, 2H), 3.90(t, J=7.8Hz, 2H), 2.50(s, 3H), 2.30-2.22(m, 2H).

[0365] Intermediate 49: 3-Methyl-6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine.

[0366] [ka] A mixture of 6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine (200 mg, 0.9 mmol), (3-(trifluoromethyl)phenyl)boronic acid (358 mg, 1.9 mmol), cesium carbonate (614.6 mg, 1.9 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (48.3 mg, 0.07 mmol) in 1,4-dioxane (8.7 mL) and distilled water (1.9 mL) was heated to 90 °C. After 16 h, the reaction mixture was concentrated in vacuo. Purification (FCC, SiO, 0-90% EtOAc in hexanes) gave the title compound (229 mg, 0.8 mmol, 87.6%). MS (ESI): C 14 H 10 Calculated mass of F3N3, 277.1; observed m / z, 278.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 13.06(s, 1H), 8.83(d, J=2.0Hz, 1H), 8.23(d, J=2.0Hz, 1H), 8.15-8.10(m, 2H), 7.84-7.74(m, 2H), 2.57(s, 3H).

[0367] Example 50: Ethyl 2-(3-methyl-6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate.

[0368] [ka] The title compound was prepared in a similar manner to Intermediate 40, using 3-methyl-6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate 49) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine. MS (ESI): C 18 H 16 Calculated mass of F3N3O2, 363.1; observed m / z, 364.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 8.85(d, J=2.1Hz, 1H), 8.35(d, J=2.1Hz, 1H), 8.16-8.10(m, 2H), 7.83-7.73(m , 2H), 5.48(s, 2H), 4.21(q, J=7.1Hz, 2H), 2.66(s, 3H), 1.24(t, J=7.1Hz, 3H).

[0369] Intermediate 51: 2-(3-methyl-6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid.

[0370] [ka] The title compound was prepared in a similar manner to Intermediate 41, using ethyl 2-(3-methyl-6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate (Intermediate 50) instead of ethyl 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate. MS (ESI): C 16 H 12 Calculated mass of F3N3O2, 335.1; observed m / z, 336.1 [M+H] + .

[0371] Intermediate 52: 2-(6-(4-fluoro-3-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid.

[0372] [ka] A mixture of 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (Intermediate 41, 90 mg, 0.27 mmol), 4-fluoro-3-methylboronic acid (63 mg, 0.41 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (9.9 mg, 0.014 mmol), sodium carbonate (86 mg, 0.82 mmol), 1,4-dioxane (1.4 mL) and water (0.8 mL) Heated at 110° C. for 16 h. The reaction mixture was diluted with water and washed with ethyl acetate (3×). The aqueous layer was acidified with 1N HCl and extracted with ethyl acetate (3×). The combined organics were dried (MgSO4) and concentrated to give the title compound (71 mg, 0.25 mmol, 92%) in sufficient purity for subsequent transformations. MS (ESI): C 15 H 12 Calculated mass of FN3O2, 285.1; observed m / z, 286.1 [M+H] + .

[0373] Intermediate 53: 2-(6-(4-fluoro-2-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid.

[0374] [ka] The title compound was prepared in a similar manner to Intermediate 52, using 4-fluoro-2-methylboronic acid instead of 4-fluoro-3-methylboronic acid. MS(ESI):C 15 H 12 Calculated mass of FN3O2, 285.1; observed m / z, 286.1 [M+H] + .

[0375] Intermediate 54: Ethyl 2-(6-(3-(hydroxymethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate.

[0376] [ka] A mixture of ethyl 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate (Intermediate 40, 1.5 g, 5.3 mmol), (3-(hydroxymethyl)phenyl)boronic acid (1.6 g, 10.6 mmol), cesium carbonate (3.4 g, 10.6 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (270 mg, 0.4 mmol) in 1,4-dioxane (49 mL) was heated to 90 °C. After 3 days, water (100 mL) was added, and the mixture was extracted with EtOAc (3 × 150 mL). The combined organics were dried (MgSO), filtered, and concentrated in vacuo. Purification (FCC, SiO2, 0-90% EtOAc in hexanes) gave the title compound (325 mg, 1.0 mmol, 20%). MS (ESI): C 17 H 17 Calculated mass of N3O3, 311.1; observed m / z, 312.2 [M+H] + . 1H NMR (500MHz, DMSO-d6)δ 8.89(d, J=1.9Hz, 1H), 8.50-8.48(m, 1H), 8.38-8.36(m, 1H), 7.78-7.75(m, 1H), 7.71-7.67(m, 1H), 7.50(t , J=7.6Hz, 1H), 7.43-7.39(m, 1H), 5.49(s, 2H), 4.61(s, 2H), 4.16(q, J=7.1Hz, 2H), 1.21(t, J=7.1Hz, 3H).

[0377] Intermediate 55: ethyl 2-(6-(3-(fluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate.

[0378] [ka] Bis(2-methoxyethyl)aminosulfur trifluoride (Deoxoxo Fluor®) (0.2 mL, 1.2 mmol) was added to a mixture of ethyl 2-(6-(3-(hydroxymethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate (Intermediate 54, 300 mg, 1.0 mmol) in DCM (6.6 mL) at 0° C. under a nitrogen atmosphere. After 3 h, the reaction mixture was slowly poured into a mixture of saturated aqueous NaHCO3 (20 mL) and DCM (20 mL) at 0° C. The mixture was extracted with DCM (3×30 mL). The combined organics were dried (MgSO4), filtered, and concentrated in vacuo to give the title compound. MS (ESI): C 17 H 16 Calculated mass of FN3O2, 313.1; observed m / z, 314.2 [M+H] + .

[0379] Intermediate 56: 2-(6-(3-(fluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid.

[0380] [ka] The title compound was prepared in a similar manner to Intermediate 41, using ethyl 2-(6-(3-(fluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate (Intermediate 55) instead of ethyl 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate. MS (ESI): C 15 H 12 Calculated mass of FN3O2, 285.1; observed m / z, 286.1 [M+H] + .

[0381] Intermediate 57: 2-(6-(3,4-difluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate ethyl ester.

[0382] [ka] The title compound was prepared in a similar manner to Intermediate 54, using 3,4-difluorophenylboronic acid instead of (3-(hydroxymethyl)phenyl)boronic acid. MS (ESI): C 16 H 13 Calculated mass of F2N3O2, 317.1; observed m / z, 318.1 [M+H] + .

[0383] Intermediate 58: 2-(6-(3,4-difluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid.

[0384] [ka] The title compound was prepared in a similar manner to Intermediate 41, using ethyl 2-(6-(3,4-difluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate (Intermediate 57) instead of ethyl 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate. MS (ESI): C 14 Calculated mass of H9FN3O2, 289.1; observed m / z, 290.1 ​​[M+H] + .

[0385] Intermediate 59: 2-Bromo-N-cyclopropylacetamide.

[0386] [ka] Bromoacetyl chloride (1 mL, 12.0 mmol) was added to a mixture of TEA (1.7 mL) and cyclopropylamine (0.8 mL, 12.0 mmol) in acetonitrile (15 mL) at -78 °C. The ice-cooled reaction mixture was allowed to warm slowly to room temperature. After 2 h, water (30 mL) was added and the mixture was extracted with DCM (3 x 40 mL). The combined organics were concentrated in vacuo to give a mixture of the title compounds contaminated with chloro derivatives. MS (ESI): mass calculated for CHBrNO, 177.0; m / z found, 178.0 [M+H] + .

[0387] Intermediate 60: 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine.

[0388] [ka] A suspension of 6-bromo-1H-pyrazolo[4,3-b]pyridine (5.0 g, 25.3 mmol), 3-(trifluoromethyl)phenylboronic acid (5.8 g, 30.3 mmol), and palladium-tetrakis(triphenylphosphine) (1.5 g, 1.3 mmol) in aqueous sodium carbonate (2 M, 32.5 mL, 64.9 mmol) and 1,4-dioxane (96.9 mL) was stirred at 120 °C under a nitrogen atmosphere. After 48 h, EtOAc was added, and the mixture was washed with HO (twice). The organic layer was dried (NaSO) and concentrated in vacuo. The residue was purified (FCC, SiO in heptane, 0-50% EtOAc) to give a yellowish solid. The solid was triturated with EtO and collected by filtration to give the title compound (2.1 g, 8.0 mmol, 31.6%). MS (ESI): C 13 Calculated mass of H8F3N3, 263.1; observed m / z, 264.1 [M+H] + .

[0389] Intermediate 61: 2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0390] [ka] A solution of 4-bromo-2-(difluoromethyl)-1-fluorobenzene (20 g, 88.9 mmol), bis(pinacolato)diboron (24.8 g, 97.8 mmol), potassium acetate (26.2 g, 267 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (3.12 g, 4.44 mmol) in 1,4-dioxane (400 mL) was purged with N and the reaction mixture was stirred at 90 °C overnight. Upon completion, the reaction mixture was cooled to room temperature, filtered through Celite®, and washed with EtOAc. The filtrate was washed with water and brine. The combined organics were dried over NaSO, filtered, and concentrated to give a clear oil (22.1 g, 81.0 mmol, 91%), which solidified on standing. 1 H NMR (400 MHz, chloroform-d) δ 8.12-8.00 (m, 1H), 7.96-7.85 (m, 1H), 7.17-7.06 (m, 1H), 6.88 (t, J = 54.9 Hz, 1H), 1.35 (s, 12H). MS (ESI): C 13 H 16 Calculated mass of BF3O2, 272.1; observed m / z, 273.0 [M+H] + .

[0391] Intermediate 62: 2-(3-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0392] [ka] Step A: 4-Bromo-2-(1,1-difluoroethyl)-1-fluorobenzene. In a round-bottom flask, a mixture of 1-(5-bromo-2-fluorophenyl)-1-ethanone (2.5 g, 11.5 mmol, 1 equiv) and DAST (1.9 mL, 14.4 mmol, 1.25 equiv) was heated at 60 °C for 16 h. Then, saturated aqueous NaHCO3 was added slowly at 0 °C, followed by extraction with DCM. The organic layers were combined, dried over MgSO4, filtered, and partially concentrated (the product is volatile). Purification (FCC, SiO2, 100% DCM) afforded the title compound (3 g, 7.5 mmol, 60% purity, 65%) as a brown oil. 1 H NMR (300MHz, CDCl3) δ7.73-7.61 (m, 1H), 7.60-7.48 (m, 1H), 7.02 (t, J=9.4Hz, 1H), 1.98 (t, J=18.6Hz, 3H).

[0393] Step B: 2-(3-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. In a round-bottom flask, bis(pinacolato)diboron (2.87 g, 11.3 mmol), potassium acetate (2.22 g, 22.6 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (615 mg, 0.75 mmol) were added to a solution of 4-bromo-2-(1,1-difluoroethyl)-1-fluorobenzene (3 g, 7.5 mmol) in dry 1,4-dioxane (40 mL). The mixture was purged with nitrogen and stirred at 90 °C for 16 h. A saturated solution of NaHCO was added, and the mixture was extracted with EtOAc. The combined organics were dried (MgSO), filtered and concentrated in vacuo to give a brown oil (2.15 g, 7.53 mmol) which was used in the next step without further purification. MS (ESI): C 14 H 18 Calculated mass of BF3O2, 286.1; observed m / z, 287.1 [M+H] + .

[0394] Intermediate 63: 2-(3-(ditetramethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0395] [ka] The title compound was prepared in a similar manner to Intermediate 61, using 1-bromo-3-(difluoromethyl)benzene instead of 4-bromo-2-(difluoromethyl)-1-fluorobenzene. No mass observed.

[0396] Intermediate 64: 2-(3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0397] [ka] The title compound was prepared in a similar manner to Intermediate 61, using 1-bromo-3-(1,1-difluoroethyl)benzene instead of 4-bromo-2-(difluoromethyl)-1-fluorobenzene. No mass observed.

[0398] Intermediate 65: 2-(3-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0399] [ka] The title compound was prepared in a similar manner to Intermediate 61, using 1-bromo-3-(1,1-difluoroethyl)benzene instead of 4-bromo-2-(difluoromethyl)-1-fluorobenzene. MS(ESI):C 13 H 16 Calculated mass for BF3O2, 272.1; observed m / z, 273.2 [M+H]+.

[0400] Intermediate 66: 2-(3-(difluoromethoxy)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0401] [ka] The title compound was prepared in a similar manner to Intermediate 61, using 4-bromo-2-(difluoromethoxy)-1-fluorobenzene instead of 4-bromo-2-(difluoromethyl)-1-fluorobenzene. MS(ESI):C 13 H 16 Calculated mass for BF3O3, 288.1; observed m / z, 289.0 [M+H]+.

[0402] Intermediate 67: 2-(4-chloro-3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0403] [ka] The title compound was prepared in a similar manner to Intermediate 61, using 4-bromo-1-chloro-2-(difluoromethoxy)benzene instead of 4-bromo-2-(difluoromethyl)-1-fluorobenzene. 1 H NMR (500MHz, CDCl3) δ 7.62-7.56 (m, 2H), 7.44 (d, J=7.9Hz, 1H), 6.56 (t, J=73.6Hz, 1H), 1.34 (s, 12H).

[0404] Intermediate 68: 2-(4-chloro-3-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0405] [ka] The title compound was prepared in a similar manner to Intermediate 62, using 5-bromo-2-chlorobenzaldehyde instead of 1-(5-bromo-2-fluorophenyl)-1-ethanone in Step A. MS(ESI): C 13 H 16 Calculated mass for BClF2O2, 288.1; observed m / z, 289.1 [M+H]+.

[0406] Intermediate 69: 2-(4-chloro-3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0407] [ka] The title compound was prepared in a similar manner to Intermediate 62, using 1-(5-bromo-2-chlorophenyl)ethanon-1-one in place of 1-(5-bromo-2-fluorophenyl)-1-ethanone in Step A. 1 H NMR (500MHz, CDCl3) δ 8.02(d, J=1.5Hz, 1H), 7.79-7.71(m, 1H), 7.47-7.39(m, 1H), 2.03(t, J=18.4Hz, 3H), 1.34(s, 12H).

[0408] Intermediate 70: 1-(2-(6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetyl)azetidin-3-yl 4-methylbenzenesulfonate.

[0409] [ka] To a solution of 1-(3-hydroxyazetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate (Example 113, 32 mg, 0.085 mmol) in DCM (2 mL) was added triethylamine (0.06 mL, 0.42 mmol), N,N-dimethylpyridin-4-amine (1 mg, 0.0085 mmol), and 4-methylbenzenesulfonyl chloride (24 mg, 0.13 mmol). The resulting mixture was stirred at room temperature for 15 h. The mixture was then diluted with EtOAc (20 mL), washed with brine (20 mL), then with water (2 × 20 mL), dried over NaSO, and concentrated. The residue was purified by FCC (hexane / EtOAc, 0–100%) to give the title compound (36 mg, 0.067 mmol). MS(ESI):C 25 H 21 Calculated mass of F3N4O4S, 530.1; observed m / z, 531.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.83(d, J=1.8Hz, 1H), 8.31(d, J=1.0Hz, 1H), 8.10-8.04(m, 1H), 7.90-7 .85(m, 1H), 7.85-7.79(m, 1H), 7.78-7.73(m, 2H), 7.73-7.68(m, 1H), 7. 67-7.60(m, 1H), 7.40-7.32(m, 2H), 5.15-5.01(m, 3H), 4.38-4.29(m, 1H) ), 4.28-4.19(m, 1H), 4.19-4.12(m, 1H), 4.04-3.94(m, 1H), 2.46(s, 3H).

[0410] Example Example 1: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]ethanone.

[0411] [ka] A stock solution of the active ester was prepared by dissolving 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (Intermediate 27, 180 mg, 0.56 mmol), DIPEA (290 μL, 1.7 mmol), HOBt (113 mg, 0.84 mmol), and EDCI (161 mg, 1.04 mmol) in dry ACN (6 mL). A 1 mL aliquot (30 mg of carboxylic acid, 0.93 mmol) was added to a vial containing 3-(trifluoromethyl)azetidin-3-ol (15.8 mg, 0.112 mmol). The reaction mixture was stirred overnight and purified by reverse-phase HPLC (METHOD D) to give the title compound (3.4 mg, 8%). MS (ESI): C 19 H 14 Calculated mass of FNO, 444.1; observed m / z, 445.0 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.81(d, J=1.9Hz, 1H), 8.30(d, J=1.0Hz, 1H), 7.95-7.91(m, 1H), 7.89-7.84(m, 1H), 7.78-7.70(m, 1H), 7.32-7.27(m, 1H), 6.98(t, J=54.9Hz, 1H), 5.12(d, J=7.2Hz, 2H), 4.37-4.29(m, 2H), 4.13-4.01(m, 2H).

[0412] Example 2: 2-[6-[3(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methyleneazetidin-1-yl)ethanone.

[0413] [ka] A solution of 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (Intermediate 27, 50 mg, 0.156 mmol), 3-methyleneazetidine hydrochloride (33 mg, 0.31 mmol), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP®) (97 mg, 0.19 mmol), and DIPEA (110 μL, 0.62 mmol) in dry DCM (2 mL) was stirred at room temperature for 30 min. The reaction mixture was loaded directly onto a silica gel column and purified by chromatography (FCC, SiO, 0-10% MeOH / DCM gradient) to give 24.9 mg (0.0669 mmol, 43% yield) of the title compound. MS (ESI): C 19 H 15 Calculated mass of FNO, 372.1; observed m / z, 373.0 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.81(d, J=1.9Hz, 1H), 8.31(d, J=1.0Hz, 1H), 7.95(dd, J=1.9, 1.0Hz, 1H), 7.89-7.85(m, 1H), 7.74(d, J=5. 1Hz, 1H), 7.30(d, J=9.3Hz, 1H), 6.98(t, J=54.9Hz, 1H), 5.12(s, 2H), 5.10-5.01(m, 2H), 4.63-4.55(m, 4H).

[0414] Example 3: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(methylamino)azetidin-1-yl]ethanone.

[0415] [ka] Step A. tert-Butyl (1-(2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetyl)azetidin-3-yl)(methyl)carbamate. The title compound was prepared in a manner similar to that of Example 1, using tert-butyl azetidin-3-yl(methyl)carbamate instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 24 H 26 Calculated mass of F3N5O3: 489.2; observed m / z: 490.0 [M+H] + .

[0416] Step B. 2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(methylamino)azetidin-1-yl]ethanone. tert-Butyl (1-(2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetyl)azetidin-3-yl)(methyl)carbamate (151 mg, 0.309 mmol) was dissolved in 4 mL of a 1:1 mixture of trifluoroacetic acid (TFA) and DCM. The reaction mixture was stirred at room temperature for 1 h, concentrated, and partitioned between DCM and saturated aqueous NaHCO3. The aqueous layer was extracted with DCM (2x) and the combined organics were concentrated and purified on silica gel (non-polar phase DCM, polar phase 10% NHOH / MeOH, 0-10% gradient) to give the title compound (45 mg, 0.116 mmol, 37% yield). MS (ESI): C 19 H 18 Calculated mass of FNO, 389.1; observed m / z, 390.0 [M+H] + . 1H NMR (400MHz, CDCl3)δ 8.80(d, J=1.9Hz, 1H), 8.29(d, J=1.0Hz, 1H), 7.95(dd, J=2.0, 1.0Hz, 1H), 7.89-7.84(m, 1H), 7.78-7.71(m, 1H), 7.32-7 .27(m, 1H), 6.98(t, J=54.9Hz, 1H), 5.08(s, 2H), 4.32-4.16(m, 2H), 3.89-3.70(m, 2H), 3.66-3.55(m, 1H), 2.37(s, 3H).

[0417] Example 4: N-[1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]azetidin-3-yl]-N-methyl-acetamide.

[0418] [ka] To a solution of 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(methylamino)azetidin-1-yl]ethanone (Example 3, 36.5 mg, 0.094 mmol) and triethylamine (40 μL, 0.28 mmol) in dry DCM (1 mL) was added acetyl chloride (10 μL, 0.14 mmol). The reaction mixture was stirred at room temperature for 15 minutes, then loaded directly onto a silica gel column and purified by chromatography (0-10% MeOH / DCM) to give 28.8 mg (0.067 mmol, 71% yield) of the title compound. MS (ESI): C 21 H 20 Calculated mass of F3N5O2, 431.2; observed m / z, 432.1 [M+H] + . 1H NMR (400MHz, CDCl3)δ 8.80(d, J=1.9Hz, 1H), 8.30(d, J=1.0Hz, 1H), 7.95(dd, J=1.9, 1.0Hz, 1H), 7.91-7.83(m, 1H), 7.79-7.64(m, 1H), 7.34-7.27(m, 1H) ), 6.98(t, J=54.9Hz, 1H), 5.33-5.19(m, 1H), 5.13-5.00(m, 2H), 4.39-4.21(m, 2H), 4.19-4.02(m, 2H), 3.01(s, 3H), 2.10(s, 3H).

[0419] Example 5: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0420] [ka] Method A. To a mixture of 6-[3-(difluoromethyl)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine (Intermediate 16, 1.10 g, 4.18 mmol) and CsCO (2.05 g, 6.29 mmol) in dry DMF (22 mL), 2-chloro-1-(3-fluoroazetidin-1-yl)ethanone (Intermediate 1, 697 mg, 4.60 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:EtOAc (100:0 → 0:100). The product was recrystallized from ethanol (20 mL) and triturated with water (20 mL) to give the title compound (950 mg, 2.51 mmol, 60%) as a white powder. MS (ESI): C 18 H 14 Calculated mass of FNO, 378.1; observed m / z, 379.1 [M+H] + .

[0421] Method B. A solution of 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12, 8.33 g, 26.6 mmol) in dioxane (200 mL) was treated with 2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.7 g, 32 mmol), cesium carbonate (26 g, 80 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (RuPhos Pd G3) (1.1 g, 1.3 mmol, 5 mol%), and the reaction mixture was stirred at reflux for 16 hours. The mixture was allowed to cool to room temperature, concentrated to remove dioxane, partitioned between DCM and water, and the aqueous layer was extracted with DCM (2x). The combined organics were washed with 4N LiOH, dried (MgSO4), filtered, and stirred overnight with SiliaMetSH thiol scavenger. Filtered through Celite®, purified on silica gel (0-10% MeOH / DCM gradient), and recrystallized from hot ethanol followed by hot ethyl acetate. 4.78 g (12.6 mmol, 47% yield) of the title compound was isolated. MS (ESI): C 18 H 14 Calculated mass of FNO, 378.1; observed m / z, 379.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ8.88 (d, J=2.0Hz, 1H), 8.43(dd, J=2.0, 1.0Hz, 1H), 8.37(d, J=0.9Hz, 1H), 8.10-8.01(m, 2H), 7.62-7.54(m, 1H), 7.30(t, J=54.1Hz, 1 H), 5.55-5.37(m, 1H), 5.36(d, J=17.0Hz, 1H), 5.32(d, J=17.0Hz, 1H), 4.60-4.47(m, 1H), 4.36-4.20(m, 2H), 4.03-3.91(m, 1H).

[0422] Example 6: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide.

[0423] [ka] Method A. To sodium hydride (60% in mineral oil, 164 mg, 4.10 mmol) in dry DMF (8.9 mL) was added a solution of 6-[3-(difluoromethyl)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine (Intermediate 16,900 mg, 3.42 mmol) in dry DMF (8.9 mL) at 0 °C under argon. The reaction mixture was stirred at 0 °C for 0.5 h. To the reaction mixture was added 2-chloro-N,N-dimethylacetamide (387 μL, 3.76 mmol, 1.18 g / mL). The reaction mixture was allowed to reach room temperature and stirred for 3 h. The reaction was then poured into water (20 mL) and diluted with ethyl acetate (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organics were dried over Na SO , filtered, and concentrated under reduced pressure. Purification (FCC, SiO, 1-20% EtOAc / EtOH) gave a solid that was recrystallized from ethanol (8 mL) to give the title compound (708 mg, 2.03 mmol, 59%) as a white powder. MS (ESI): 17 H 15 Calculated mass of FNO, 348.1; observed m / z, 349.2 [M+H] + .

[0424] Method B. To a solution of 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-N,N-dimethylacetamide (Intermediate 10, 14.0 g, 49.5 mmol) in dioxane (400 mL) was added 2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (16.2 g, 59.4 mmol), cesium carbonate (48.4 g, 149 mmol), and RuPhos Pd G3 (2.35 g, 2.81 mmol). The reaction mixture was stirred at reflux for 4 h, concentrated to approximately 25 mL of dioxane, and diluted with water (300 mL). The resulting precipitate was collected by filtration, then adsorbed onto Celite® and purified by silica gel chromatography (FCC; 0-10% MeOH / DCM). The product obtained in this manner was recrystallized from hot ethyl acetate and then a second time from hot ethanol. The crystals were redissolved in hot ethyl acetate and reconcentrated. This process was repeated three times until all remaining traces of ethanol were removed. The product was dried in a vacuum oven at 60°C for 72 h to give 6.97 g (20.0 mmol, 40% yield) of the title compound. MS (ESI): C 17 H 15 Calculated mass of FNO, 348.1; observed m / z, 349.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.87(d, J=2.0Hz, 1H), 8.42-8.39(m, 1H), 8.33(d, J=1.0Hz, 1H), 8.08-8.01(m, 2H) , 7.60-7.54(m, 1H), 7.30(t, J=54.1Hz, 1H), 5.53(s, 2H), 3.13(s, 3H), 2.85(s, 3H).

[0425] Example 7: 2-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide.

[0426] [ka] A mixture of 2-(6-bromopyrazolo[4,3-b]pyridin-1-yl)-N,N-dimethyl-acetamide (Intermediate 10, 583 mg, 2.06 mmol), 4-fluoro-3-methylphenylboronic acid (381 mg, 2.47 mmol), sodium carbonate (655 mg, 6.18 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (196 mg, 0.268 mmol) in water (1.72 mL) and acetonitrile (11.2 mL) in a capped vial flushed with argon was stirred under microwave irradiation at 120 °C for 2 h. The reaction mixture was evaporated, and the residue was purified by gradient silica gel column chromatography eluting with n-hexane:ethyl acetate:methanol (1:3:0 → 0:1:0 → 0:98:2 → 0:9:1). The product obtained from FCC was then recrystallized from ethanol (20 mL) to give the title compound (380 mg, 1.22 mmol, 59%) as an off-white crystalline solid. MS (ESI): C 17 H 17 Calculated mass of FNO, 312.1; observed m / z, 313.2 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.83(d, J=1.9Hz, 1H), 8.36-8.29(m, 1H), 8.30(s, 1H), 7.79-7.70(m, 1H), 7.69-7.59(m , 1H), 7.31(t, J=9.1Hz, 1H), 5.51(s, 2H), 3.13(s, 3H), 2.85(s, 3H), 2.40-2.27(m, 3H).

[0427] Example 8: N,N-Dimethyl-2-[6-[6-(trifluoromethyl)-2-pyridyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide.

[0428] [ka] To a solution of 2-(6-bromopyrazolo[4,3-b]pyridin-1-yl)-N,N-dimethyl-acetamide (Intermediate 10, 50 mg, 0.177 mmol) in degassed 1,4-dioxane (550 μL) was added 2-(tributylstannyl)-6-(trifluoromethyl)pyridine (85 mg, 0.195 mmol) and bis(triphenylphosphine)palladium(II) chloride (13.0 mg, 0.0185 mmol). The reaction mixture was stirred at 100 °C for 17 h. The reaction mixture was evaporated. Purification (FCC, SiO, 10-100% hexane / EtOAc) afforded the title compound (35 mg, 0.100 mmol, 56%) as a white powder after trituration with diethyl ether (4 mL). MS (ESI): C 16 H 14 Calculated mass of FNO, 349.1; observed m / z, 350.2 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 9.26(d, J=1.9Hz, 1H), 8.79-8.67(m, 1H), 8.44(d, J=8.1Hz, 1H), 8.38(s, 1H), 8.2 8(t, J=7.9Hz, 1H), 7.96(d, J=7.7Hz, 1H), 5.59(s, 2H), 3.15(s, 3H), 2.86(s, 3H).

[0429] Example 9: 2-[6-[4-chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0430] [ka] To a solution of 2-(6-bromopyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethanone (Intermediate 12,400 mg, 1.28 mmol) in degassed 1,4-dioxane (24.7 mL) and water (7.38 mL) was added 2-[4-chloro-3-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (408 mg, 1.34 mmol), potassium fluoride (223 mg, 3.84 mmol), and tetrakis(triphenylphosphine)palladium(0) (104 mg, 0.090 mmol). The reaction mixture was stirred under argon at 80 °C for 2 h. Additional 2-[4-chloro-3-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (117 mg, 0.384 mmol), potassium fluoride (223 mg, 3.84 mmol), and tetrakis(triphenylphosphine)palladium(0) (104 mg, 0.090 mmol) were added, and the reaction mixture was stirred at 80 °C for 15 h. The mixture was diluted with water (32 mL) and DCM (50 mL), and the layers were separated. The aqueous layer was extracted with DCM (2 × 40 mL), and the combined organics were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:methanol:ethyl acetate (1:1:0 → 0:1:0 → 0:95:5). The residue was recrystallized from ethanol (30 mL) to give the title compound (288 mg, 0.701 mmol, 55%). was obtained as a white powder. MS(ESI):C 18 H 14 Calculated mass for ClF3N4O2: 410.1; observed m / z: 411.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.91(d, J=1.9Hz, 1H), 8.47-8.40(m, 1H), 8.41-8.34(m, 1H), 7.85-7.77(m, 2H), 7.73(dd, J=8.4, 2.0Hz, 1H), 7.45(t , J=73.2Hz, 1H), 5.61-5.34(m, 2H), 5.31(d, J=17.2Hz, 1H), 4.66-4.45(m, 1H), 4.39-4.15(m, 2H), 4.07-3.88(m, 1H).

[0431] Example 10: 2-[6-[4-chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethylacetamide.

[0432] [ka] A mixture of 2-(6-bromopyrazolo[4,3-b]pyridin-1-yl)-N,N-dimethylacetamide (Intermediate 10, 46 mg, 0.162 mmol), 2-[4-chloro-3-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (59 mg, 0.194 mmol), 1,1'-bis(diphenylphosphino)ferroceradium(II) dichloride (12 mg, 0.0164 mmol), and KCO (45 mg, 0.326 mmol) in degassed 1,4-dioxane (920 μL) and water (92 μL) was stirred at 80 °C for 4 h under argon. The reaction mixture was evaporated. Purification (FCC, SiO2, 0-5% EtOAc / EtOH) gave the title compound (32 mg, 0.084 mmol, 52%) as an off-white powder. MS (ESI): C 17 H 15 Calculated mass for ClF2N4O2: 380.1; observed m / z: 381.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.90(d, J=1.9Hz, 1H), 8.44-8.39(m, 1H), 8.34(s, 1H), 7.82-7.79(m, 1H), 7.76(d, J=8.6Hz, 1H ), 7.72(dd, J=8.4, 1.9Hz, 1H), 7.44(t, J=73.2Hz, 1H), 5.52(s, 2H), 3.13(s, 3H), 2.85(s, 3H).

[0433] Example 11: N,N-Dimethyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide.

[0434] [ka] A mixture of 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-N,N-dimethylacetamide (Intermediate 10, 100 mg, 0.35 mmol), 3-(trifluoromethyl)phenylboronic acid (100 mg, 0.53 mmol), cesium carbonate (230 mg, 0.71 mmol), and PdCl(dppf) (18 mg, 0.07 mmol) was suspended in dioxane / water (1:1). The reaction mixture was heated to 90° C. under argon for 3 hours, then cooled to room temperature and extracted with ethyl acetate (×3). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. Purification (Method A) gave the title compound (95 mg, 77%). MS (ESI): C 17 H 15 Calculated mass of FNO, 348.1; observed m / z, 349.1 [M+H] + . 1 H NMR (500MHz, CDCl3)δ8.83 (d, J=1.8Hz, 1H), 8.32(d, J=0.9Hz, 1H), 7.97(dd, J=1.9, 1.0Hz, 1H), 7.89(s, 1H), 7.84(d, J=7.7Hz , 1H), 7.70(d, J=7.8Hz, 1H), 7.63(t, J=7.7Hz, 1H), 5.31(d, J=5.0Hz, 2H), 3.20(s, 3H), 3.00(s, 3H).

[0435] Example 12: 2-[6-[3-(difluoromethyl)-4-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-morpholino-ethanone.

[0436] [ka] To 6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate 16, 31.2 mg, 0.117 mmol) in DMF (1 mL) stirring at room temperature was added CsCO (114.7 mg, 0.352 mmol), followed by 4-(2-chloroacetyl)morpholine (34.1 mg, 0.208 mmol). The reaction was stirred overnight at room temperature, then filtered through a 0.45 μM syringe filter and purified by preparative HPLC (Method D). Repurification (FCC, SiO, 0-5% MeOH in DCM) gave the title compound. MS (ESI): C 19 H 17 Calculated mass of F3N4O2, 390.1; observed m / z, 391.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.79 (d, J=1.9Hz, 1H), 8.30(d, J=1.0Hz, 1H), 7.93(dd, J=1.9, 1.0Hz, 1H), 7.88-7.82(m, 1H), 7. 78-7.69(m, 1H), 7.31-7.24(m, 1H), 6.97(t, J=54.9Hz, 1H), 5.29(s, 2H), 3.72-3.56(m, 8H).

[0437] Example 13: 1-Morpholino-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0438] [ka] To a stirred solution of 2-(6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (Intermediate 39, 100 mg, 0.3 mmol), morpholine (40.7 mg, 0.5 mmol), and HATU (177.5 mg, 0.5 mmol) in DMF (1.4 mL) was added DIPEA (0.11 mL, 0.6 mmol) at room temperature. After 16 h, EtOAc was added, and the mixture was washed with brine (twice). The residue was purified (FCC, SiO, 0-10% MeOH in DCM) to give a yellowish solid. Purification by Method F. (Stationary phase: C18 XBridge 30 x 100 mm 5 um), Mobile phase: 60% 0.1% NH4CO3H / NH4OH pH 9 in water, 40% CH3CN to 43% 0.1% NH4CO3H / NH4OH pH 9 in water, gradient to 57% CH3CN) gave the title compound (55 mg, 45%). MS (ESI): C 19 H 17 Calculated mass of F3N4O2, 390.1; observed m / z, 391.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.84(d, J=1.85Hz, 1H), 8.32(d, J=0.92Hz, 1H), 7.98(dd, J=1.85, 1.16Hz, 1H), 7.89(s, 1H), 7 .84(d, J=7.63Hz, 1H), 7.73-7.68(m, 1H), 7.67-7.60(m, 1H), 5.31(s, 2H), 3.74-3.58(m, 8H).

[0439] Example 14: N-Cyclopropyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide.

[0440] [ka] 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate 60, 170 mg, 0.65 mmol) was dissolved in DMF (5 mL) and placed under a nitrogen atmosphere. Sodium hydride (60% dispersion in mineral oil, 78 mg, 1.94 mmol) was added, and the reaction mixture was stirred for 10 minutes, at which point 2-bromo-N-cyclopropylacetamide (Intermediate 59, 230 mg, 1.29 mmol) was added. The reaction mixture was stirred at 80 °C for 5 hours, cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate (3 times), and the combined organics were dried (MgSO4), and concentrated. Purification (FCC, SiO2, 0-90% EtOAc / hexanes) afforded 44.2 mg (0.123 mmol, 19% yield) of the title compound. MS (ESI): C 18 H 15 Calculated mass of FNO, 360.1; observed m / z, 361.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.94(d, J=2.0Hz, 1H), 8.57-8.54(m, 1H), 8.40-8.33(m, 2H), 8.18-8.13(m, 2H), 7.85 -7.76(m, 2H), 5.15(s, 2H), 2.69-2.62(m, 1H), 0.66-0.61(m, 2H), 0.48-0.42(m, 2H).

[0441] Example 15: N-(1-Methylazetidin-3-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide.

[0442] [ka] A mixture of 2-(6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (Intermediate 39, 78.8 mg, 0.2 mmol), 1-methylazetidin-3-amine (25.4 mg, 0.3 mmol), HATU (102.6, 0.3 mmol), and DIPEA (0.13 mL, 0.7 mmol) in DMF (1.5 mL) was stirred at room temperature. Upon completion, the reaction mixture was purified using reverse-phase HPLC (Method C) to afford the desired product along with minor impurities. The material was loaded onto a catch-and-release column (Agilent Bond Elut SCX). The column was washed with MeOH, and the filtrate was discarded. The column was then washed with a solution of approximately 5% NH in MeOH to afford the title compound (28.3 mg, 0.07 mmol, 29.6%). (ESI):C 19 H 18 Calculated mass of FNO, 389.2; observed m / z, 390.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.94(d, J=1.9Hz, 1H), 8.83-8.77(m, 1H), 8.58-8.55(m, 1H), 8.36-8.34(m, 1H), 8.18-8.13(m, 2H), 7.84- 7.76(m, 2H), 5.21(s, 2H), 4.29-4.20(m, 1H), 3.54(t, J=7.0Hz, 2H), 3.01-2.88(m, 2H), 2.29-2.23(s, 3H).

[0443] Example 16: 1-(3-Fluoroazetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate.

[0444] [ka] A mixture of 2-(6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (Intermediate 39, 78.8 mg, 0.2 mmol), 3-fluoroazetidine hydrochloride (32.8 mg, 0.3 mmol), T3P® (50% solution in DMF, 0.44 mL, 0.7 mmol), DIPEA (0.13 mL, 0.7 mmol) in DMF (2.0 mL) was stirred at room temperature. After completion, the reaction mixture was purified using reverse-phase HPLC (Method C) to give the title compound (29.4 mg, 0.06 mmol, 24.3%). MS (ESI): C 18 H 14 Calculated mass of FNO, 378.1; observed m / z, 379.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 8.94(d, J=1.9Hz, 1H), 8.51-8.49(m, 1H), 8.39-8.38(m, 1H), 8.17-8.12(m, 2H), 7.86-7 .76(m, 2H), 5.56-5.29(m, 3H), 4.61-4.48(m, 1H), 4.37-4.18(m, 2H), 4.04-3.90(m, 1H).

[0445] Example 17: 1-(3,3-Difluoroazetidin-1-yl)-2-[6-(2,4-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0446] [ka] A mixture of 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3,3-difluoroazetidin-1-yl)ethan-1-one (Intermediate 42, 116 mg, 0.4 mmol), (2,4-difluorophenyl)boronic acid (111 mg, 0.7 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (18.0 mg, 0.02 mmol), and cesium carbonate (229.0 mg, 0.7 mmol) in 1,4-dioxane (3.2 mL) was heated to 75° C. After 16 h, the reaction mixture was concentrated in vacuo. The crude material was purified (FCC, SiO, 0-90% EtOAc in hexanes) to give the title compound (29.7 mg, 0.08 mmol, 23.1%). MS (ESI): C 17 H 12 Calculated mass of FNO, 364.1; observed m / z, 365.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.68(t, J=1.9Hz, 1H), 8.39(d, J=1.0Hz, 1H), 8.29-8.26(m, 1H), 7.72(td, J=8.8, 6.5Hz, 1H), 7. 52-7.45(m, 1H), 7.33-7.27(m, 1H), 5.41(s, 2H), 4.74(t, J=12.3Hz, 2H), 4.37(t, J=12.5Hz, 2H).

[0447] Example 18: 1-(Azetidin-1-yl)-2-[6-(5-chloro-2-thienyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0448] [ka] The title compound was prepared in a similar manner to Example 9, except that 1-(azetidin-1-yl)-2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (intermediate 14) was used instead of intermediate 12, and 5-chlorothiophene-2-boronic acid was used instead of 2-[4-chloro-3-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS (ESI): C 15 H 12 Calculated mass of ClFN4OS, 350.1; observed m / z, 351.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.91(d, J=1.9Hz, 1H), 8.39-8.28(m, 1H), 7.68(d, J=4.0Hz, 1H), 7.29(d, J=4.0 Hz, 1H), 5.12(s, 2H), 4.31-4.15(m, 2H), 4.00-3.79(m, 2H), 2.38-2.18(m, 2H).

[0449] Example 19: 1-(Azetidin-1-yl)-2-[6-[5-(difluoromethyl)-2-thienyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0450] [ka] The title compound was prepared in a similar manner to Example 9, except that 1-(azetidin-1-yl)-2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (Intermediate 14) was used in place of Intermediate 12, and 2-(5-(difluoromethyl)thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 8) was used in place of 2-[4-chloro-3-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS (ESI): C 16 H 13 Calculated mass of F3N4OS, 366.1; observed m / z, 367.1 [M+H] + . 1H NMR (300MHz, DMSO-d6)δ 8.99(d, J=1.8Hz, 1H), 8.52-8.42(m, 1H), 7.83-7.74(m, 1H), 7.64-7.54(m, 1H), 7.38(t , J=55.1Hz, 1H), 5.15(s, 2H), 4.30-4.15(m, 2H), 3.99-3.84(m, 2H), 2.36-2.19(m, 2H).

[0451] Example 20: 1-(Azetidin-1-yl)-2-[3-fluoro-6-[5-(trifluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0452] [ka] The title compound was prepared in a similar manner to Example 9, using 1-(azetidin-1-yl)-2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (intermediate 14) instead of intermediate 12 and 4,4,5,5-tetramethyl-2-(5-(trifluoromethyl)thiophen-2-yl)-1,3,2-dioxaborolane instead of 4-fluoro-3-methylboronic acid. MS (ESI): C 16 H 12 Calculated mass of F4N4OS, 384.1; observed m / z, 385.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 9.01 (d.

[0453] Example 21: 1-(Azetidin-1-yl)-2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0454] [ka] The title compound was prepared in a manner similar to that of Example 13, using 2-(6-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (Intermediate 31) instead of Intermediate 16 and azetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 17 H 15 Calculated mass of FNO, 310.1; observed m / z, 311.2 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 8.80(d, J=1.9Hz, 1H), 8.27(d, J=1.0Hz, 1H), 7.98-7.96(m, 1H), 7.67-7.61( m, 2H), 7.24-7.17(m, 2H), 5.06(s, 2H), 4.13-4.05(m, 4H), 2.34-2.26(m, 2H).

[0455] Example 22: 1-(Azetidin-1-yl)-2-[6-(3-chlorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0456] [ka] The title compound was prepared in a similar manner to Example 17, using 1-(azetidin-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (Intermediate 13) instead of Intermediate 42, (3-chlorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C. MS (ESI): C 17 H 15 Calculated mass for ClNO, 326.1; observed m / z, 327.2 [M+H] + . 1H NMR (500MHz, DMSO-d6)δ 8.90-8.89(m, 1H), 8.47-8.45(m, 1H), 8.36-8.34(m, 1H), 7.93-7.89(m, 1H), 7.84-7.79(m, 1H), 7.61-7.5 6(m, 1H), 7.55-7.51(m, 1H), 5.26(s, 2H), 4.20(t, J=7.7Hz, 2H), 3.91(t, J=7.7Hz, 2H), 2.31-2.22(m, 2H).

[0457] Example 23: 1-(Azetidin-1-yl)-2-[6-[3-(fluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0458] [ka] The title compound was prepared in a similar manner to Example 16, using azetidine instead of 3-fluoroazetidine hydrochloride, 2-(6-(3-(fluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (Intermediate 56) instead of Intermediate 39, and DCM instead of DMF. MS (ESI): C 18 H 17 Calculated mass of FNO, 324.1; observed m / z, 325.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.89(d, J=1.9Hz, 1H), 8.41-8.40(m, 1H), 8.35-8.34(m, 1H), 7.89-7.82(m, 2H), 7.63-7.58(m, 1H), 7.54-7.50 (m, 1H), 5.54(d, J=47.7Hz, 2H), 5.27(s, 2H), 4.20(t, J=7.7Hz, 2H), 3.91(t, J=7.7Hz, 2H), 2.31-2.22(m, 2H).

[0459] Example 24: 1-(Azetidin-1-yl)-2-[6-[3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0460] [ka] In a similar manner to Example 17, 1-(azetidin-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (Intermediate 13) was used in place of Intermediate 42, (3-(difluoromethyl)phenyl)boronic acid was used in place of 2,4-difluorophenylboronic acid, and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) was used in place of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The title compound was prepared using [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex. The reaction mixture was heated to 90°C. MS (ESI): C 18 H 16 Calculated mass of FNO, 342.1; observed m / z, 343.1 [M+H] + . 1 H NMR (600 MHz, DMSO-d6)δ 8.90(d, J=1.9Hz, 1H), 8.45-8.43(m, 1H), 8.37-8.35(m, 1H), 8.02-7.99(m, 2H), 7.73-7.65(m, 2H), 7 .14(t, J=55.8Hz, 1H), 5.27(s, 2H), 4.20(t, J=7.7Hz, 2H), 3.91(t, J=7.7Hz, 2H), 2.30-2.23(m, 2H).

[0461] Example 25: 1-(Azetidin-1-yl)-2-[6-[3-(1,1-difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0462] [ka] The title compound was prepared in a manner similar to Example 6, Method A, using 6-[3-(1,1-difluoroethyl)phenyl]pyrazolo[4,3-b]pyridine (Intermediate 20) instead of Intermediate 16 and 1-(azetidin-1-yl)-2-chloroethan-1-one instead of 2-chloro-N,N-dimethylacetamide. MS (ESI): C 19 H 18Calculated mass of FNO, 356.1; observed m / z, 357.2 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.91(d, J=1.9Hz, 1H), 8.48-8.40(m, 1H), 8.36(s, 1H), 8.05-7.88(m, 2H), 7.74-7.57(m, 2H), 5.27(s, 2H), 4.27-4.13(m, 2H), 3.97-3.83(m, 2H), 2.33-2.19(m, 2H), 2.07(t, J=18.9Hz, 3H).

[0463] Example 26: 1-(Azetidin-1-yl)-2-[6- [3-(1,1-difluoroethyl)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0464] [ka] The title compound was prepared in a manner similar to Example 5, Method A, using 6-(3-(1,1-difluoroethyl)phenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 24) in place of Intermediate 16 and 1-(azetidin-1-yl)-2-chloroethan-1-one in place of Intermediate 1. MS (ESI): C 19 H 17 Calculated mass of FNO, 374.1; observed m / z, 375.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.96(d, J=1.8Hz, 1H), 8.53-8.42(m, 1H), 8.06-7.88(m, 2H), 7.75-7.60(m, 2H), 5.16(s , 2H), 4.30-4.15(m, 2H), 3.98-3.82(m, 2H), 2.36-2.18(m, 2H), 2.06(t, J=18.9Hz, 3H).

[0465] Example 27: 1-(Azetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0466] [ka] The title compound was prepared in a similar manner to Example 16, using azetidine instead of 3-fluoroazetidine hydrochloride and DCM instead of DMF. MS(ESI):C 18 H 15 Calculated mass of FNO, 360.1; observed m / z, 361.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 8.94(d, J=1.9Hz, 1H), 8.52-8.50(m, 1H), 8.38-8.36(m, 1H), 8.18-8.12(m, 2H), 7.85-7. 76(m, 2H), 5.27(s, 2H), 4.20(t, J=7.6Hz, 2H), 3.91(t, J=7.7Hz, 2H), 2.31-2.22(m, 2H).

[0467] Example 28: 1-(Azetidin-1-yl)-2-[3-methyl-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0468] [ka] The title compound was prepared in a similar manner to Example 17, using 1-(azetidin-1-yl)-2-(6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (Intermediate 48) instead of Intermediate 42, (3-(trifluoromethyl)phenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C. MS (ESI): C 19 H 17 Calculated mass of FNO, 374.1; observed m / z, 375.2 [M+H] + . 1H NMR (500MHz, DMSO-d6)δ 8.87(d, J=1.9Hz, 1H), 8.43(d, J=2.0Hz, 1H), 8.17-8.10(m, 2H), 7.85-7.76(m, 2H), 5.1 7(s, 2H), 4.17(t, J=7.7Hz, 2H), 3.90(t, J=7.7Hz, 2H), 2.56(s, 3H), 2.30-2.21(m, 2H).

[0469] Example 29: 1-(Azetidin-1-yl)-2-[6-(3,4-dichlorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0470] [ka] The title compound was prepared in a similar manner to Example 17, using 1-(azetidin-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (Intermediate 13) instead of Intermediate 42, (3,4-dichlorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C. MS (ESI): C 17 H 14 Calculated mass for ClNO, 360.1; observed m / z, 361.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.91(d, J=2.0Hz, 1H), 8.50-8.47(m, 1H), 8.37-8.34(m, 1H), 8.13(d, J=2.1Hz, 1H), 7.87- 7.79(m, 2H), 5.25(s, 2H), 4.20(t, J=7.7Hz, 2H), 3.91(t, J=7.7Hz, 2H), 2.31-2.22(m, 2H).

[0471] Example 30: 1-(azetidin-1-yl)-2-[6-(2,3-dichlorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0472] [ka] The title compound was prepared in a similar manner to Example 17, using 1-(azetidin-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (Intermediate 13) instead of Intermediate 42, (2,3-dichlorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C. MS (ESI): C 17 H 14 Calculated mass for ClNO, 360.1; observed m / z, 361.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.59(d, J=1.8Hz, 1H), 8.39-8.37(m, 1H), 8.22-8.20(m, 1H), 7.79-7.76(m, 1H), 7.56-7. 49(m, 2H), 5.23(s, 2H), 4.20(t, J=7.7Hz, 2H), 3.90(t, J=7.7Hz, 2H), 2.30-2.20(m, 2H).

[0473] Example 31: 1-(Azetidin-1-yl)-2-[6-(3-chloro-2-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0474] [ka] The title compound was prepared in a similar manner to Example 17, using 1-(azetidin-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (Intermediate 13) instead of Intermediate 42, (3-chloro-2-fluorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C. MS (ESI): C 17 H 14 Calculated mass of ClFNO, 344.1; observed m / z, 345.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.71(t, J=1.9Hz, 1H), 8.39-8.37(m, 1H), 8.35-8.33(m, 1H), 7.73-7.68(m, 1H), 7.65-7.61(m, 1H) , 7.44-7.39(m, 1H), 5.25(s, 2H), 4.21(t, J=7.7Hz, 2H), 3.90(t, J=7.7Hz, 2H), 2.31-2.22(m, 2H).

[0475] Example 32: 1-(azetidin-1-yl)-2-[6-(3,4-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0476] [ka] The title compound was prepared in a similar manner to Example 17, using 1-(azetidin-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (Intermediate 13) instead of Intermediate 42, (3,4-difluorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C. MS (ESI): C 17 H 14 Calculated mass of FNO, 328.1; observed m / z, 329.1 [M+H] + . 1 H NMR (600MHz, DMSO-d6)δ 8.89(d, J=1.9Hz, 1H), 8.46-8.43(m, 1H), 8.36-8.34(m, 1H), 7.97(ddd, J=12.1, 7.8, 2.4Hz, 1H), 7.73-7.6 8(m, 1H), 7.66-7.60(m, 1H), 5.25(s, 2H), 4.20(t, J=7.7Hz, 2H), 3.91(t, J=7.7Hz, 2H), 2.30-2.23(m, 2H).

[0477] Example 33: 1-(Azetidin-1-yl)-2-[6-[2-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0478] [ka] The title compound was prepared in a similar manner to Example 17, using 1-(azetidin-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (Intermediate 13) instead of Intermediate 42, (2-fluoro-3-(trifluoromethyl)phenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C. MS (ESI): C 18 H 14 Calculated mass of FNO, 378.1; observed m / z, 379.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.72(t, J=1.8Hz, 1H), 8.41-8.36(m, 2H), 8.03-7.98(m, 1H), 7.93-7.88(m, 1H), 7.60(t, J =7.8Hz, 1H), 5.27(s, 2H), 4.21(t, J=7.7Hz, 2H), 3.90(t, J=7.7Hz, 2H), 2.30-2.22(m, 2H).

[0479] Example 34: 1-(Azetidin-1-yl)-2-[6-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0480] [ka] The title compound was prepared in a manner similar to Example 6, Method A, using 6-(3-(1,1-difluoroethyl))-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate 19) instead of Intermediate 16 and 1-(azetidin-1-yl)-2-chloroethan-1-one instead of 2-chloro-N,N-dimethylacetamide. MS (ESI): C 19 H 17 Calculated mass of FNO, 374.1; observed m / z, 375.1 [M+H] + .1 H NMR (500MHz, DMSO-d6)δ 8.88(d, J=2.0Hz, 1H), 8.45-8.39(m, 1H), 8.37-8.33(m, 1H), 8.03-7.97(m, 1H), 7.94(dd, J=7.2, 2.4Hz, 1H), 7.55(d d, J=11.0, 8.6Hz, 1H), 5.26(s, 2H), 4.24-4.14(m, 2H), 3.96-3.87(m, 2H), 2.32-2.22(m, 2H), 2.10(t, J=19.2Hz, 3H).

[0481] Example 35: 1-(Azetidin-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0482] [ka] The title compound was prepared in a manner similar to Example 5, Method A, using 1-(azetidin-1-yl)-2-chloroethan-1-one instead of 2-chloro-1-(3-fluoroazetidin-1-yl)ethanone. MS (ESI): C 18 H 15 Calculated mass of FNO, 360.1; observed m / z, 361.2 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.88(d, J=1.9Hz, 1H), 8.48-8.40(m, 1H), 8.40-8.32(m, 1H), 8.13-8.00(m, 2H), 7.64-7.52(m, 1H), 7 .31(t, J=54.1Hz, 1H), 5.27(s, 2H), 4.20(t, J=7.7Hz, 2H), 3.91(t, J=7.7Hz, 2H), 2.36-2.17(m, 2H).

[0483] Example 36: 1-(Azetidin-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0484] [ka] The title compound was prepared in a manner similar to Method A of Example 6, using 6-[3-(difluoromethyl)-4-fluorophenyl]-3-fluoro-pyrazolo[4,3-b]pyridine (Intermediate 21) instead of Intermediate 16 and 1-(azetidin-1-yl)-2-chloroethan-1-one instead of 2-chloro-N,N-dimethylacetamide. MS (ESI): C 18 H 14 Calculated mass of FNO, 378.1; observed m / z, 379.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.93(d, J=1.9Hz, 1H), 8.50-8.46(m, 1H), 8.12-8.04(m, 2H), 7.64-7.56(m, 1H), 7.31(t , J=54.1Hz, 1H), 5.15(s, 2H), 4.27-4.17(m, 2H), 3.94-3.86(m, 2H), 2.33-2.22(m, 2H).

[0485] Example 37: 1-(Azetidin-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-methyl-pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0486] [ka] The title compound was prepared in a manner similar to that of Example 1, using 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (Intermediate 32) instead of Intermediate 27 and azetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS(ESI):C 19 H 17 Calculated mass of FNO, 374.1; observed m / z, 375.1 [M+H] + . 1H NMR (400MHz, CDCl3)δ 8.74(d, J=1.9Hz, 1H), 7.90-7.80(m, 2H), 7.78-7.69(m, 1H), 7.33-7.22(m, 1H), 6 .97(t, J=54.9Hz, 1H), 4.98(s, 2H), 4.1(dt, 4H), 2.70(s, 3H), 2.39-2.23(m, 2H).

[0487] Example 38: 1-(Azetidin-1-yl)-2-[6-(4-chloro-3-methylphenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0488] [ka] The title compound was prepared in a similar manner to Example 17, using 1-(azetidin-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (Intermediate 13) instead of Intermediate 42, (4-chloro-3-methylphenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C. MS (ESI): C 18 H 17 Calculated mass for ClNO, 340.1; observed m / z, 341.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.87(d, J=1.9Hz, 1H), 8.40-8.37(m, 1H), 8.35-8.32(m, 1H), 7.85-7.83(m, 1H), 7.69-7.65(m, 1H), 7.60 -7.57(m, 1H), 5.25(s, 2H), 4.20(t, J=7.7Hz, 2H), 3.91(t, J=7.7Hz, 2H), 2.45(s, 3H), 2.31-2.23(m, 2H).

[0489] Example 39: 1-(Azetidin-1-yl)-2-[6-(4-chloro-3-methylphenyl)-3-methyl-pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0490] [ka] The title compound was prepared in a similar manner to Example 17, using 1-(azetidin-1-yl)-2-(6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (Intermediate 48) instead of Intermediate 42, (4-chloro-3-methylphenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C. MS (ESI): C 19 H 19 Calculated mass for ClNO, 354.1; observed m / z, 355.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.81(d, J=1.9Hz, 1H), 8.31(d, J=1.9Hz, 1H), 7.83-7.80(m, 1H), 7.67-7.63(m, 1H), 7.60-7.56(m, 1H), 5.15(s, 2H), 4.17(t, J=7.7Hz, 2H), 3.90(t, J=7.7Hz, 2H), 2.54(s, 3H), 2.44(s, 3H), 2.30-2.21(m, 2H).

[0491] Example 40: 1-(Azetidin-1-yl)-2-[6-(2-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0492] [ka] The title compound was prepared in a similar manner to Example 17, using 1-(azetidin-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (Intermediate 13) instead of Intermediate 42, (2-fluoro-3-methylphenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C. MS (ESI): C 18 H 17 Calculated mass of FNO, 324.1; observed m / z, 325.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.68(t, J=1.9Hz, 1H), 8.36-8.34(m, 1H), 8.27-8.24(m, 1H), 7.47-7.42(m, 1H), 7.41-7.37(m, 1H), 7.29-7. 24(m, 1H), 5.24(s, 2H), 4.20(t, J=7.7Hz, 2H), 3.90(t, J=7.7Hz, 2H), 2.36-2.32(m, 3H), 2.30-2.22(m, 2H).

[0493] Example 41: 1-(Azetidin-1-yl)-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0494] [ka] The title compound was prepared in a manner similar to Example 6, Method A, using 6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine (Intermediate 17) instead of Intermediate 16 and 1-(azetidin-1-yl)-2-chloroethan-1-one instead of 2-chloro-N,N-dimethylacetamide. MS (ESI): C 18 H 15 Calculated mass of F3N4O2, 376.1; observed m / z, 377.1 [M+H]+ . 1 H NMR (500MHz, DMSO-d6)δ 8.88(d, J=2.0Hz, 1H), 8.42-8.38(m, 1H), 8.37-8.33(m, 1H), 7.83(dd, J=7.6, 2.3Hz, 1H), 7.78-7.73(m, 1H), 7.60(dd, J =10.5, 8.6Hz, 1H), 7.38(t, J=73.2Hz, 1H), 5.25(s, 2H), 4.20(t, J=7.7Hz, 2H), 3.91(t, J=7.7Hz, 2H), 2.34-2.20(m, 2H).

[0495] Example 42: 1-(Azetidin-1-yl)-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0496] [ka] The title compound was prepared in a manner similar to Example 5, Method A, using 6-(3-(difluoromethoxy)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 23) in place of Intermediate 16 and 1-(azetidin-1-yl)-2-chloroethan-1-one in place of Intermediate 1. MS (ESI): C 18 H 14 Calculated mass of F4N4O2, 394.1; observed m / z, 395.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.93(d, J=1.9Hz, 1H), 8.46-8.44(m, 1H), 7.85(dd, J=7.6, 2.3Hz, 1H), 7.80-7.74(m, 1H), 7.62(dd, J=10.5 , 8.6Hz, 1H), 7.38(t, J=73.2Hz, 1H), 5.14(s, 2H), 4.27-4.18(m, 2H), 3.95-3.84(m, 2H), 2.33-2.21(m, 2H).

[0497] Example 43: 1-(Azetidin-1-yl)-2-[6-[4-chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0498] [ka] The title compound was prepared in a manner similar to Example 6, Method A, using 6-[4-chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridine (Intermediate 18) instead of Intermediate 16 and 1-(azetidin-1-yl)-2-chloroethan-1-one instead of 2-chloro-N,N-dimethylacetamide. MS (ESI): C 18 H 15 Calculated mass for ClF2N4O2: 392.1; observed m / z: 393.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.91(d, J=1.9Hz, 1H), 8.48-8.41(m, 1H), 8.40-8.34(m, 1H), 7.85-7.77(m, 2H), 7.74(dd, J=8.4, 1.9Hz, 1 H), 7.45(t, J=73.2Hz, 1H), 5.26(s, 2H), 4.20(t, J=7.6Hz, 2H), 3.91(t, J=7.7Hz, 2H), 2.34-2.20(m, 2H).

[0499] Example 44: 1-(Azetidin-1-yl)-2-[6-[4-chloro-3-(difluoromethoxy)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0500] [ka] The title compound was prepared in a manner similar to Example 5, Method A, using 6-(4-chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate 22) in place of Intermediate 16 and 1-(azetidin-1-yl)-2-chloroethan-1-one in place of Intermediate 1. MS (ESI): C 18 H14 Calculated mass for ClF3N4O2: 410.1; observed m / z: 411.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 9.02-8.88(m, 1H), 8.54-8.39(m, 1H), 7.89-7.70(m, 3H), 7.45(t, J=73.2Hz , 1H), 5.15(s, 2H), 4.33-4.12(m, 2H), 4.01-3.80(m, 2H), 2.37-2.18(m, 2H).

[0501] Example 45: 1-(Azetidin-1-yl)-2-[6-(4-fluoro-2-methoxy-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0502] [ka] The title compound was prepared in a manner similar to that of Example 17, using 1-(azetidin-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (Intermediate 13) instead of Intermediate 42 and (4-fluoro-2-methoxyphenyl)boronic acid instead of 2,4-difluorophenylboronic acid. MS (ESI): C 18 H 17 Calculated mass of FN4O2, 340.1; observed m / z, 341.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.60(d, J=1.8Hz, 1H), 8.30(d, J=1.0Hz, 1H), 8.11-8.09(m, 1H), 7.43(dd, J=8.5, 6.9Hz, 1H), 7.11(dd, J=11.5, 2.5Hz, 1H ), 6.95(td, J=8.4, 2.5Hz, 1H), 5.21(s, 2H), 4.18(t, J=7.7Hz, 2H), 3.89(t, J=7.7Hz, 2H), 3.81(s, 3H), 2.29-2.21(m, 2H).

[0503] Example 46: 2-[6-(3-acetyl-4-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(azetidin-1-yl)ethanone.

[0504] [ka] The title compound was prepared in a similar manner to Example 17, using 1-(azetidin-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (Intermediate 13) instead of Intermediate 42, (3-acetyl-4-fluorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C. MS (ESI): C 19 H 17 Calculated mass of FN4O2, 352.1; observed m / z, 353.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.88(d, J=1.9Hz, 1H), 8.44-8.42(m, 1H), 8.36-8.34(m, 1H), 8.19-8.16(m, 1H), 8.12-8.08(m, 1H), 7.56(dd, J=10. 9, 8.6Hz, 1H), 5.27(s, 2H), 4.20(t, J=7.6Hz, 2H), 3.91(t, J=7.7Hz, 2H), 2.68(d, J=4.1Hz, 3H), 2.31-2.23(m, 2H).

[0505] Example 47: 1-(azetidin-1-yl)-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0506] [ka] The title compound was prepared in a similar manner to Example 17, using 1-(azetidin-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (Intermediate 13) instead of Intermediate 42, (3,4,5-trifluorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C. MS (ESI): C 17 H 13 Calculated mass of FNO, 346.1; observed m / z, 347.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 8.93(d, J=2.0Hz, 1H), 8.52-8.48(m, 1H), 8.38-8.35(m, 1H), 7.94-7.85(m, 2H) , 5.24(s, 2H), 4.20(t, J=7.7Hz, 2H), 3.91(t, J=7.8Hz, 2H), 2.32-2.22(m, 2H).

[0507] Example 48: 1-(Azetidin-1-yl)-2-[6-[2-(trifluoromethyl)-4-pyridyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0508] [ka] The title compound was prepared in a similar manner to Example 7, using 1-(azetidin-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (Intermediate 13) instead of Intermediate 10, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine instead of 4-fluoro-3-methylphenylboronic acid. MS (ESI): C 17 H 14 Calculated mass of FNO, 361.1; observed m / z, 362.1 [M+H] + . 1H NMR (500MHz, DMSO-d6)δ 9.08(d, J=2.0Hz, 1H), 8.91(d, J=5.1Hz, 1H), 8.72(dd, J=2.0, 1.0Hz, 1H), 8.42(d, J=0.9Hz, 1H), 8.38-8.35 (m, 1H), 8.23(dd, J=5.1, 1.7Hz, 1H), 5.29(s, 2H), 4.26-4.16(m, 2H), 3.95-3.88(m, 2H), 2.32-2.23(m, 2H).

[0509] Example 49: 2-[6-(5-chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl-1-(3-fluoroazetidin-1-yl)ethanone.

[0510] [ka] The title compound was prepared in a manner similar to Example 5, Method A, using 6-(5-chloro-2-thienyl)pyrazolo[4,3-b]pyridine (Intermediate 37) instead of Intermediate 16. MS (ESI): C 15 H 12 Calculated mass of ClFN4OS, 350.0; observed m / z, 351.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.87(d, J=2.0Hz, 1H), 8.37-8.32(m, 1H), 8.32-8.28(m, 1H), 7.62(d, J=4.0Hz, 1H), 7.27(d, J=4.0Hz, 1H), 5.63- 5.32(m, 1H), 5.39-5.31(m, 1H), 5.28(d, J=16.4Hz, 1H), 4.65-4.46(m, 1H), 4.40-4.16(m, 2H), 4.08-3.87(m, 1H).

[0511] Example 50: 2-[6-(5-chloro-2-thienyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0512] [ka] The title compound was prepared in a manner similar to that of Example 9, using 2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 15) and 5-chlorothiophene-2-boronic acid instead of 2-[4-chloro-3-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS (ESI): C 15 H 11 Calculated mass of ClF2N4OS, 368.0; observed m / z, 369.0 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.92(d, J=1.9Hz, 1H), 8.36-8.29(m, 1H), 7.67(d, J=3.9Hz, 1H), 7.29(d, J=3.9Hz, 1H), 5.56-5.37(m, 1H) , 5.22(d, J=17.1Hz, 1H), 5.17(d, J=17.0Hz, 1H), 4.63-4.52(m, 1H), 4.39-4.19(m, 2H), 4.03-3.91(m, 1H).

[0513] Example 51: 2-[6-[5-(difluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0514] [ka] The title compound was prepared in a manner similar to that of Example 9, using Intermediate 12 and 2-(5-(difluoromethyl)thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 8) instead of 2-[4-chloro-3-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS (ESI): C 16 H 13 Calculated mass of F3N4OS, 366.1; observed m / z, 367.1 [M+H] + . 1H NMR (500MHz, DMSO-d6)δ 8.95(d, J=2.0Hz, 1H), 8.42(dd, J=2.0, 1.0Hz, 1H), 8.36(d, J=1.0Hz, 1H), 7.76-7.71(m, 1H), 7.63-7.54(m, 1H), 7.37(t, J=55.2Hz) , 1H), 5.56-5.37(m, 1H), 5.35(d, J=16.7Hz, 1H), 5.31(d, J=17.0Hz, 1H), 4.62-4.50(m, 1H), 4.40-4.19(m, 2H), 4.05-3.92(m, 1H).

[0515] Example 52: 2-[6-[5-(difluoromethyl)-2-thienyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0516] [ka] The title compound was prepared in a similar manner to Example 9, using 2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 15) and 2-(5-(difluoromethyl)thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 8) instead of 2-[4-chloro-3-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS (ESI): C 16 H 12 Calculated mass of F4N4OS, 384.1; observed m / z, 385.1 [M+H] + . 1H NMR (300MHz, DMSO-d6)δ 9.05-8.94(m, 1H), 8.52-8.40(m, 1H), 7.85-7.71(m, 1H), 7.63-7.56(m, 1H), 7.39(t, J=55.3Hz, 1H), 5.65-5.32( m, 1H), 5.26(d, J=17.2Hz, 1H), 5.19(d, J=17.7Hz, 1H), 4.73-4.46(m, 1H), 4.46-4.15(m, 2H), 4.10-3.85(m, 1H).

[0517] Example 53: 1-(3-fluoroazetidin-1-yl)-2-[6-[5-(trifluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0518] [ka] The title compound was prepared in a similar manner to Example 7, except that 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) was used in place of Intermediate 10, and 4,4,5,5-tetramethyl-2-(5-(trifluoromethyl)thiophen-2-yl)-1,3,2-dioxaborolane was used in place of 4-fluoro-3-methylboronic acid. MS (ESI): C 16 H 12 Calculated mass of F4N4OS, 384.1; observed m / z, 385.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.98(d, J=2.0Hz, 1H), 8.51-8.46(m, 1H), 8.38(d, J=1.0Hz, 1H), 7.88-7.79(m, 2H), 5.56-5.39(m, 1H), 5 .36(d, J=16.8Hz, 1H), 5.31(d, J=16.8Hz, 1H), 4.62-4.50(m, 1H), 4.40-4.19(m, 2H), 4.04-3.91(m, 1H).

[0519] Example 54: 1-(3-fluoroazetidin-1-yl)-2-[3-fluoro-6-[5-(trifluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0520] [ka] The title compound was prepared in a manner similar to that of Example 9, using 2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 15) and 4,4,5,5-tetramethyl-2-(5-(trifluoromethyl)thiophen-2-yl)-1,3,2-dioxaborolane instead of 4-fluoro-3-methylboronic acid. MS (ESI): C 16 H 11 Calculated mass of F5N4OS, 402.1; observed m / z, 403.0 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 9.02(d, J=1.9Hz, 1H), 8.56-8.49(m, 1H), 7.91-7.82(m, 2H), 5.58-5.37(m, 1H), 5.25(d, J=1 7.1Hz, 1H), 5.20(d, J=17.1Hz, 1H), 4.65-4.52(m, 1H), 4.41-4.19(m, 2H), 4.06-3.91(m, 1H).

[0521] Example 55: 1-(3-fluoroazetidin-1-yl)-2-[6-(3-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0522] [ka] The title compound was prepared in a manner similar to that of Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) instead of Intermediate 10 and 3-fluorophenylboronic acid instead of 4-fluoro-3-methylboronic acid. MS (ESI): C17 H 14 Calculated mass of FNO, 328.1; observed m / z, 329.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.91(d, J=1.9Hz, 1H), 8.47-8.42(m, 1H), 8.38-8.33(m, 1H), 7.72-7.67(m, 1H), 7.70-7.66(m, 1H), 7.60(dt, J=8.1, 6.2Hz, 1H), 7.34-7 .26(m, 1H), 5.55-5.37(m, 1H), 5.35(d, J=17.0Hz, 1H), 5.31(d, J=17.1Hz, 1H), 4.61-4.48(m, 1H), 4.36-4.18(m, 2H), 4.04-3.90(m, 1H).

[0523] Example 56: 1-(3-fluoroazetidin-1-yl)-2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0524] [ka] The title compound was prepared in a manner similar to that of Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) instead of Intermediate 10 and 4-fluorophenylboronic acid instead of 4-fluoro-3-methylboronic acid. MS (ESI): C 17 H 14 Calculated mass of FNO, 328.1; observed m / z, 329.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.86(d, J=1.9Hz, 1H), 8.36(d, J=1.9Hz, 1H), 8.34(s, 1H), 7.91-7.82(m, 2H), 7.44-7.34(m, 2H), 5.54-5.37(m , 1H), 5.34(d, J=17.0Hz, 1H), 5.30(d, J=17.1Hz, 1H), 4.60-4.48(m, 1H), 4.35-4.19(m, 2H), 4.03-3.91(m, 1H).

[0525] Example 57: 2-[6-(3-chlorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0526] [ka] The title compound was prepared in a manner similar to that of Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) instead of Intermediate 10 and 3-chlorophenylboronic acid instead of 4-fluoro-3-methylphenylboronic acid. MS (ESI): C 17 H 14 Calculated mass of ClFN4, 344.1; observed m / z, 345.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.90(d, J=1.9Hz, 1H), 8.48-8.42(m, 1H), 8.39-8.32(m, 1H), 7.92-7.87(m, 1H), 7.84-7.77(m, 1H), 7.58(t, J=7.8Hz, 1H), 7.55-7.49 (m, 1H), 5.55-5.36(m, 1H), 5.36(d, J=17.1Hz, 1H), 5.31(d, J=17.1Hz, 1H), 4.60-4.49(m, 1H), 4.35-4.19(m, 2H), 4.04-3.90(m, 1H).

[0527] Example 58: 1-(3-fluoroazetidin-1-yl)-2-[6-(m-tolyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0528] [ka] The title compound was prepared in a manner similar to that of Example 17, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) instead of Intermediate 42, m-tolylboronic acid instead of 2,4-difluorophenylboronic acid, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). MS (ESI): C 18 H 17 Calculated mass of FNO, 324.1; observed m / z, 325.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.86(d, J=1.9Hz, 1H), 8.36-8.33(m, 2H), 7.65-7.62(m, 1H), 7.62-7.58(m, 1H), 7.43(t, J=7.6Hz, 1H), 7. 30-7.25(m, 1H), 5.54-5.28(m, 3H), 4.60-4.50(m, 1H), 4.35-4.20(m, 2H), 4.02-3.92(m, 1H), 2.42(s, 3H).

[0529] Example 59: 1-(3-fluoroazetidin-1-yl)-2-[6-[3-(fluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0530] [ka] The title compound was prepared in a similar manner to Example 16, using 2-(6-(3-(fluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (Intermediate 56) instead of Intermediate 39 and DCM instead of DMF. MS (ESI): C 18 H 16 Calculated mass of FNO, 342.1; observed m / z, 343.2 [M+H] + . 1H NMR (500MHz, DMSO-d6)δ 8.89(d, J=1.9Hz, 1H), 8.41-8.39(m, 1H), 8.36-8.35(m, 1H), 7.88-7.82(m, 2H), 7.64-7.58(m, 1H) ), 7.54-7.49(m, 1H), 5.60-5.29(m, 5H), 4.59-4.50(m, 1H), 4.36-4.20(m, 2H), 4.04-3.92(m, 1H).

[0531] Example 60: 2-[6-[3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0532] [ka] The title compound was prepared in a similar manner to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) instead of Intermediate 10 and 2-(3-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 4-fluoro-3-methylboronic acid. MS(ESI):C 18 H 15 Calculated mass of FNO, 360.1; observed m / z, 361.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.90(d, J=1.9Hz, 1H), 8.53-8.41(m, 1H), 8.40-8.31(m, 1H), 8.09-7.90(m, 2H), 7.77-7.62(m, 2H), 7.15(t, J=55.8Hz, 1H), 5.62-5.32(m, 1H), 5.38(d, J=16.8Hz, 1H), 5.32(d, J=16.9Hz, 1H), 4.64-4.45(m, 1H), 4.40-4.15(m, 2H), 4.08-3.85(m, 1H).

[0533] Example 61: 2-[6-[3-(1,1-difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0534] [ka] The title compound was prepared in a manner similar to Example 6, Method A, using 3-(1,1-difluoroethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate 20) instead of Intermediate 16 and 2-chloro-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 1) instead of 2-chloro-N,N-dimethylacetamide. MS (ESI): C 19 H 17 Calculated mass of FNO, 374.1; observed m / z, 375.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.92(d, J=1.9Hz, 1H), 8.50-8.40(m, 1H), 8.40-8.31(m, 1H), 8.02-7.85(m, 2H), 7.76-7.58(m, 2H), 5.61-5.29(m, 1H), 5.36 (d, J=17.1Hz, 1H), 5.35(d, J=17.2Hz, 1H), 4.63-4.45(m, 1H), 4.39-4.15(m, 2H), 4.07-3.85(m, 1H), 2.06(t, J=18.9Hz, 3H).

[0535] Example 62: 2-[6-[3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0536] [ka] The title compound was prepared in a similar manner to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) instead of Intermediate 10, and 2-(3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 4-fluoro-3-methylphenylboronic acid. MS(ESI):C 18 H 15 Calculated mass of F3N4O2, 376.1; observed m / z, 377.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.90(d, J=1.9Hz, 1H), 8.45-8.39(m, 1H), 8.39-8.33(m, 1H), 7.74-7.67(m, 1H), 7.65-7.57(m, 2H), 7.37(t, J=74.0Hz, 1H), 7.30-7.2 5(m, 1H), 5.55-5.38(m, 1H), 5.36(d, J=17.2Hz, 1H), 5.31(d, J=17.2Hz, 1H), 4.60-4.49(m, 1H), 4.36-4.19(m, 2H), 4.04-3.90(m, 1H).

[0537] Example 63: 2-[6-(2,3-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0538] [ka] The title compound was prepared in a manner similar to that of Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) instead of Intermediate 10 and (2,3-difluorophenyl)boronic acid instead of 4-fluoro-3-methylphenylboronic acid. MS (ESI): C 17 H 13 Calculated mass of FNO, 346.1; observed m / z, 347.1 [M+H] + . 1H NMR (300MHz, DMSO-d6)δ 8.77-8.69(m, 1H), 8.42-8.38(m, 1H), 8.37-8.30(m, 1H), 7.62-7.45(m, 2H), 7.44-7.34(m, 1H), 5.61-5.29( m, 1H), 5.42-5.34(m, 1H), 5.33(d, J=17.1Hz, 1H), 4.65-4.48(m, 1H), 4.40-4.18(m, 2H), 4.05-3.88(m, 1H).

[0539] Example 64: 2-[6-(2,4-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0540] [ka] The title compound was prepared in a manner similar to that of Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) instead of Intermediate 10 and 2,4-difluorophenylboronic acid instead of 4-fluoro-3-methylboronic acid. MS (ESI): C 17 H 13 Calculated mass of FNO, 346.1; observed m / z, 347.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.71-8.66(m, 1H), 8.41-8.34(m, 1H), 8.30-8.24(m, 1H), 7.72(dt, J=8.8, 6.5Hz, 1H), 7.52-7.44(m, 1H), 7.34-7.25(m, 1H), 5.54-5.37(m, 1H), 5.35(d, J=17.1Hz, 1H), 5.30(d, J=17.1Hz, 1H), 4.61-4.50(m, 1H), 4.37-4.18(m, 2H), 4.03-3.90(m, 1H).

[0541] Example 65: 2-[6-(3,4-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0542] [ka] The title compound was prepared in a manner similar to that of Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) instead of Intermediate 10 and 3,4-difluorophenylboronic acid instead of 4-fluoro-3-methylboronic acid. MS (ESI): C 17 H 13 Calculated mass of FNO, 346.1; observed m / z, 347.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.93-8.87(m, 1H), 8.46-8.41(m, 1H), 8.36(s, 1H), 8.01-7.90(m, 1H), 7.75-7.57(m, 2H), 5.58-5.36(m, 1H), 5.39-5.33(m, 1H), 5.32(d, J=17.1Hz, 1H), 4.64-4.46(m, 1H), 4.38-4.17(m, 2H), 4.05-3.90(m, 1H).

[0543] Example 66: 2-[6-(3,5-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0544] [ka] The title compound was prepared in a manner similar to that of Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) instead of Intermediate 10 and 3,5-difluorophenylboronic acid instead of 4-fluoro-3-methylboronic acid. MS (ESI): C 17 H 13 Calculated mass of FNO, 346.1; observed m / z, 347.1 [M+H] + . 1H NMR (300MHz, DMSO-d6)δ 9.00-8.90(m, 1H), 8.56-8.47(m, 1H), 8.42-8.33(m, 1H), 7.72-7.57(m, 2H), 7.42-7.28(m, 1H), 5.63-5.28( m, 1H), 5.39-5.33(m, 1H), 5.30(d, J=17.5Hz, 1H), 4.66-4.45(m, 1H), 4.40-4.13(m, 2H), 4.08-3.85(m, 1H).

[0545] Example 67: 2-[6-(3-chloro-2-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0546] [ka] The title compound was prepared in a manner similar to that of Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) instead of Intermediate 10 and 3-chloro-2-fluorophenylboronic acid instead of 4-fluoro-3-methylboronic acid. MS (ESI): C 17 H 13 Calculated mass for ClF2N4O: 362.1; observed m / z: 363.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.74-8.69(m, 1H), 8.40(s, 1H), 8.37-8.31(m, 1H), 7.75-7.67(m, 1H), 7.67-7.59(m, 1H), 7.45-7.37(m, 1H), 5.59 -5.36(m, 1H), 5.39-5.33(m, 1H), 5.33(d, J=17.1Hz, 1H), 4.66-4.45(m, 1H), 4.42-4.16(m, 2H), 4.06-3.88(m, 1H).

[0547] Example 68: 2-[6-(3-chloro-4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0548] [ka] The title compound was prepared in a manner similar to that of Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) instead of Intermediate 10 and 3-chloro-4-fluorophenylboronic acid instead of 4-fluoro-3-methylboronic acid. MS (ESI): C 17 H 13 Calculated mass for ClF2N4O: 362.1; observed m / z: 363.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.90(d, J=1.9Hz, 1H), 8.48-8.41(m, 1H), 8.39-8.32(m, 1H), 8.07(dd, J=7.1, 2.3Hz, 1H), 7.90-7.80(m, 1H), 7.61(t, J=9.0Hz , 1H), 5.60-5.33(m, 1H), 5.39-5.33(m, 1H), 5.30(d, J=17.3Hz, 1H), 4.64-4.44(m, 1H), 4.39-4.15(m, 2H), 4.07-3.86(m, 1H).

[0549] Example 69: 1-(3-chloroazetidin-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0550] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-chloroazetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 18 H 14 Calculated mass for ClF3N4O: 394.1; observed m / z: 395.1 [M+H] + . 1H NMR (400MHz, CDCl3)δ 8.82(d, J=1.9Hz, 1H), 8.31(d, J=1.0Hz, 1H), 7.93(dd, J=1.9, 1.0Hz, 1H), 7.93-7.84(m, 1H), 7.82-7.67(m , 1H), 7.35-7.27(m, 1H), 6.98(t, J=54.8Hz, 1H), 5.34-4.90(m, 2H), 4.72-4.41(m, 3H), 4.26-4.14(m, 2H).

[0551] Example 70: 2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0552] [ka] The title compound was prepared in a manner similar to Example 6, Method A, using 6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridine (Intermediate 21) instead of Intermediate 16 and 2-chloro-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 1) instead of 2-chloro-N,N-dimethylacetamide. MS (ESI): C 18 H 13 Calculated mass of FNO, 396.1; observed m / z, 397.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.93(d, J=1.8Hz, 1H), 8.52-8.42(m, 1H), 8.14-8.01(m, 2H), 7.66-7.54(m, 1H), 7.31(t, J=54.1Hz, 1H), 5.62-5.3 1(m, 1H), 5.27(d, J=17.1Hz, 1H), 5.20(d, J=17.2Hz, 1H), 4.66-4.49(m, 1H), 4.43-4.15(m, 2H), 4.07-3.87(m, 1H).

[0553] Example 71: 2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-methyl-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0554] [ka] The title compound was prepared in a manner similar to that of Example 13, using 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (Intermediate 32) instead of Intermediate 27 and 3-fluoroazetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 19 H 16 Calculated mass of FNO, 392.1; observed m / z, 393.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.75(d, J=1.9Hz, 1H), 7.93-7.79(m, 2H), 7.78-7.69(m, 1H), 7.36-7.21(m, 1H), 6.97(t, J=54 .8Hz, 1H), 5.47-5.13(m, 1H), 5.02(s, 2H), 4.44-4.25(m, 2H), 4.25-4.07(m, 2H), 2.69(s, 3H).

[0555] Example 72: 2-[6-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0556] [ka] The title compound was prepared in a similar manner to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) instead of Intermediate 10, and 2-(3-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 4-fluoro-3-methylphenylboronic acid. MS(ESI):C 19 H 16 Calculated mass of FNO, 392.1; observed m / z, 393.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.89(d, J=1.9Hz, 1H), 8.46-8.39(m, 1H), 8.39-8.34(m, 1H), 8.08-7.96(m, 1H), 7.97-7.89(m, 1H), 7.56(dd, J=11.0, 8.6Hz, 1H ), 5.62-5.33(m, 2H), 5.31(d, J=16.8Hz, 1H), 4.64-4.45(m, 1H), 4.39-4.15(m, 2H), 4.07-3.87(m, 1H), 2.10(t, J=19.1Hz, 3H).

[0557] Example 73: 2-[6-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0558] [ka] The title compound was prepared in a similar manner to Example 7, except that 2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 15) was used in place of Intermediate 10, and 2-(3-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used in place of 4-fluoro-3-methylphenylboronic acid. MS(ESI):C 19 H 15Calculated mass of FNO, 410.1; observed m / z, 411.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.93(d, J=1.8Hz, 1H), 8.51-8.42(m, 1H), 8.08-7.98(m, 1H), 7.98-7.91(m, 1H), 7.58(dd, J=11.0, 8.6Hz, 1H), 5.61-5.31(m, 1H), 5.27(d, J=17.2Hz, 1H), 5.20(d, J=17.2Hz, 1H), 4.67-4.47(m, 1H), 4.42-4.15(m, 2H), 4.07-3.88(m, 1H), 2.10(t, J=19.1Hz, 3H).

[0559] Example 74: 2-[6-[4-chloro-3-(1,1-difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0560] [ka] The title compound was prepared in a similar manner to Example 7, except that 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) was used in place of Intermediate 10, and 2-(4-chloro-3-(1,1-difluoroethyl))-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used in place of 4-fluoro-3-methylphenylboronic acid. MS(ESI):C 19 H 16 Calculated mass for ClF3N4O: 408.1; observed m / z: 409.1 [M+H] + . 1H NMR (300MHz, DMSO-d6)δ 8.91(d, J=1.9Hz, 1H), 8.49-8.41(m, 1H), 8.38(s, 1H), 8.04-7.98(m, 1H), 7.99-7.90(m, 1H), 7.77(d, J=8.3Hz, 1H), 5.6 1-5.35(m, 2H), 5.32(d, J=17.0Hz, 1H), 4.66-4.46(m, 1H), 4.40-4.14(m, 2H), 4.07-3.88(m, 1H), 2.13(t, J=19.0Hz, 3H).

[0561] Example 75: 2-[6-[4-chloro-3-(1,1-difluoroethyl)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0562] [ka] The title compound was prepared in a similar manner to Example 7, except that 2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 15) was used in place of Intermediate 10, and 2-(4-chloro-3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used in place of 4-fluoro-3-methylphenylboronic acid. MS (ESI): C 19 H 15 Calculated mass for ClFNO, 426.1; observed m / z, 427.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.95(d, J=1.8Hz, 1H), 8.54-8.44(m, 1H), 8.05-7.92(m, 2H), 7.79(d, J=8.3Hz, 1H), 5.62-5.32(m, 1H), 5.27(d, J=17) .0Hz, 1H), 5.21(d, J=17.0Hz, 1H), 4.68-4.47(m, 1H), 4.43-4.14(m, 2H), 4.06-3.87(m, 1H), 2.13(t, J=19.0Hz, 3H).

[0563] Example 76: 2-[6-[4-chloro-3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0564] [ka] The title compound was prepared in a manner similar to that of Example 7, except that 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) was used in place of Intermediate 10, and 2-(4-chloro-3-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used in place of 4-fluoro-3-methylboronic acid. MS(ESI):C 18 H 14 Calculated mass for ClF3N4O: 394.1; observed m / z: 395.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.91(d, J=2.0Hz, 1H), 8.48(dd, J=2.0, 1.0Hz, 1H), 8.38(d, J=1.0Hz, 1H), 8.10(d, J=2.3Hz, 1H), 8.06-8.01(m, 1H), 7.82-7.77(m, 1H), 7.3 1(t, J=54.1Hz, 1H), 5.56-5.37(m, 1H), 5.39-5.35(m, 1H), 5.33(d, J=17.2Hz, 1H), 4.60-4.47(m, 1H), 4.36-4.19(m, 2H), 4.03-3.91(m, 1H).

[0565] Example 77: 2-[6-(4-chloro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0566] [ka] The title compound was prepared in a similar manner to Example 17, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) instead of Intermediate 42, (4-chloro-3-methylphenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90° C. MS (ESI): C 18 H 16 Calculated mass for ClFNO, 358.1; observed m / z, 359.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.88(d, J=1.9Hz, 1H), 8.40-8.38(m, 1H), 8.36-8.34(m, 1H), 7.85-7.82(m, 1H), 7.68-7.65(m, 1H), 7.60 -7.57(m, 1H), 5.55-5.27(m, 3H), 4.61-4.49(m, 1H), 4.37-4.19(m, 2H), 4.03-3.91(m, 1H), 2.45(s, 3H).

[0567] Example 78: 1-(3-Fluoroazetidin-1-yl)-2-[6-(4-fluoro-2-methoxy-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0568] [ka] The title compound was prepared in a manner similar to that of Example 17, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) instead of Intermediate 42 and (4-fluoro-2-methoxyphenyl)boronic acid instead of 2,4-difluorophenylboronic acid. MS (ESI): C 18 H 16 Calculated mass of F2N4O2, 358.1; observed m / z, 359.1 [M+H]+ . 1H NMR (500MHz, DMSO-d6)δ 8.60(d, J=1.8Hz, 1H), 8.31(d, J=1.0Hz, 1H), 8.11-8.09(m, 1H), 7.43(dd, J=8.4, 6.9Hz, 1H), 7.11(dd, J=11.5, 2.5Hz, 1H), 6.95(t d, J=8.4, 2.5Hz, 1H), 5.53-5.35(m, 1H), 5.34-5.23(m, 2H), 4.58-4.47(m, 1H), 4.35-4.17(m, 2H), 4.01-3.90(m, 1H), 3.81(s, 3H).

[0569] Example 79: 2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0570] [ka] The title compound was prepared in a manner similar to Example 5, Method A, using 6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate 17) instead of Intermediate 16. MS (ESI): C 18 H 14 Calculated mass of F4N4O2, 394.1; observed m / z, 395.1 [M+H] + . 1 H NMR (500 MHz, DMSO-d) δ 8.88 (d. 38(t, J=73.2Hz, 1H), 5.54-5.38(m, 1H), 5.33(d, J=17.4Hz, 1H), 5.30(d, J=17.1Hz, 1H), 4.59-4.50(m, 1H), 4.35-4.19(m, 2H), 4.03-3.91(m, 1H).

[0571] Example 80: 2-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0572] [ka] The title compound was prepared in a similar manner to Example 7, except that 2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 15) was used in place of Intermediate 10, and 2-(3-(difluoromethoxy)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used in place of 4-fluoro-3-methylphenylboronic acid. MS(ESI):C 18 H 13 Calculated mass of F5N4O2, 412.1; observed m / z, 413.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.93(d, J=1.8Hz, 1H), 8.51-8.36(m, 1H), 7.90-7.81(m, 1H), 7.81-7.71(m, 1H), 7.68-7.58(m, 1H), 7.38(t, J=73.2Hz, 1H), 5.62-5.30(m, 1H), 5.26(d, J=17.3Hz, 1H), 5.19(d, J=17.7Hz, 1H), 4.68-4.46(m, 1H), 4.44-4.15(m, 2H), 4.07-3.86(m, 1H).

[0573] Example 81: 2-[6-[4-chloro-3-(difluoromethoxy)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0574] [ka] The title compound was prepared in a similar manner to Example 7, except that 2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 15) was used in place of Intermediate 10, and 2-(4-chloro-3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used in place of 4-fluoro-3-methylphenylboronic acid. MS (ESI): C 18 H 13 Calculated mass for ClF4N4O2: 428.1; observed m / z: 429.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.95(d, J=1.9Hz, 1H), 8.51-8.44(m, 1H), 7.83(d, J=2.1Hz, 1H), 7.80(d, J=8.3Hz, 1H), 7.74(dd, J=8.4, 2.1Hz, 1H), 7.44(t, J=73.2 Hz, 1H), 5.56-5.35(m, 1H), 5.25(d, J=17.2Hz, 1H), 5.20(d, J=17.0Hz, 1H), 4.64-4.52(m, 1H), 4.39-4.19(m, 2H), 4.04-3.91(m, 1H).

[0575] Example 82: 2-[6-(2,4-difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0576] [ka] The title compound was prepared in a similar manner to Example 7, except that 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) was used in place of Intermediate 10, and 2-(2,4-difluoro-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used in place of 4-fluoro-3-methylboronic acid. MS(ESI):C 18 H 15Calculated mass of FNO, 360.1; observed m / z, 361.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.72-8.60(m, 1H), 8.42-8.32(m, 1H), 8.30-8.21(m, 1H), 7.61-7.45(m, 1H), 7.32-7.19(m, 1H), 5.63-5.29(m, 1H) , 5.41-5.33(m, 1H), 5.29(d, J=17.7Hz, 1H), 4.65-4.44(m, 1H), 4.42-4.13(m, 2H), 4.07-3.83(m, 1H), 2.26(s, 3H).

[0577] Example 83: 2-[6-(3,4-difluoro-5-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone.

[0578] [ka] The title compound was prepared in a similar manner to Example 7, except that 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) was used in place of Intermediate 10, and 2-(3,4-difluoro-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used in place of 4-fluoro-3-methylboronic acid. MS (ESI): C 18 H 15 Calculated mass of FNO, 360.1; observed m / z, 361.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.88(d, J=2.0Hz, 1H), 8.43-8.38(m, 1H), 8.37-8.33(m, 1H), 7.79-7.71(m, 1H), 7.64-7.58(m, 1H), 5.54-5.37(m, 1H), 5. 34(d, J=17.0Hz, 1H), 5.29(d, J=17.0Hz, 1H), 4.60-4.48(m, 1H), 4.36-4.19(m, 2H), 4.04-3.92(m, 1H), 2.43-2.38(m, 3H).

[0579] Example 84: 1-(3-fluoroazetidin-1-yl)-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0580] [ka] The title compound was prepared in a manner similar to that of Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) instead of Intermediate 10 and 3,4,5-trifluorophenylboronic acid instead of 4-fluoro-3-methylboronic acid. MS (ESI): C 17 H 12 Calculated mass of FNO, 364.1; observed m / z, 365.1 [M+H] + . 1 H NMR(500MH, DMSO-d6)δ 8.93(d, J=2.0Hz, 1H), 8.51-8.46(m, 1H), 8.41-8.35(m, 1H), 7.92-7.84(m, 2H), 5.54-5.37(m, 1H), 5. 34(d, J=17.1Hz, 1H), 5.29(d, J=17.1Hz, 1H), 4.60-4.49(m, 1H), 4.35-4.19(m, 2H), 4.04-3.91(m, 1H).

[0581] Example 85: 1-(3-fluoroazetidin-1-yl)-2-[6-[2-(trifluoromethyl)-4-pyridyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0582] [ka] The title compound was prepared in a similar manner to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazetidin-1-yl)ethan-1-one (Intermediate 12) instead of Intermediate 10, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine instead of 4-fluoro-3-methylphenylboronic acid. MS (ESI): C 17 H 13 Calculated mass of FNO, 379.1; observed m / z, 380.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 9.08(d, J=2.0Hz, 1H), 8.92(d, J=5.1Hz, 1H), 8.73-8.68(m, 1H), 8.45-8.41(m, 1H), 8.38-8.33(m, 1H), 8.22(dd, J=5.2, 1.7Hz , 1H), 5.55-5.38(m, 1H), 5.40-5.36(m, 1H), 5.35(d, J=17.2Hz, 1H), 4.61-4.49(m, 1H), 4.37-4.20(m, 2H), 4.03-3.92(m, 1H).

[0583] Example 86: 1-(3-Methylazetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate.

[0584] [ka] The title compound was prepared in a similar manner to Example 16, using 3-methylazetidine instead of 3-fluoroazetidine hydrochloride and DCM instead of DMF. MS(ESI):C 19 H 17 Calculated mass of FNO, 374.1; observed m / z, 375.2 [M+H] + . 1H NMR (400MHz, DMSO-d6)δ 8.95(d, J=1.9Hz, 1H), 8.52-8.50(m, 1H), 8.38-8.36(m, 1H), 8.17-8.13(m, 2H), 7.86-7.77(m, 2H), 5.28(s, 2H), 4.30 (t, J=8.4Hz, 1H), 4.04-3.98(m, 1H), 3.78-3.73(m, 1H), 3.49-3.44(m, 1H), 2.79-2.69(m, 1H), 1.21(d, J=6.9Hz, 3H).

[0585] Example 87: (racemic) 1-(2-methylazetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0586] [ka] The title compound was prepared in a similar manner to Example 15, using 2-methylazetidine hydrochloride instead of 1-methylazetidin-3-amine and DCM instead of DMF. MS(ESI):C 19 H 17 Calculated mass of FNO, 374.1; observed m / z, 375.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.95-8.92(m, 1H), 8.53-8.49(m, 1H), 8.38-8.35(m, 1H), 8.17-8.12(m, 2H), 7.85-7.76(m, 2H), 5.38-5.16(m, 2H), 4.79-3.77(m, 3H), 2.48-2.34(m, 1H), 1.92-1.81(m, 1H), 1.58-1.31(m, 3H).

[0587] Example 88: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methylazetidin-1-yl)ethanone.

[0588] [ka] The title compound was prepared in a manner similar to Example 5, Method A, using 2-chloro-1-(3-methylazetidin-1-yl)ethan-1-one (Intermediate 6) instead of 2-chloro-1-(3-fluoroazetidin-1-yl)ethanone. MS (ESI): C 19 H 17 Calculated mass of FNO, 374.1; observed m / z, 375.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.88(d, J=2.0Hz, 1H), 8.43(dd, J=2.0, 1.0Hz, 1H), 8.35(d, J=0.9Hz, 1H), 8.08-8.03(m, 2H), 7.62-7.54(m, 1H), 7.30(t, J=54.1Hz, 1H) ), 5.26(s, 2H), 4.32-4.26(m, 1H), 4.04-3.99(m, 1H), 3.78-3.73(m, 1H), 3.49-3.43(m, 1H), 2.78-2.68(m, 1H), 1.21(d, J=6.9Hz, 3H).

[0589] Example 89: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methylazetidin-1-yl)ethanone.

[0590] [ka] The title compound was prepared in a manner similar to Example 6, Method A, using 6-(3-(difluoromethyl)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 21) instead of Intermediate 10 and 2-chloro-1-(3-methylazetidin-1-yl)ethan-1-one (Intermediate 6) instead of 4-fluoro-3-methylphenylboronic acid. MS (ESI): C 19 H 16 Calculated mass of FNO, 392.1; observed m / z, 393.1 [M+H] + . 1H NMR (300MHz, DMSO-d6)δ 8.93(d, J=1.8Hz, 1H), 8.52-8.44(m, 1H), 8.13-8.00(m, 2H), 7.65-7.55(m, 1H), 7.31(t, J=54.1Hz, 1H), 5.16(s, 2H), 4.37-4.28(m, 1H), 4.06-3.96(m, 1H), 3.83-3.74(m, 1H), 3.51-3.41(m, 1H), 2.82-2.67(m, 1H), 1.21(d, J=6.9Hz, 3H).

[0591] Example 90: (racemic) 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(2-methylazetidin-1-yl)ethanone.

[0592] [ka] The title compound was prepared in a manner similar to that of Example 1, using 2-methylazetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS(ESI):C 19 H 17 Calculated mass of FNO, 374.1; observed m / z, 375.1 [M+H] + . 1 H NMR (400 MHz, CDCl) δ 8.82-8.76(m, 1H), 8.33-8.26(m, 1H), 7.98(d, J=13.5Hz, 1H), 7.89-7. 84(m, 1H), 7.79-7.72(m, 1H), 7.32-7.25(m, 1H), 6.98(t, J=54.8Hz, 1H) , 5.16-4.88(m, 2H), 4.71-4.48(m, 1H), 4.18-3.88(m, 2H), 2.62-2.38( m, 1H), 1.98-1.84 (m, 1H), 1.64 (d, J=6.3Hz, 1H), 1.45 (d, J=6.3Hz, 2H).

[0593] Example 91: 2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methylazetidin-1-yl)ethanone.

[0594] [ka] The title compound was prepared in a manner similar to Example 6, Method A, using 6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine (Intermediate 17) instead of Intermediate 16 and 2-chloro-1-(3-methylazetidin-1-yl)ethan-1-one (Intermediate 6) instead of 2-chloro-N,N-dimethylacetamide. MS (ESI): C 19 H 17 Calculated mass of F3N4O2, 390.1; observed m / z, 391.1 [M+H] + . 1 H NMR (500 MHz, DMSO-d) δ 8.88(d, J=1.9Hz, 1H), 8.42-8.39(m, 1H), 8.35(d, J=0.9Hz, 1H), 7.83(dd, J=7.6, 2.3Hz, 1H), 7.78-7.73(m, 1H), 7.60(dd, J=10.5, 8.6Hz, 1H), 7.38( t, J=73.2Hz, 1H), 5.25(s, 2H), 4.33-4.26(m, 1H), 4.05-3.97(m, 1H), 3.79 -3.73(m, 1H), 3.49-3.44(m, 1H), 2.78-2.68(m, 1H), 1.21(d, J=6.9Hz, 3H).

[0595] Example 92: 2-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methylazetidin-1-yl)ethanone.

[0596] [ka] The title compound was prepared in a manner similar to Example 5, Method A, using 6-(3-(difluoromethoxy)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 23) instead of Intermediate 16 and 2-chloro-1-(3-methylazetidin-1-yl)ethan-1-one (Intermediate 6) instead of Intermediate 1. MS (ESI): C19 H 16 Calculated mass of F4N4O2, 408.1; observed m / z, 409.2 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.93(d, J=1.8Hz, 1H), 8.51-8.38(m, 1H), 7.89-7.82(m, 1H), 7.82-7.72(m, 1H), 7.62(dd, J=10.7, 8.4Hz, 1H), 7.38(t, J=73.2Hz, 1H) , 5.15(s, 2H), 4.40-4.26(m, 1H), 4.07-3.94(m, 1H), 3.84-3.71(m, 1H), 3.51-3.41(m, 1H), 2.82-2.67(m, 1H), 1.21(d, J=6.9Hz, 3H).

[0597] Example 93: 2-[6-[4-chloro-3-(difluoromethoxy)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methylazetidin-1-yl)ethanone.

[0598] [ka] The title compound was prepared in a manner similar to Example 5, Method A, using 6-(4-chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate 22) in place of Intermediate 16 and 2-chloro-1-(3-methylazetidin-1-yl)ethan-1-one (Intermediate 6) in place of Intermediate 1. MS (ESI): C 19 H 16 Calculated mass for ClF3N4O2: 424.1; observed m / z: 425.1 [M+H] + . 1H NMR (300MHz, DMSO-d6)δ 8.95(d, J=1.8Hz, 1H), 8.52-8.44(m, 1H), 7.86-7.78(m, 2H), 7.75(dd, J=8.4, 2.0Hz, 1H), 7.44(t, J=73.2Hz, 1H), 5.15(s, 2H), 4.38-4.27(m, 1H), 4.06-3.94(m, 1H), 3.84-3.74(m, 1H), 3.51-3.41(m, 1H), 2.82-2.67(m, 1H), 1.21(d, J=6.9Hz, 3H).

[0599] Example 94: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-ethynylazetidin-1-yl)ethanone.

[0600] [ka] The title compound was prepared in a similar manner to Example 2, using 3-ethynylazetidine (Intermediate 33) instead of 3-methyleneazetidine. MS (ESI): C 20 H 15 Calculated mass of FNO, 384.1; observed m / z, 385.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.81(d, J=1.9Hz, 1H), 8.30(d, J=1.0Hz, 1H), 7.93(dd, J=1.9, 1.0Hz, 1H), 7.90-7.84(m, 1H), 7.78-7.71(m, 1H), 7.32-7.27(m, 1H), 6.98(t, J=54.9Hz, 1H), 5.17-4.89(m, 2H), 4.37-4.25(m, 2H), 4.18-4.03(m, 2H), 3.55-3.28(m, 1H), 2.32(d, J=2.4Hz, 1H).

[0601] Example 95: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-vinylazetidin-1-yl)ethanone.

[0602] [ka] The title compound was prepared in a similar manner to Example 2, using 3-ethenylazetidine instead of 3-methyleneazetidine. MS(ESI):C 20 H 17 Calculated mass of FNO, 386.1; observed m / z, 387.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.79(d, J=1.9Hz, 1H), 8.29(d, J=1.0Hz, 1H), 7.95(dd, J=1.9, 1.0Hz, 1H), 7.90-7.82(m, 1H), 7.77-7.69(m, 1H), 7.33-7.21(m, 1H), 6.98(t, J =54.8Hz, 1H), 5.95(ddd, J=17.0, 10.4, 7.7Hz, 1H), 5.16-5.08(m, 2H), 5.07(s, 2H), 4.31-4.18(m, 2H), 3.96-3.82(m, 2H), 3.37-3.24(m, 1H).

[0603] Example 96: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-[(Z)-prop-1-enyl]azetidin-1-yl]ethanone.

[0604] [ka] The title compound was prepared in a manner similar to Example 2, using (Z)-3-(prop-1-en-1-yl)azetidine (Intermediate 34) instead of 3-methyleneazetidine. MS (ESI): C 21 H 19 Calculated mass of FNO, 400.2; observed m / z, 401.1 [M+H] + . 1H NMR (400MHz, CDCl3)δ 8.80(d, J=1.9Hz, 1H), 8.29(d, J=1.0Hz, 1H), 7.96(dd, J=1.9, 1.0Hz, 1H), 7.89-7.84(m, 1H), 7.79-7.68(m, 1H), 7.33-7.27(m, 1H), 6.98 (t, J=54.9Hz, 1H), 5.65-5.49(m, 2H), 5.06(t, J=1.9Hz, 2H), 4.35-4.23(m, 2H), 3.90-3.76(m, 2H), 3.64-3.51(m, 1H), 1.60-1.56(m, 3H).

[0605] Example 97: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(fluoromethyl)azetidin-1-yl]ethanone.

[0606] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-fluoromethylazetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 19 H 16 Calculated mass of FNO, 392.1; observed m / z, 393.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.80(d, J=1.9Hz, 1H), 8.30(d, J=1.0Hz, 1H), 7.95(dd, J=2.0, 1.0Hz, 1H), 7.89-7.85(m, 1H), 7.79-7.71(m, 1H), 7.34-7.27(m, 1H), 6 .98(t, J=54.9Hz, 1H), 5.08(d, J=4.0Hz, 2H), 4.51(dd, J=46.9, 5.2Hz, 2H), 4.25-4.10(m, 2H), 4.04-3.89(m, 2H), 3.06-2.88(m, 1H).

[0607] Example 98: 1-[3-(difluoromethyl)azetidin-1-yl]-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0608] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-(difluoromethyl)azetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 19 H 15 Calculated mass of FNO, 410.1; observed m / z, 411.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.81(d, J=1.9Hz, 1H), 8.30(d, J=0.9Hz, 1H), 7.94(dd, J=1.9, 1.0Hz, 1H), 7.89-7.84(m, 1H), 7.80-7.70(m, 1H), 7.34-7. 28(m, 1H), 6.98(t, J=54.9Hz, 1H), 5.94(td, J=55.9, 3.7Hz, 1H), 5.22-4.98(m, 2H), 4.25-3.97(m, 4H), 3.15-2.93(m, 1H).

[0609] Example 99: 1-[3-(trifluoromethyl)azetidin-1-yl]-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate.

[0610] [ka] The title compound was prepared in a similar manner to Example 16, using 3-(trifluoromethyl)azetidine hydrochloride instead of 3-fluoroazetidine hydrochloride. MS (ESI): C 19 H 14 Calculated mass of FNO, 428.1; observed m / z, 429.2 [M+H] + . 1H NMR (500MHz, DMSO-d6)δ 8.95(d, J=1.9Hz, 1H), 8.50-8.49(m, 1H), 8.40-8.38(m, 1H), 8.16-8.12(m, 2H), 7.85-7.77(m, 2H), 5.43-5.31( m, 2H), 4.48(t, J=9.1Hz, 1H), 4.28(dd, J=9.4, 5.4Hz, 1H), 4.16(t, J=9.6Hz, 1H), 3.91(dd, J=10.3, 5.4Hz, 1H).

[0611] Example 100: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(trifluoromethyl)azetidin-1-yl]ethanone.

[0612] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-trifluoromethylazetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 19 H 14 Calculated mass of FNO, 428.1; observed m / z, 429.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.82(d, J=1.9Hz, 1H), 8.31(d, J=1.0Hz, 1H), 7.93(dd, J=1.9, 1.0Hz, 1H), 7.89-7.83(m, 1H), 7.79-7.71(m , 1H), 7.34-7.26(m, 1H), 6.98(t, J=54.8Hz, 1H), 5.17-4.95(m, 2H), 4.30-4.08(m, 4H), 3.37-3.16(m, 1H).

[0613] Example 101: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-[(Z)-2-fluorovinyl]azetidin-1-yl]ethanone.

[0614] [ka] The title compound was prepared in a manner similar to Example 2, using (Z)-3-(2-fluorovinyl)azetidine (Intermediate 36) instead of 3-methyleneazetidine. MS (ESI): C 20 H 16 Calculated mass of FNO, 404.1; observed m / z, 405.1 [M+H] + . 1 H NMR (400 MHz, CDCl) δ 8.79(d, J=1.9Hz, 1H), 8.29(d, J=1.0Hz, 1H), 7.95(dd, J=2.0, 1.0Hz, 1H), 7.89-7.82(m, 1H), 7.78-7.70(m, 1H), 7.32-7.24(m, 1H), 6.97(t, J=54.8H z, 1H), 6.48(ddd, J=83.3, 4.7, 1.2Hz, 1H), 5.06(s, 2H), 5.05-4.91(m, 1H) , 4.36-4.24(m, 2H), 3.88(ddd, J=30.9, 9.4, 6.2Hz, 2H), 3.76-3.66(m, 1H).

[0615] Example 102: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(2,2-difluorovinyl)azetidin-1-yl]ethanone.

[0616] [ka] The title compound was prepared in a similar manner to Example 2, using 3-(2,2-difluorovinyl)azetidine (Intermediate 35) instead of 3-methyleneazetidine. MS (ESI): C 20 H 15 Calculated mass of FNO, 422.1; observed m / z, 423.1 [M+H] + . 1H NMR (400MHz, CDCl3)δ 8.81(d, J=1.9Hz, 1H), 8.30(d, J=1.0Hz, 1H), 7.94(dd, J=1.9, 1.0Hz, 1H), 7.91-7.83(m, 1H), 7.81-7.70(m, 1H), 7.33-7.27(m, 1H) , 6.98(t, J=54.9Hz, 1H), 5.06(s, 2H), 4.43(ddd, J=24.2, 9.6, 1.7Hz, 1H), 4.35-4.24(m, 2H), 3.95-3.80(m, 2H), 3.53-3.40(m, 1H).

[0617] Example 103: 1-(3-Methoxyazetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0618] [ka] The title compound was prepared in a similar manner to Example 16, using 3-methoxyazetidine hydrochloride instead of 3-fluoroazetidine hydrochloride and DCM instead of DMF. MS(ESI):C 19 H 17 Calculated mass of F3N4O2, 390.1; observed m / z, 391.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 8.94(d, J=1.9Hz, 1H), 8.52-8.50(m, 1H), 8.37(d, J=1.0Hz, 1H), 8.17-8.12(m, 2H), 7.86-7.75(m, 2H), 5.40-5. 25(m, 2H), 4.42-4.35(m, 1H), 4.30-4.23(m, 1H), 4.13-4.01(m, 2H), 3.72(dd, J=10.5, 3.8Hz, 1H), 3.23(s, 3H).

[0619] Example 104: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methoxyazetidin-1-yl)ethanone.

[0620] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-methoxyazetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 19 H 17 Calculated mass of F3N4O2, 390.1; observed m / z, 391.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.80(d, J=1.9Hz, 1H), 8.30(d, J=1.0Hz, 1H), 7.94(dd, J=2.0, 1.0Hz, 1H), 7.86(d, J=6.5Hz, 1H), 7.80-7.68(m, 1H), 7.33-7.26(m, 1H), 6.98(t, J=54.9Hz, 1H), 5.08(d, J=2.3Hz, 2H), 4.29-4.13(m, 3H), 4.00-3.88(m, 2H), 3.28(s, 3H).

[0621] Example 105: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-ethoxyazetidin-1-yl)ethanone.

[0622] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-ethoxyazetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 20 H 19 Calculated mass of F3N4O2, 404.1; observed m / z, 405.1 [M+H] + . 1H NMR (400MHz, CDCl3)δ 8.80(d, J=1.9Hz, 1H), 8.29(d, J=1.0Hz, 1H), 7.94(dd, J=1.9, 1.0Hz, 1H), 7.90-7.83(m, 1H), 7.80-7.71(m, 1H), 7.34-7.27(m, 1H), 6.98(t, J=54.9Hz, 1H), 5.15-5.00(m, 2H), 4.34-4.16(m, 3H), 4.02-3.89(m, 2H), 3.47-3.37(m, 2H), 1.20(t, J=7.0Hz, 3H).

[0623] Example 106: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(methoxymethyl)azetidin-1-yl]ethanone.

[0624] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-(methoxymethyl)azetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 20 H 19 Calculated mass of F3N4O2, 404.1; observed m / z, 405.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.80(d, J=1.9Hz, 1H), 8.29(d, J=1.0Hz, 1H), 7.95(dd, J=1.9, 1.0Hz, 1H), 7.90-7.84(m, 1H), 7.81-7.73(m, 1H), 7.34-7.26(m, 1H), 6.98(t, J=54.8Hz, 1H), 5.21-4.84(m, 2H), 4.24-4.03(m, 2H), 3.99-3.77(m, 2H), 3.53-3.44(m, 2H), 3.35(s, 3H), 2.92-2.80(m, 1H).

[0625] Example 107: 1-[3-(methoxymethyl)azetidin-1-yl]-2-[6- [3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0626] [ka] The title compound was prepared in a similar manner to Example 16, using 3-(methoxymethyl)azetidine hydrochloride instead of 3-fluoroazetidine hydrochloride and DCM instead of DMF. MS (ESI): C 20 H 19 Calculated mass of F3N4O2, 404.2; observed m / z, 405.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.94(d, J=2.0Hz, 1H), 8.51-8.49(m, 1H), 8.38-8.36(m, 1H), 8.17-8.13(m, 2H), 7.85-7.77(m, 2H), 5.28(s, 2H), 4.23( t, J=8.5Hz, 1H), 3.97-3.90(m, 2H), 3.62(dd, J=9.7, 5.6Hz, 1H), 3.49(d, J=6.4Hz, 2H), 3.28(s, 3H), 2.92-2.82(m, 1H).

[0627] Example 108: (racemic) 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(1-hydroxyethyl)azetidin-1-yl]ethanone.

[0628] [ka] The title compound was prepared in a manner similar to that of Example 1, using 1-(azetidin-3-yl)ethan-1-ol instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 20 H 19 Calculated mass of F3N4O2, 404.1; observed m / z, 405.1 [M+H] + . 1H NMR (400MHz, CDCl3)δ 8.79(d, J=1.9Hz, 1H), 8.37-8.24(m, 1H), 8.01-7.92(m, 1H), 7.92-7.83(m, 1H), 7.83-7.68(m, 1H), 7.34-7.22(m, 1H), 6.9 7(t, J=54.9Hz, 1H), 5.17-4.92(m, 2H), 4.20-3.76(m, 6H), 2.60(dtd, J=14.7, 6.1, 2.3Hz, 1H), 1.14(dd, J=6.3, 0.9Hz, 3H).

[0629] Example 109: 1-[3-(Difluoromethoxy)azetidin-1-yl]-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0630] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-(difluoromethoxy)azetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 19 H 15 Calculated mass of F5N4O2, 426.1; observed m / z, 427.0 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.81(d, J=1.9Hz, 1H), 8.31(d, J=1.0Hz, 1H), 7.93(dd, J=1.9, 1.0Hz, 1H), 7.91-7.85(m, 1H), 7.81-7.68(m, 1H), 7.34-7.27(m, 1H) ), 6.98(t, J=54.8Hz, 1H), 6.23(t, J=72.3Hz, 1H), 5.08(d, J=1.3Hz, 2H), 5.02-4.90(m, 1H), 4.43-4.31(m, 2H), 4.17-4.06(m, 2H).

[0631] Example 110: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(trifluoromethoxy)azetidin-1-yl]ethanone.

[0632] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-(trifluoromethoxy)azetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 19 H 14 Calculated mass of FNO, 444.1; observed m / z, 445.0 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.82(d, J=1.9Hz, 1H), 8.31(d, J=1.0Hz, 1H), 7.93(dd, J=1.9, 1.0Hz, 1H), 7.89-7.85(m, 1H), 7.79-7.71(m, 1H), 7.30(t , J=9.1Hz, 1H), 6.98(t, J=54.8Hz, 1H), 5.09(d, J=2.8Hz, 2H), 4.99-4.89(m, 1H), 4.42-4.34(m, 2H), 4.24-4.14(m, 2H).

[0633] Example 111: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-hydroxyazetidin-1-yl)ethanone.

[0634] [ka] The title compound was prepared in a manner similar to that of Example 1, using azetidin-3-ol instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 18 H 15 Calculated mass of F3N4O2, 376.1; observed m / z, 377.1 [M+H] + . 1H NMR (400MHz, CDCl3)δ 8.80(d, J=1.9Hz, 1H), 8.29(d, J=1.0Hz, 1H), 7.95-7.92(m, 1H), 7.89-7.84(m, 1H), 7.78-7.71(m, 1H), 7.32 -7.26(m, 1H), 6.98(t, J=54.9Hz, 1H), 5.08(s, 2H), 4.73-4.63(m, 1H), 4.34-4.27(m, 2H), 3.98-3.89(m, 2H).

[0635] Example 112: 2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-hydroxyazetidin-1-yl)ethanone.

[0636] [ka] The title compound was prepared in a manner similar to that of Example 1, using 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (Intermediate 28) instead of Intermediate 27 and azetidin-3-ol instead of 3-(trifluoromethyl)azetidin-3-ol. MS(ESI):C 18 H 14 Calculated mass of F4N4O2, 394.1; observed m / z, 395.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.93(d, J=1.9Hz, 1H), 8.52-8.45(m, 1H), 8.13-8.03(m, 2H), 7.63-7.55(m, 1H), 7.31(t, J=54.1Hz, 1H), 5.79(d, J=5.8Hz, 1H), 5.20(d, J=17.0Hz, 1H), 5.16(d, J=16.7Hz, 1H), 4.56-4.49(m, 1H), 4.42-4.36(m, 1H), 4.13-4.06(m, 1H), 4.00-3.92(m, 1H), 3.68-3.59(m, 1H).

[0637] Example 113: 1-(3-hydroxyazetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate.

[0638] [ka] The title compound was prepared in a similar manner to Example 15, using azetidin-3-ol hydrochloride instead of 1-methylazetidin-3-amine. MS(ESI):C 18 H 15 Calculated mass of F3N4O2, 376.1; observed m / z, 377.0 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.95(d, J=1.9Hz, 1H), 8.54-8.51(m, 1H), 8.39-8.36(m, 1H), 8.17-8.13(m, 2H), 7.86-7.76(m, 2H), 5.31(d, J =2.7Hz, 2H), 4.56-4.48(m, 1H), 4.39-4.32(m, 1H), 4.13-4.08(m, 1H), 3.96-3.91(m, 1H), 3.68-3.62(m, 1H).

[0639] Example 114: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(hydroxymethyl)azetidin-1-yl]ethanone.

[0640] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-(hydroxymethyl)azetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 19 H 17 Calculated mass of F3N4O2, 390.1; observed m / z, 391.2 [M+H] + . 1H NMR (400MHz, CDCl3)δ 8.79(d, J=1.9Hz, 1H), 8.29(d, J=0.9Hz, 1H), 7.96(dd, J=1.9, 1.0Hz, 1H), 7.88-7.84( m, 1H), 7.78-7.71(m, 1H), 7.32-7.27(m, 1H), 6.97(t, J=54.8Hz, 1H), 5.07(s, 2H), 4.1 6(t, J=8.6Hz, 1H), 4.09(dd, J=10.1, 8.6Hz, 1H), 3.97(dd, J=8.8, 5.4Hz, 1H), 3.86(dd , J=10.3, 5.5Hz, 1H), 3.75(d, J=5.9Hz, 2H), 2.81(tt, J=8.5, 5.6Hz, 1H), 2.08(s, 1H).

[0641] Example 115: 1-(3,3-Difluoroazetidin-1-yl)-2-[6-(4-methyl-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0642] [ka] The title compound was prepared in a manner similar to that of Example 17, using 4-methylthiophene-2-boronic acid pinacol ester instead of 2,4-difluorophenylboronic acid and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C. MS (ESI): C 16 H 14 Calculated mass of FNO, 348.1; observed m / z, 349.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 8.86(d, J=1.9Hz, 1H), 8.33-8.31(m, 1H), 8.27-8.25(m, 1H), 7.57-7.54(m, 1H), 7.28-7.2 5(m, 1H), 5.39(s, 2H), 4.75(t, J=12.4Hz, 2H), 4.39(t, J=12.5Hz, 2H), 2.30-2.26(m, 3H).

[0643] Example 116: 1-(3,3-Difluoroazetidin-1-yl)-2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0644] [ka] The title compound was prepared in a manner similar to that of Example 1, using 2-(6-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (Intermediate 31) instead of Intermediate 16 and 3,3-difluoroazetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 17 H 13 Calculated mass of FNO, 346.1; observed m / z, 347.1 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 8.83 (d.

[0645] Example 117: 2-[6-(3-chlorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3,3-difluoroazetidin-1-yl)ethanone.

[0646] [ka] The title compound was prepared in a manner similar to that of Example 17, using (3-chlorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). MS(ESI):C 17 H 13 Calculated mass for ClF2N4O: 362.1; observed m / z: 363.1 [M+H]+ . 1 H NMR (400MHz, DMSO-d6)δ 8.90(d, J=1.9Hz, 1H), 8.45-8.43(m, 1H), 8.38-8.37(m, 1H), 7.89(t, J=1.8Hz, 1H), 7.82-7 .78(m, 1H), 7.61-7.51(m, 2H), 5.42(s, 2H), 4.74(t, J=12.4Hz, 2H), 4.38(t, J=12.6Hz, 2H).

[0647] Example 118: 1-(3,3-Difluoroazetidin-1-yl)-2-[6-(m-tolyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0648] [ka] The title compound was prepared in a manner similar to that of Example 17, using m-tolylboronic acid instead of 2,4-difluorophenylboronic acid, (II), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C overnight. MS (ESI): C 18 H 16 Calculated mass of FNO, 342.1; observed m / z, 343.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 8.89-8.83(m, 1H), 8.39-8.31(m, 2H), 7.66-7.56(m, 2H), 7.44(t, J=7.6Hz, 1H), 7.32- 7.24(m, 1H), 5.41(s, 2H), 4.74(t, J=12.5Hz, 2H), 4.38(t, J=12.4Hz, 2H), 2.42(s, 3H).

[0649] Example 119: 1-(3,3-Difluoroazetidin-1-yl)-2-[6-[3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0650] [ka] The title compound was prepared in a manner similar to that of Example 17, using (3-(difluoromethyl)phenyl)boronic acid instead of 2,4-difluorophenylboronic acid and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). MS(ESI):C 18 H 14 Calculated mass of FNO, 378.1; observed m / z, 379.0 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.90(d, J=2.0Hz, 1H), 8.44-8.42(m, 1H), 8.39-8.37(m, 1H), 8.01-7.97(m, 2H), 7.74-7.65( m, 2H), 7.14(t, J=55.8Hz, 1H), 5.43(s, 2H), 4.74(t, J=12.4Hz, 2H), 4.38(t, J=12.5Hz, 2H).

[0651] Example 120: 1-(3,3-Difluoroazetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate.

[0652] [ka] The title compound was prepared in a similar manner to Example 15, using 3,3-difluoroazetidine hydrochloride instead of 1-methylazetidin-3-amine. MS(ESI):C 18 H 13 Calculated mass of FNO, 396.1; observed m / z, 397.1 [M+H] + . 1H NMR (400MHz, DMSO-d6)δ 8.95(d, J=1.9Hz, 1H), 8.50-8.47(m, 1H), 8.40(d, J=0.9Hz, 1H), 8.16-8.11(m, 2H ), 7.86-7.77(m, 2H), 5.43(s, 2H), 4.73(t, J=12.4Hz, 2H), 4.38(t, J=12.5Hz, 2H).

[0653] Example 121: 3-[1-[2-(3,3-difluoroazetidin-1-yl)-2-oxo-ethyl]pyrazolo[4,3-b]pyridin-6-yl]benzonitrile.

[0654] [ka] The title compound was prepared in a manner similar to that of Example 17, using (3-cyanophenyl)boronic acid instead of 2,4-difluorophenylboronic acid, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and sodium carbonate instead of cesium carbonate. MS(ESI):C 18 H 13 Calculated mass of FNO, 353.1; observed m / z, 354.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 8.98-8.93(m, 1H), 8.52-8.49(m, 1H), 8.41-8.39(m, 1H), 8.34-8.31(m, 1H), 8.21-8.16(m, 1H), 7.97- 7.92(m, 1H), 7.81-7.73(t, J=7.9Hz, 1H), 5.42(s, 2H), 4.75(t, J=12.1Hz, 2H), 4.39(t, J=12.6Hz, 2H).

[0655] Example 122: 1-(3,3-Difluoroazetidin-1-yl)-2-[6-[6-(trifluoromethyl)-2-pyridyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate

[0656] [ka] The title compound was prepared in a manner similar to that of Example 17, using 6-(trifluoromethyl)pyridine-2-boronic acid pinacol ester instead of 2,4-difluorophenylboronic acid and palladium-tetrakis(triphenylphosphine) instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). MS (ESI): C 17 H 12 Calculated mass of FNO, 397.1; observed m / z, 398.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 9.28(s, 1H), 8.74(s, 1H), 8.48-8.41(m, 2H), 8.29(t, J=7.9Hz, 1H), 7.97(d , J=7.7Hz, 1H), 5.48(s, 2H), 4.77(t, J=13.0Hz, 2H), 4.39(t, J=12.5Hz, 2H).

[0657] Example 123: 1-(3,3-Difluoroazetidin-1-yl)-2-[6-[2-(trifluoromethyl)-4-pyridyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0658] [ka] The title compound was prepared in a manner similar to that of Example 17, using (2-(trifluoromethyl)pyridin-4-yl)boronic acid instead of 2,4-difluorophenylboronic acid and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C. MS (ESI): C 17 H 12 Calculated mass of FNO, 397.1; observed m / z, 398.1 [M+H] +. 1H NMR (400MHz, DMSO-d6)δ 9.08(d, J=1.9Hz, 1H), 8.94-8.91(m, 1H), 8.70-8.67(m, 1H), 8.46-8.44(m, 1H), 8.37-8.3 4(m, 1H), 8.23-8.20(m, 1H), 5.45(s, 2H), 4.75(t, J=12.3Hz, 2H), 4.39(t, J=12.5Hz, 2H).

[0659] Example 124: 1-(3,3-Difluoroazetidin-1-yl)-2-[6-[5-(trifluoromethyl)-3-pyridyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0660] [ka] The title compound was prepared in a similar manner to Example 17, using (5-(trifluoromethyl)pyridin-3-yl)boronic acid instead of 2,4-difluorophenylboronic acid and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C. MS (ESI): C 17 H 12 Calculated mass of FNO, 397.1; observed m / z, 398.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 9.36-9.34(m, 1H), 9.08-9.06(m, 1H), 9.04(d, J=1.9Hz, 1H), 8.66-8.63(m, 1H), 8.62-8.5 9(m, 1H), 8.44-8.42(m, 1H), 5.43(s, 2H), 4.74(t, J=12.6Hz, 2H), 4.38(t, J=12.5Hz, 2H).

[0661] Example 125: 1-(3,3-difluoroazetidin-1-yl)-2-[6-(3,4-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0662] [ka] The title compound was prepared in a manner similar to that of Example 17, using (3,4-difluorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). MS(ESI):C 17 H 12 Calculated mass of FNO, 364.1; observed m / z, 365.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.92-8.88(m, 1H), 8.43-8.41(m, 1H), 8.38-8.37(m, 1H), 7.98-7.91(m, 1H), 7 .71-7.60(m, 2H), 5.40(s, 2H), 4.74(t, J=12.5Hz, 2H), 4.38(t, J=12.5Hz, 2H).

[0663] Example 126: 1-(3,3-Difluoroazetidin-1-yl)-2-[6-(3,5-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0664] [ka] The title compound was prepared in a similar manner to Intermediate 17, using (3,5-difluorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid. MS (ESI): C 17 H 12 Calculated mass of FNO, 364.1; observed m / z, 365.1 [M+H] + . 1H NMR (400MHz, DMSO-d6)δ 8.95(d, J=2.0Hz, 1H), 8.50-8.48(m, 1H), 8.40-8.38(m, 1H), 7.67-7.58(m, 2H), 7.35 (tt, J=9.3, 2.4Hz, 1H), 5.41(s, 2H), 4.73(t, J=12.4Hz, 2H), 4.38(t, J=12.6Hz, 2H).

[0665] Example 127: 2-[6-(3-chloro-4-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3,3-difluoroazetidin-1-yl)ethanone.

[0666] [ka] The title compound was prepared in a manner similar to that of Example 17, using (3-chloro-4-fluorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid and palladium-tetrakis(triphenylphosphine) instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). MS (ESI): C 17 H 12 Calculated mass for ClF3N4O: 380.1; observed m / z: 381.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.89(d, J=1.9Hz, 1H), 8.44-8.41(m, 1H), 8.38-8.36(m, 1H), 8.06(dd, J=7.1, 2.3Hz, 1H), 7.85(ddd, J=8 .6, 4.6, 2.4Hz, 1H), 7.61(t, J=8.9Hz, 1H), 5.41(s, 2H), 4.73(t, J=12.4Hz, 2H), 4.38(t, J=12.5Hz, 2H).

[0667] Example 128: 2-[6-(3-chloro-2-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3,3-difluoroazetidin-1-yl)ethanone.

[0668] [ka] The title compound was prepared in a manner similar to that of Example 17, using (3-chloro-2-fluorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). MS(ESI):C 17 H 12 Calculated mass for ClF3N4O: 380.1; observed m / z: 381.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 8.72(t, J=1.9Hz, 1H), 8.42-8.40(m, 1H), 8.35-8.33(m, 1H), 7.74-7.68(m, 1H), 7.66-7.61(m, 1H), 7.42(td, J=7.9, 1.0Hz, 1H), 5.42(s, 2H), 4.75(t, J=12.5Hz, 2H), 4.37(t, J=12.6Hz, 2H).

[0669] Example 129: 1-(3,3-Difluoroazetidin-1-yl)-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate.

[0670] [ka] The title compound was prepared in a similar manner to Example 13, using 2-(6-(4-fluoro-3-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (Intermediate 52) instead of Intermediate 39 and 3,3-difluoroazetidine hydrochloride instead of morpholine. MS (ESI): C 18 H 15 Calculated mass of FNO, 360.1; observed m / z, 361.2 [M+H] + . 1H NMR (500MHz, DMSO-d6)δ 8.85(d, J=1.9Hz, 1H), 8.36-8.33(m, 2H), 7.76-7.72(m, 1H), 7.67-7.63(m, 1H), 7.34-7.2 9(m, 1H), 5.40(s, 2H), 4.73(t, J=12.4Hz, 2H), 4.38(t, J=12.6Hz, 2H), 2.35-2.34(m, 3H).

[0671] Example 130: 1-(3,3-Difluoroazetidin-1-yl)-2-[6-(4-fluoro-2-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate.

[0672] [ka] The title compound was prepared in a similar manner to Example 1, using 2-(6-(4-fluoro-2-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (Intermediate 53) instead of Intermediate 39 and 3,3-difluoropyrrolidine hydrochloride instead of morpholine. MS (ESI): C 18 H 15 Calculated mass of FNO, 360.1; observed m / z, 361.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.54-8.50(m, 1H), 8.38-8.35(m, 1H), 8.11-8.09(m, 1H), 7.36(dd, J=8.5, 6.0Hz, 1H), 7.26(dd, J=10.1, 2.8H z, 1H), 7.17(td, J=8.6, 2.8Hz, 1H), 5.38(s, 2H), 4.72(t, J=12.4Hz, 2H), 4.36(t, J=12.5Hz, 2H), 2.27(s, 3H).

[0673] Example 131: 1-(3,3-Difluoroazetidin-1-yl)-2-[6-(2-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0674] [ka] The title compound was prepared in a manner similar to that of Example 17, using (2-fluoro-3-methylphenyl)boronic acid instead of 2,4-difluorophenylboronic acid and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C. MS (ESI): C 18 H 15 Calculated mass of FNO, 360.1; observed m / z, 361.2 [M+H] + . 1 H NMR (600MHz, DMSO-d6)δ 8.69(t, J=1.9Hz, 1H), 8.39-8.36(m, 1H), 8.28-8.25(m, 1H), 7.46-7.42(m, 1H), 7.42-7.37(m, 1H), 7 .27(t, J=7.6Hz, 1H), 5.41(s, 2H), 4.74(t, J=12.4Hz, 2H), 4.37(t, J=12.5Hz, 2H), 2.35-2.32(m, 3H).

[0675] Example 132: 1-(3,3-Difluoroazetidin-1-yl)-2-[6-[2-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0676] [ka] The title compound was prepared in a manner similar to that of Example 17, using (2-fluoro-3-(trifluoromethyl)phenyl)boronic acid instead of 2,4-difluorophenylboronic acid. MS (ESI): C 18 H 12 Calculated mass of FNO, 414.1; observed m / z, 415.1 [M+H] + . 1H NMR (400MHz, DMSO-d6)δ 8.73(t, J=1.7Hz, 1H), 8.43-8.42(m, 1H), 8.38-8.36(m, 1H), 8.04-7.98(m, 1H), 7.94-7.88(t, J =7.3Hz, 1H), 7.60(t, J=7.8Hz, 1H), 5.43(s, 2H), 4.75(t, J=12.4Hz, 2H), 4.37(t, J=12.6Hz, 2H).

[0677] Example 133: 1-(3,3-Difluoroazetidin-1-yl)-2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0678] [ka] The title compound was prepared in a manner similar to that of Example 17, using (4-fluoro-3-(trifluoromethyl)phenyl)boronic acid instead of 2,4-difluorophenylboronic acid and palladium-tetrakis(triphenylphosphine) instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). MS (ESI): C 18 H 12 Calculated mass of FNO, 414.1; observed m / z, 415.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 8.93(d, J=1.9Hz, 1H), 8.47-8.46(m, 1H), 8.40-8.38(m, 1H), 8.22-8.14(m, 2H), 7.76-7.69(m, 1H), 5.42(s, 2H), 4.73(t, J=12.3Hz, 2H), 4.38(t, J=12.6Hz, 2H).

[0679] Example 134: 1-(3,3-Difluoroazetidin-1-yl)-2-[6-[2-fluoro-5-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0680] [ka] The title compound was prepared in a manner similar to that of Example 17, using (2-fluoro-5-(trifluoromethyl)phenyl)boronic acid instead of 2,4-difluorophenylboronic acid and palladium-tetrakis(triphenylphosphine) instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). MS (ESI): C 18 H 12 Calculated mass of FNO, 414.1; observed m / z, 415.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 8.57(t, J=2.0Hz, 1H), 8.24-8.21(m, 1H), 8.20-8.16(m, 1H), 7.88-7.83(m, 1H), 7.77-7.71 (m, 1H), 7.48 (t, J=9.4Hz, 1H), 5.23 (s, 2H), 4.54 (t, J=12.5Hz, 2H), 4.17 (t, J=12.5Hz, 2H).

[0681] Example 135: 1-(3,3-difluoroazetidin-1-yl)-2-[6-[2-methyl-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0682] [ka] The title compound was prepared in a manner similar to that of Example 17, using (2-methyl-3-(trifluoromethyl)phenyl)boronic acid instead of 2,4-difluorophenylboronic acid and palladium-tetrakis(triphenylphosphine) instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). MS (ESI): C 19 H 15 Calculated mass of FNO, 410.1; observed m / z, 411.2 [M+H] + . 1H NMR (400MHz, DMSO-d6)δ 8.54(d, J=1.8Hz, 1H), 8.40(d, J=1.0Hz, 1H), 8.16-8.14(m, 1H), 7.84-7.79(m, 1H), 7.65-7 .51(m, 2H), 5.38(s, 2H), 4.72(t, J=12.4Hz, 2H), 4.36(t, J=12.5Hz, 2H), 2.35-2.29(m, 3H).

[0683] Example 136: 1-(3,3-Difluoroazetidin-1-yl)-2-[6-(4-fluoro-2-methoxy-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0684] [ka] The title compound was prepared in a similar manner to Example 17, using (4-fluoro-2-methoxyphenyl)boronic acid instead of 2,4-difluorophenylboronic acid. The reaction mixture was heated to 90° C. instead of 75° C. MS (ESI): C 18 H 15 Calculated mass of F3N4O2, 376.1; observed m / z, 377.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.60(d, J=1.8Hz, 1H), 8.33(d, J=1.0Hz, 1H), 8.12-8.10(m, 1H), 7.43(dd, J=8.4, 6.9Hz, 1H), 7.11(dd, J=11.4, 2 .5Hz, 1H), 6.95(td, J=8.4, 2.5Hz, 1H), 5.37(s, 2H), 4.72(t, J=12.4Hz, 2H), 4.36(t, J=12.5Hz, 2H), 3.81(s, 3H).

[0685] Example 137: 1-(3,3-difluoroazetidin-1-yl)-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0686] [ka] The title compound was prepared in a manner similar to that of Example 17, using (3,4,5-trifluorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C. MS (ESI): C 17 H 11 Calculated mass of FNO, 382.1; observed m / z, 383.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.93 (d.

[0687] Example 138: 1-(3,3-Dimethylazetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate.

[0688] [ka] The title compound was prepared in a similar manner to Example 16, using 3,3-dimethylazetidine hydrochloride instead of 3-fluoroazetidine hydrochloride. MS(ESI):C 20 H 19 Calculated mass of FNO, 388.2; observed m / z, 389.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.94(d, J=1.9Hz, 1H), 8.52-8.50(m, 1H), 8.38-8.36(m, 1H), 8.17-8.13(m, 2H), 7.85-7.77(m, 2H), 5.29(s, 2H), 3.89(s, 2H), 3.59(s, 2H), 1.26(s, 6H).

[0689] Example 139: 1-(3-Fluoro-3-methyl-azetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0690] [ka] The title compound was prepared in a similar manner to Example 16, using 3-fluoro-3-methylazetidine instead of 3-fluoroazetidine hydrochloride and DCM instead of DMF. MS(ESI):C 19 H 16 Calculated mass of FNO, 392.1; observed m / z, 393.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.94(d, J=1.9Hz, 1H), 8.51-8.49(m, 1H), 8.39-8.37(m, 1H), 8.17-8.12(m, 2H), 7.85-7.7 7(m, 2H), 5.42-5.30(m, 2H), 4.40-4.26(m, 2H), 4.07-3.96(m, 2H), 1.61(d, J=22.1Hz, 3H).

[0691] Example 140: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3,3-dimethylazetidin-1-yl)ethanone.

[0692] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3,3-dimethylazetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 20 H 19 Calculated mass of FNO, 388.2; observed m / z, 389.1 [M+H] + . 1H NMR (400MHz, CDCl3)δ 8.80(d, J=1.9Hz, 1H), 8.29(d, J=1.0Hz, 1H), 7.96(dd, J=1.9, 1.0Hz, 1H), 7.93-7.84(m, 1H), 7.81-7.68 (m, 1H), 7.37-7.27(m, 1H), 6.98(t, J=54.9Hz, 1H), 5.06(s, 2H), 3.79(s, 2H), 3.73(s, 2H), 1.27(s, 6H).

[0693] Example 141: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoro-3-methyl-azetidin-1-yl)ethanone.

[0694] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-fluoro-3-methylazetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 19 H 16 Calculated mass of FNO, 392.1; observed m / z, 393.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.81(d, J=1.9Hz, 1H), 8.31(d, J=1.0Hz, 1H), 7.94(dd, J=2.0, 1.0Hz, 1H), 7.93-7.83(m, 1H), 7.79-7.71(m, 1H), 7. 34-7.26(m, 1H), 6.98(t, J=54.8Hz, 1H), 5.10(s, 2H), 4.32-4.15(m, 2H), 4.12-3.88(m, 2H), 1.61(d, J=21.4Hz, 3H).

[0695] Example 142: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-ethyl-3-fluoro-azetidin-1-yl)ethanone.

[0696] [ka] The title compound was prepared in a similar manner to Example 2, using 3-ethyl-3-fluoroazetidine instead of 3-ethyl-3-methyleneazetidine. MS(ESI):C 20 H 18 Calculated mass of FNO, 406.1; observed m / z, 407.3 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.81(d, J=1.9Hz, 1H), 8.31(d, J=1.0Hz, 1H), 7.94(dd, J=1.9, 1.0Hz, 1H), 7.92-7.83(m, 1H), 7.81-7.68(m, 1H), 7. 37-7.28(m, 1H), 6.98(t, J=54.9Hz, 1H), 5.10(s, 2H), 4.25-3.94(m, 4H), 1.95-1.75(m, 2H), 0.97(t, J=7.4Hz, 3H).

[0697] Example 143: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-fluoro-3-(fluoromethyl)azetidin-1-yl]ethanone.

[0698] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-fluoro-3-(fluoromethyl)azetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 19 H 15 Calculated mass of FNO, 410.1; observed m / z, 411.1 [M+H] + . 1H NMR (400MHz, CDCl3)δ 8.82(d, J=1.9Hz, 1H), 8.32(d, J=1.0Hz, 1H), 7.93(dd, J=1.9, 1.0Hz, 1H), 7.90-7.85(m, 1H), 7.80-7.66(m, 1 H), 7.37-7.29(m, 1H), 6.98(t, J=54.8Hz, 1H), 5.12(s, 2H), 4.58(dd, J=46.8, 18.2Hz, 2H), 4.32-4.13(m, 4H).

[0699] Example 144: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methoxy-3-methyl-azetidin-1-yl)ethanone.

[0700] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-methoxy-3-methylazetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 20 H 19 Calculated mass of F3N4O2, 404.1; observed m / z, 405.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.80(d, J=1.9Hz, 1H), 8.30(d, J=1.0Hz, 1H), 7.96-7.93(m, 1H), 7.88-7.84(m, 1H), 7.78-7.72(m, 1H), 7.32-7.26(m, 1H), 6.9 8(t, J=54.9Hz, 1H), 5.09(s, 2H), 4.03(dd, J=14.6, 9.7Hz, 2H), 3.83(ddd, J=24.8, 9.7, 1.3Hz, 2H), 3.21(s, 3H), 1.46(s, 3H).

[0701] Example 145: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-ethyl-3-hydroxy-azetidin-1-yl)ethanone.

[0702] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-ethyl-3-hydroxyazetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 20 H 19 Calculated mass of F3N4O2, 404.1; observed m / z, 405.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.80(d, J=1.9Hz, 1H), 8.30(d, J=1.0Hz, 1H), 7.96-7.93(m, 1H), 7.89-7.84(m, 1H), 7.78-7.72(m, 1H), 7.33-7.26(m, 1 H), 6.98(t, J=54.8Hz, 1H), 5.09(s, 2H), 4.06-3.85(m, 4H), 2.01(s, 1H), 1.77(q, J=7.4Hz, 2H), 0.95(t, J=7.4Hz, 3H).

[0703] Example 146: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-hydroxy-3-methyl-azetidin-1-yl)ethanone.

[0704] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-hydroxy-3-methylazetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 19 H 17 Calculated mass of F3N4O2, 390.1; observed m / z, 391.2 [M+H] + . 1H NMR (400MHz, methanol-d4)δ 8.79(d, J=1.8Hz, 1H), 8.29(d, J=0.9Hz, 1H), 8.16(dd, J=1.9, 1.0Hz, 1H), 7.97-7.90(m, 1H), 7.90-7.79 (m, 1H), 7.42-7.30(m, 1H), 7.02(t, J=54.8Hz, 1H), 5.19(s, 2H), 4.12(s, 2H), 3.95(s, 2H), 1.53(s, 3H).

[0705] Example 147: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-fluoro-3-(hydroxymethyl)azetidin-1-yl]ethanone.

[0706] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-fluoro-3-hydroxymethylazetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 19 H 16 Calculated mass of F4N4O2, 408.1; observed m / z, 409.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.81(d, J=1.9Hz, 1H), 8.31(d, J=1.0Hz, 1H), 7.93(dd, J=2.0, 1.0Hz, 1H), 7.87(d, J=6.5Hz, 1H), 7.75(s, 1H), 7 .33-7.26(m, 1H), 6.98(t, J=54.9Hz, 1H), 5.11(s, 2H), 4.29-4.12(m, 4H), 3.94-3.78(m, 2H), 1.98-1.88(m, 1H).

[0707] Example 148: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-fluoro-3-(methoxymethyl)azetidin-1-yl]ethanone.

[0708] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-fluoro-3-methoxymethylazetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 20 H 18 Calculated mass of F4N4O2, 422.1; observed m / z, 423.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.81(d, J=1.9Hz, 1H), 8.31(d, J=1.0Hz, 1H), 7.93(dd, J=1.9, 1.0Hz, 1H), 7.90-7.84(m, 1H), 7.80-7.71(m, 1H), 7.32-7.27(m, 1H), 6.98(t, J=54.8Hz, 1H), 5.11(s, 2H), 4.28-4.07(m, 4H), 3.60(d, J=17.5Hz, 2H), 3.41(s, 3H).

[0709] Example 149: [6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-hydroxy-2-methyl-azetidin-1-yl)ethanone.

[0710] [ka] The title compound was prepared in a manner similar to that of Example 1, using a diastereomeric mixture of 3-hydroxy-2-methylazetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 19 H 17 Calculated mass of F3N4O2, 390.1; observed m / z, 391.0 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 8.81-8.77 (m, 1H), 8.32-8.27 (m, 1H), 8.00-7.92 (m, 1H), 7.89-7.83 (m, 1H), 7.78-7.71 (m, 1H), 7.31-7.26 (m, 1H), 6.98 (t, J = 54.9 Hz, 1H), 5.21-4.93 (m, 2H), 4.78-4.11 (m, 3H), 3.96-3.75 (m, 1H), 2.59-2.06 (m, 1H), 1.50-1.35 (m, 3H).

[0711] Example 150: 1-[2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]azetidine-3-carbonitrile.

[0712] [ka] The title compound was prepared in a similar manner to Example 16, using azetidine-3-carbonitrile hydrochloride instead of azetidine 3-fluoroazetidine hydrochloride and DCM instead of DMF. MS (ESI): C 19 H 14 Calculated mass of FNO, 385.1; observed m / z, 386.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6)δ 8.95(d, J=1.9Hz, 1H), 8.50-8.47(m, 1H), 8.40-8.38(m, 1H), 8.18-8.11(m, 2H), 7.87-7.77(m, 2H) ), 5.40-5.28(m, 2H), 4.54-4.39(m, 2H), 4.25-4.16(m, 1H), 4.13-4.05(m, 1H), 3.91-3.82(m, 1H).

[0713] Example 151: 1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]azetidine-3-carbonitrile.

[0714] [ka] The title compound was prepared in a similar manner to Example 2, using 3-cyanoazetidine instead of 3-methyleneazetidine. MS(ESI):C 19 H 14 Calculated mass of FNO, 385.1; observed m / z, 386.0 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.83(d, J=1.9Hz, 1H), 8.32(d, J=1.0Hz, 1H), 7.92(dd, J=2.0, 1.0Hz, 1H), 7.90-7.84(m, 1H), 7.80-7.69(m, 1H), 7.34-7.28(m, 1H), 6.98(t, J=54.8Hz, 1H), 5.09(d, J=3.1Hz, 2H), 4.44-4.17(m, 3H), 3.58-3.42(m, 2H).

[0715] Example 152: 1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]-3-methyl-azetidine-3-carbonitrile.

[0716] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-cyano-3-methylazetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 20 H 16 Calculated mass of FNO, 399.1; observed m / z, 400.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.83(d, J=1.9Hz, 1H), 8.32(d, J=1.0Hz, 1H), 7.92(dd, J=1.9, 1.0Hz, 1H), 7.90-7.85(m, 1H), 7.79-7.72(m, 1H) , 7.34-7.27(m, 1H), 6.98(t, J=54.9Hz, 1H), 5.09(s, 2H), 4.45-4.34(m, 2H), 3.97(t, J=9.0Hz, 2H), 1.67(s, 3H).

[0717] Example 153: 1-(3-acetylazetidin-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0718] [ka] The title compound was prepared in a manner similar to that of Example 1, using 1-(azetidin-3-yl)ethan-1-one instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 20 H 17 Calculated mass of F3N4O2, 402.1; observed m / z, 403.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.80(d, J=1.9Hz, 1H), 8.30(d, J=1.0Hz, 1H), 7.93(dd, J=1.9, 1.0Hz, 1H), 7.89-7.84(m, 1H), 7.78-7.72(m, 1H), 7.32-7.27(m, 1H), 6.98(t, J=54.8Hz, 1H), 5.21-4.94(m, 2H), 4.33(dd, J=8.8, 6.0Hz, 1H), 4.27-4.08(m, 3H), 3.57-3.43(m, 1H), 2.18(s, 3H).

[0719] Example 154: N-[1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]azetidin-3-yl]acetamide.

[0720] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-acetamidoazetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 20 H 18 Calculated mass of F3N5O2, 417.1; observed m / z, 418.2 [M+H] + . 1H NMR (400MHz, CDCl3)δ 8.81(d, J=1.9Hz, 1H), 8.30(d, J=1.0Hz, 1H), 7.93(dd, J=1.9, 1.0Hz, 1H), 7.90-7.83(m, 1H), 7.81-7.70(m, 1H), 7.32-7.27(m, 1H), 6. 98(t, J=54.8Hz, 1H), 5.96(d, J=7.1Hz, 1H), 5.19-5.01(m, 2H), 4.76-4.61(m, 1H), 4.47-4.30(m, 2H), 4.01-3.83(m, 2H), 1.96(s, 3H).

[0721] Example 155: 1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]-N,N-dimethyl-azetidine-3-carboxamide.

[0722] [ka] The title compound was prepared in a manner similar to that of Example 1, using N,N-dimethylazetidine-3-carboxamide instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 21 H 20 Calculated mass of F3N5O2, 431.2; observed m / z, 432.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.79(d, J=1.9Hz, 1H), 8.29(d, J=1.0Hz, 1H), 7.95(dd, J=2.0, 1.0Hz, 1H), 7.89-7.83(m, 1H), 7.79-7.71(m, 1H), 7.33-7.23(m, 1H), 6. 98(t, J=54.8Hz, 1H), 5.20-4.89(m, 2H), 4.57-4.47(m, 1H), 4.31-4.07(m, 3H), 3.59(tt, J=9.0, 6.2Hz, 1H), 2.97(s, 3H), 2.89(s, 3H).

[0723] Example 156: Methyl N-[1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]azetidin-3-yl]carbamate.

[0724] [ka] The title compound was prepared in a similar manner to Example 1, using methyl azetidin-3-ylcarbamate instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 20 H 18 Calculated mass of F3N5O3: 433.1; observed m / z: 434.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.81(d, J=1.9Hz, 1H), 8.30(d, J=1.0Hz, 1H), 7.93(dd, J=2.0, 1.0Hz, 1H), 7.91-7.85(m, 1H), 7.80-7.73(m, 1H), 7.33-7.2 7(m, 1H), 6.98(t, J=54.9Hz, 1H), 5.12-5.07(m, 3H), 4.58-4.45(m, 1H), 4.41-4.31(m, 2H), 4.03-3.83(m, 2H), 3.68(s, 3H).

[0725] Example 157: N-[1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]azetidin-3-yl]-2,2,2-trifluoro-acetamide.

[0726] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-(2,2,2-trifluoroacetamido)azetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS(ESI):C 20 H 15 Calculated mass of FNO, 471.1; observed m / z, 472.0 [M+H] + .1 H NMR (400MHz, CDCl3)δ 8.82(d, J=1.9Hz, 1H), 8.31(d, J=1.0Hz, 1H), 7.93(dd, J=1.9, 1.0Hz, 1H), 7.89-7.85(m, 1H), 7.79-7.73(m, 1H), 7.3 3-7.26(m, 1H), 6.98(t, J=54.8Hz, 1H), 5.24-5.00(m, 2H), 4.82-4.63(m, 1H), 4.57-4.29(m, 2H), 4.16-3.97(m, 2H).

[0727] Example 158: N-[1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]azetidin-3-yl]cyclopropanecarboxamide.

[0728] [ka] The title compound was prepared in a manner similar to that of Example 1, using N-(azetidin-3-yl)cyclopropanecarboxamide instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 22 H 20 Calculated mass of F3N5O2, 443.2; observed m / z, 444.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.81-8.77(m, 1H), 8.32-8.25(m, 1H), 7.96-7.91(m, 1H), 7.88-7.83(m, 1H), 7.77-7.71(m, 1H), 7.31-7.27(m, 1H), 6.98(t, J=54.9Hz, 1H), 5.21(s, 2H), 3.86-3.41(m, 4H), 3.38-3.22(m, 4H), 2.71-2.43(m, 1H), 2.22-1.96(m, 1H), 1.94-1.64(m, 1H).

[0729] Example 159: N-[1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]azetidin-3-yl]methanesulfonamide.

[0730] [ka] The title compound was prepared in a manner similar to that of Example 1, using N-(azetidin-3-yl)methanesulfonamide instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 19 H 18 Calculated mass of F3N5O3S, 453.1; observed m / z, 454.0 [M+H] + . 1 H NMR (400MHz, methanol-d4)δ 8.79(d, J=1.9Hz, 1H), 8.30(d, J=1.0Hz, 1H), 8.15(dd, J=1.9, 1.0Hz, 1H), 7.96-7.89(m, 1H), 7.88-7.81(m, 1H), 7.35(ddd, J=9.8, 8.6, 1 .2Hz, 1H), 7.02(t, J=54.8Hz, 1H), 5.18(s, 2H), 4.59-4.49(m, 1H), 4.42-4.27(m, 2H), 4.24-4.16(m, 1H), 4.04-3.95(m, 1H), 2.96(s, 3H).

[0731] Example 160: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methylsulfonylazetidin-1-yl)ethanone.

[0732] [ka] The title compound was prepared in a manner similar to that of Example 1, using 3-(methylsulfonyl)azetidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 19 H 17 Calculated mass of F3N4O3S, 438.1; observed m / z, 439.0 [M+H] + . 1H NMR (400MHz, DMSO-D6)δ 8.90(d, J=2.0Hz, 1H), 8.44(dd, J=2.0, 1.0Hz, 1H), 8.39(d, J=1.0Hz, 1H), 8.12-7.98(m, 2H), 7.59(t, J=9.8Hz, 1H), 7.31(t, J=54.1Hz) , 1H), 5.48-5.25(m, 2H), 4.60-4.52(m, 1H), 4.50-4.44(m, 1H), 4.44-4.35(m, 1H), 4.26-4.17(m, 1H), 4.16-4.07(m, 1H), 3.07(s, 3H).

[0733] Example 161: 1-[1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]azetidin-3-yl]pyrrolidin-2-one.

[0734] [ka] The title compound was prepared in a manner similar to that of Example 1, using 1-(azetidin-3-yl)pyrrolidin-2-one instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 22 H 20 Calculated mass of F3N5O2, 443.2; observed m / z, 444.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.81(d, J=1.9Hz, 1H), 8.30(d, J=1.0Hz, 1H), 7.95(dd, J=2.0, 1.0Hz, 1H), 7.89-7.82(m, 1H), 7.81-7.67(m, 1H), 7.37-7.27(m, 1H), 6.98(t, J=54.8Hz, 1H), 5.09(s, 2H), 5.06-4.96(m, 1H), 4.31-4.11(m, 4H), 3.57-3.30(m, 2H), 2.50-2.26(m, 2H), 2.13-2.04(m, 2H).

[0735] Example 162: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(1H-imidazol-2-yl)azetidin-1-yl]ethanone.

[0736] [ka] The title compound was prepared in a manner similar to that of Example 2, using 2-(azetidin-3-yl)-1H-imidazole instead of 3-methyleneazetidine. MS(ESI):C 21 H 17 Calculated mass for F3NO, 426.1; observed m / z, 427.2 [M+H]+. 1 H NMR (400MHz, CDCl3)δ 8.92-8.60(m, 1H), 8.21(s, 1H), 7.96(s, 1H), 7.88-7.82(m, 1H), 7.73(t, J=6.7Hz, 1H), 7.30-7.22(m, 1H), 6.9 6(t, J=54.9Hz, 1H), 6.76(s, 2H), 5.40-5.02(m, 3H), 4.51-4.36(m, 2H), 4.34-4.22(m, 2H), 4.00-3.84(m, 1H).

[0737] Example 163: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(4-pyridyl)azetidin-1-yl]ethanone.

[0738] [ka] The title compound was prepared in a similar manner to Example 2, using 4-(azetidin-3-yl)pyridine instead of 3-methyleneazetidine. MS (ESI): C 23 H 18 Calculated mass of FNO, 437.1; observed m / z, 438.1 [M+H] + . 1H NMR (400 MHz, CDCl) δ 8.81(d, J=1.9Hz, 1H), 8.62-8.55(m, 2H), 8.31(d, J=1.0Hz, 1H), 7.98(dd , J=2.0, 1.0Hz, 1H), 7.91-7.84(m, 1H), 7.81-7.68(m, 1H), 7.36-7.25(m, 1 H), 7.21-7.15(m, 2H), 6.98(t, J=54.8Hz, 1H), 5.13(d, J=1.0Hz, 2H), 4.5 6-4.43(m, 2H), 4.13(dt, J=10.3, 6.7Hz, 2H), 3.83(tt, J=8.9, 6.0Hz, 1H).

[0739] Example 164: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-pyrimidin-4-ylazetidin-1-yl)ethanone.

[0740] [ka] The title compound was prepared in a similar manner to Example 2, using 4-(azetidin-3-yl)pyrimidine instead of 3-methyleneazetidine. MS (ESI): C 22 H 17 Calculated mass of FNO, 438.1; observed m / z, 439.2 [M+H] + . 1 H NMR (400 MHz, CDCl) δ 9.19(d, J=1.5Hz, 1H), 8.80(d, J=1.9Hz, 1H), 8.68(d, J=5.1Hz, 1H), 8.30( d, J=1.0Hz, 1H), 8.05-7.97(m, 1H), 7.93-7.83(m, 1H), 7.81-7.69(m, 1H), 7.34-7.25(m, 1H), 7.18(dd, J=5.1, 1.4Hz, 1H), 6.98(t, J=54.8Hz, 1H), 5. 23-5.04(m, 2H), 4.47-4.38(m, 3H), 4.33-4.24(m, 1H), 3.96-3.85(m, 1H).

[0741] Example 165: 1-(5-Azaspiro[2.3]hexan-5-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0742] [ka] The title compound was prepared in a manner similar to that of Example 1, using 5-azaspiro[3.2]hexane instead of 3-(trifluoromethyl)azetidin-3-ol. MS(ESI):C 20 H 17 Calculated mass of FNO, 386.1; observed m / z, 387.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.80(d, J=1.9Hz, 1H), 8.29(d, J=1.0Hz, 1H), 7.97(dd, J=1.9, 1.0Hz, 1H), 7.90-7.85(m, 1H), 7.80-7.7 1(m, 1H), 7.32-7.27(m, 1H), 6.98(t, J=54.8Hz, 1H), 5.11(s, 2H), 4.22-4.07(m, 4H), 0.79-0.56(m, 4H).

[0743] Example 166: 1-(2,2-Difluoro-5-azaspiro[2.3]hexan-5-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin- 1-yl]ethanone.

[0744] [ka] The title compound was prepared in a manner similar to that of Example 1, using 1,1-difluoro-5-azaspiro[2.3]hexane instead of 3-(trifluoromethyl)azetidin-3-ol. MS(ESI):C 20 H 15 Calculated mass of FNO, 422.1; observed m / z, 423.1 [M+H] + . 1H NMR (400MHz, CDCl3)δ 8.82(d, J=1.9Hz, 1H), 8.31(d, J=1.1Hz, 1H), 7.95(dd, J=2.0, 1.1Hz, 1H), 7.90-7.84(m, 1H), 7.80-7.73(m, 1H), 7.3 3-7.27(m, 1H), 6.98(t, J=54.9Hz, 1H), 5.21-5.00(m, 2H), 4.32-4.19(m, 2H), 4.17-4.03(m, 2H), 1.53-1.42(m, 2H).

[0745] Example 167: 1-(6-Azaspiro[3.3]heptan-6-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0746] [ka] The title compound was prepared in a manner similar to that of Example 1, using azaspiro[3.3]heptane instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 21 H 19 Calculated mass of FNO, 400.2; observed m / z, 401.3 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.79(d, J=1.9Hz, 1H), 8.29(d, J=0.9Hz, 1H), 7.95(dd, J=2.0, 1.0Hz, 1H), 7.89-7.82(m, 1H), 7.78-7.70(m, 1H), 7.3 3-7.24(m, 1H), 6.97(t, J=54.8Hz, 1H), 5.05(s, 2H), 4.05(s, 2H), 4.00(s, 2H), 2.22-2.04(m, 3H), 1.91-1.70(m, 3H).

[0747] Example 168: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-oxa-6-azaspiro[3.3]heptan-6-yl)ethanone.

[0748] [ka] The title compound was prepared in a manner similar to that of Example 1, using 1-oxa-6-azaspiro[3.3]heptane instead of 3-(trifluoromethyl)azetidin-3-ol. MS(ESI):C 20 H 17 Calculated mass of F3N4O2, 402.1; observed m / z, 403.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.80(d, J=1.9Hz, 1H), 8.30(d, J=1.0Hz, 1H), 7.92(dd, J=1.9, 1.0Hz, 1H), 7.90-7.82(m, 1H), 7.80-7.68(m, 1H), 7.34-7.27(m, 1H), 6.98(t, J=54.8Hz, 1H), 5.08(s, 2H), 4.58-4.42(m, 2H), 4.31-4.11(m, 4H), 2.91-2.76(m, 2H).

[0749] Example 169: 1-(6-oxa-2-azaspiro[3.3]heptan-2-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0750] [ka] The title compound was prepared in a manner similar to that of Example 16, using 2-oxa-6-azaspiro[3.3]heptane instead of 3-fluoroazetidine hydrochloride and DCM instead of DMF. MS (ESI): C 20 H 17 Calculated mass of F3N4O2, 402.1; observed m / z, 403.2 [M+H] + . 1H NMR (400MHz, DMSO-d6)δ 8.94(d, J=1.9Hz, 1H), 8.48-8.45(m, 1H), 8.38-8.36(m, 1H), 8.16-8.12(m, 2H) , 7.86-7.76(m, 2H), 5.28(s, 2H), 4.73-4.65(m, 4H), 4.38(s, 2H), 4.10(s, 2H).

[0751] Example 170: 2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-pyrrolidin-1-yl-ethanone.

[0752] [ka] The title compound was prepared in a manner similar to that of Example 1, using 2-(6-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (Intermediate 31) instead of Intermediate 16 and pyrrolidine instead of 3-(trifluoromethyl)azetidin-3-ol. MS (ESI): C 18 H 17 Calculated mass of FNO, 324.1; observed m / z, 325.2 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 8.78(d, J=1.9Hz, 1H), 8.28-8.26(m, 1H), 7.96-7.94(m, 1H), 7.65-7.59(m, 2H), 7.23 -7.15(m, 2H), 5.20(s, 2H), 3.61-3.47(m, 4H), 2.06-1.99(m, 2H), 1.92-1.85(m, 2H).

[0753] Example 171: 1-Pyrrolidin-1-yl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone.

[0754] [ka] The title compound was prepared in a similar manner to Example 17, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one (Intermediate 43) instead of Intermediate 42, (3-(trifluoromethyl)phenyl)boronic acid instead of (2,4-difluorophenylboronic acid), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90° C. MS (ESI): C 19 H 17 Calculated mass of FNO, 374.1; observed m / z, 375.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.93(d, J=2.0Hz, 1H), 8.51-8.48(m, 1H), 8.37-8.34(m, 1H), 8.16-8.12(m, 2H), 7.85- 7.77(m, 2H), 5.45(s, 2H), 3.61(t, J=6.8Hz, 2H), 2.00-1.93(m, 2H), 1.85-1.77(m, 2H).

[0755] Example 172: 2-[6-(3-cyclopropylphenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-pyrrolidin-1-yl-ethanone.

[0756] [ka] The title compound was prepared in a similar manner to Example 17, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one (Intermediate 43) instead of Intermediate 42, 2-(3-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 2,4-difluorophenylboronic acid, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex instead of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction mixture was heated to 90°C. MS (ESI): C 21 H 22 Calculated mass of NO, 346.2; observed m / z, 347.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.84(d, J=1.9Hz, 1H), 8.34-8.32(m, 1H), 8.32-8.30(m, 1H), 7.55-7.52(m, 1H), 7.50-7.47(m, 1H), 7.41(t, J=7.7Hz, 1H), 7.16 -7.12(m, 1H), 5.43(s, 2H), 3.60(t, J=6.8Hz, 2H), 2.06-1.92(m, 3H), 1.84-1.77(m, 2H), 1.02-0.98(m, 2H), 0.82-0.78(m, 2H).

[0757] Example 173: 2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-pyrrolidin-1-yl-ethanone.

[0758] [ka] The title compound was prepared in a manner similar to Example 5, Method A, using 6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine (Intermediate 17) instead of Intermediate 16 and 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one instead of Intermediate 1. MS (ESI): C 19 H 17Calculated mass of F3N4O2, 390.1; observed m / z, 391.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6)δ 8.96-8.80(m, 1H), 8.45-8.36(m, 1H), 8.34(s, 1H), 7.89-7.78(m, 1H), 7.81-7.70(m, 1H), 7.68-7.53(m, 1H), 7. 38(t, J=73.3Hz, 1H), 5.43(s, 2H), 3.72-3.47(m, 2H), 3.37-3.22(m, 2H), 2.05-1.88(m, 2H), 1.88-1.72(m, 2H).

[0759] Example 174: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-pyrrolidin-1-yl-ethanone.

[0760] [ka] The title compound was made in a similar manner to Example 5, Method A, using 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one in place of Intermediate 1. MS (ESI): C 19 H 17 Calculated mass of FNO, 374.1; observed m / z, 375.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 8.93-8.83(m, 1H), 8.47-8.39(m, 1H), 8.34(s, 1H), 8.09-8.01(m, 2H), 7.62-7.53(m, 1H), 7.30(t, J=5 5.2Hz, 1H), 5.44(s, 2H), 3.66-3.54(m, 2H), 3.38-3.27(m, 2H), 2.03-1.92(m, 2H), 1.87-1.76(m, 2H).

[0761] Example 175: 2-[6-(3,5-Difluoro-4-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-pyrrolidin-1-yl-ethanone trifluor...

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, R １ is H, halo, or CH ３ and Ar １ teeth, (a) Halo, C １～６ Alkyl, O.C. １～６ Alkyl, C １～６ Perhaloalkyl, OC １～６ Perhaloalkyl, CN, and C ３～６ phenyl substituted with one member selected from the group consisting of cycloalkyl; (b) Halo, C １～６ Alkyl, C １～６ Perhaloalkyl, OC １～６ Alkyl, O.C. １～６ Perhaloalkyl, and (C=O)CH ３ phenyl substituted with two or three members each independently selected from the group consisting of: (c) Halo, C １～６ Alkyl, and C １～６ thienyl substituted with one or two members independently selected from perhaloalkyl, and CF ３ Pyridine substituted with is selected from the group consisting of R ２ teeth, (a) 【Chemistry 2】 (In the formula, R ａ are H, halo, OH, and C, respectively. １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, CH ２ OH, CH(OH)(CH ３ ), C.H. ２ OCH ３ , O.C. １～６ Haloalkyl, O.C. １～６ Alkyl, NH(CH ３ ), N.H.C.O. ２ CH ３ ,NHC(=O)CH ３ ,NHC(=O)CF ３ , NHC(=O)cyclopropyl, N(CH ３ )C(=O)CH ３ , C(=O)N(CH ３ ) ２ , C(=O)CH ３ , C.N., N.H.S.O. ２ CH ３ , S.O. ２ CH ３ , 1H-imidazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidin-4-yl, and pyrrolidin-2-one-1-yl, or two R ａ The members combine to form C ３～６ cycloalkyl or heterocycloalkyl, said cycloalkyl and heterocycloalkyl being optionally substituted with one or two F atoms; (b) 【Chemistry 3】 (In the formula, R ｂ are H, OH, F, and OCH, respectively. ３ , C.H. ２ OCH ３ and NHC(=O)CH ３ or two R ｂ The members together form =O; (c) 【Chemistry 4】 and, (d) 【Chemistry 5】 (In the formula, R ｄ is C １～６ Alkyl, C ２～６ Alkenyl, C １～６ Haloalkyl, CH ２ CH ２ OCH ３ , C.H. ２ CH ２ O.H., C.H. ２ C.N., N.H. ２ ,NH-C(=O)CH ３ , C ３～６ Cycloalkyl, C substituted with 2 F atoms ３～６ selected from the group consisting of alkenyl, 1-methylazetidin-3-yl, and oxetan-3-yl; R ｅ is H or CH ３ It is.) selected from the group consisting of: n is 1 or 2; m is 1 or 2. or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

2. R １ is H, or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

3. R １ is F, or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

4. R １ CH ３ 2. The compound of claim 1, wherein:

5. Ar １ is Cl, F, CH ３ , O.C.H. ３ , C.H. ２ F, C.H.F. ２ , C.F. ３ , C.H.F. ２ CH ３ , O.C.H.F. ２ 5. The compound of claim 1, wherein the aryl group is phenyl substituted with a member selected from the group consisting of aryl, aryloxy ...

6. Ar １ but, 【Chemistry 6】 5. The compound of any one of claims 1 to 4, selected from the group consisting of: or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopomer, or N-oxide thereof.

7. Ar １ is Cl, F, CH ３ , C.H.F. ２ , C.F. ３ , C.H.F. ２ CH ３ , O.C.H. ３ , O.C.H.F. ２ and (C=O)CH ３ or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

8. Ar １ but, 【Chemistry 7】 5. The compound of any one of claims 1 to 4, selected from the group consisting of: or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopomer, or N-oxide thereof.

9. Ar １ Halo and CH ３ or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotope, or N-oxide thereof.

10. Ar １ but, 【Chemistry 8】 5. The compound of any one of claims 1 to 4, selected from the group consisting of: or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopomer, or N-oxide thereof.

11. Ar １ is Cl, CH ３ , C.F. ３ and CHF ２ or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

12. Ar １ but, 【Chemistry 9】 5. The compound of any one of claims 1 to 4, selected from the group consisting of: or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopomer, or N-oxide thereof.

13. Ar １ but, 【Chemistry 10】 5. The compound of any one of claims 1 to 4, selected from the group consisting of: or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopomer, or N-oxide thereof.

14. Formula (I): 【Chemistry 11-1】 (In the formula, R １ is H, halo, or CH ３ and Ar １ teeth, (a) Halo, C １～６ Alkyl, O.C. １～６ Alkyl, C １～６ Perhaloalkyl, OC １～６ Perhaloalkyl, CN, and C ３～６ phenyl substituted with one member selected from the group consisting of cycloalkyl; (b) Halo, C １～６ Alkyl, C １～６ Perhaloalkyl, OC １～６ Alkyl, O.C. １～６ Perhaloalkyl, and (C=O)CH ３ phenyl substituted with two or three members each independently selected from the group consisting of: (c) Halo, C １～６ Alkyl, and C １～６ thienyl substituted with one or two members independently selected from perhaloalkyl, and CF ３ Pyridine substituted with is selected from the group consisting of R ２ teeth, 【Chemistry 11-2】 (In the formula, R ａ are H, Cl, F, OH, and CH ３ , C.H. ２ CH ３ , C.H. ２ F, C.H.F. ２ , C.F. ３ , =CH ２ , CH=CH ２ , CH=CH(CH ３ ), CH=CH(F), CH=CF(F), C=CH, CH ２ OH, CH(OH)(CH ３ ), C.H. ２ OCH ３ , O.C.H.F. ２ , O.C.F. ３ , O.C.H. ３ , C.H. ２ CH ３ , NH(CH ３ ), N.H.C.O. ２ CH ３ ,NHC(=O)CH ３ ,NHC(=O)CF ３ , NHC(=O)cyclopropyl, N(CH ３ )C(=O)CH ３ , C(=O)N(CH ３ ) ２ , C(=O)CH ３ , C.N., N.H.S.O. ２ CH ３ , S.O. ２ CH ３ , 1H-imidazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidin-4-yl, and pyrrolidin-2-one-1-yl, or two R ａ members join to form a cyclopropyl, cyclobutyl, or oxetanyl, said cyclopropyl being optionally substituted with one or two F atoms; n is 1 or 2. It is.) or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

15. Formula (I): 【Chemistry 12-1】 (In the formula, R １ is H, halo, or CH ３ and Ar １ teeth, (a) Halo, C １～６ Alkyl, O.C. １～６ Alkyl, C １～６ Perhaloalkyl, OC １～６ Perhaloalkyl, CN, and C ３～６ phenyl substituted with one member selected from the group consisting of cycloalkyl; (b) Halo, C １～６ Alkyl, C １～６ Perhaloalkyl, OC １～６ Alkyl, O.C. １～６ Perhaloalkyl, and (C=O)CH ３ phenyl substituted with two or three members each independently selected from the group consisting of: (c) Halo, C １～６ Alkyl, and C １～６ thienyl substituted with one or two members independently selected from perhaloalkyl, and CF ３ Pyridine substituted with is selected from the group consisting of R ２ teeth, 【Chemistry 12-2】 is selected from the group consisting of or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

16. R ２ but, 【Chemistry 13】 14. The compound of any one of claims 1 to 13, selected from the group consisting of: or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

17. R ２ but, 【Chemistry 14】 14. The compound of any one of claims 1 to 13, selected from the group consisting of: or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

18. R ２ but, 【Chemistry 15】 14. The compound of any one of claims 1 to 13, selected from the group consisting of: or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

19. Formula (I): 【Chemistry 16-1】 (In the formula, R １ is H, halo, or CH ３ and Ar １ teeth, (a) Halo, C １～６ Alkyl, O.C. １～６ Alkyl, C １～６ Perhaloalkyl, OC １～６ Perhaloalkyl, CN, and C ３～６ phenyl substituted with one member selected from the group consisting of cycloalkyl; (b) Halo, C １～６ Alkyl, C １～６ Perhaloalkyl, OC １～６ Alkyl, O.C. １～６ Perhaloalkyl, and (C=O)CH ３ phenyl substituted with two or three members each independently selected from the group consisting of: (c) Halo, C １～６ Alkyl, and C １～６ thienyl substituted with one or two members independently selected from perhaloalkyl, and CF ３ Pyridine substituted with is selected from the group consisting of R ２ teeth, 【Chemistry 16-2】 is selected from the group consisting of or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

20. R ２ but, 【Chemistry 17】 14. The compound of any one of claims 1 to 13, selected from the group consisting of: or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

21. R ２ but, 【Chemistry 18】 14. The compound of any one of claims 1 to 13, selected from the group consisting of: or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

22. R ２ but, 【Chemistry 19】 14. The compound of any one of claims 1 to 13, selected from the group consisting of: or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

23. Formula (IA): 【Chemistry 20-1】 (In the formula, R １ is H, F, or CH ３ and Ar １ but, (a) Halo, C １～６ Alkyl, O.C. １～６ Alkyl, C １～６ Perhaloalkyl, OC １～６ Perhaloalkyl, CN, and C ３～６ phenyl substituted with one member selected from the group consisting of cycloalkyl; (b) Halo, C １～６ Alkyl, C １～６ Perhaloalkyl, OC １～６ Alkyl, O.C. １～６ Perhaloalkyl, and (C=O)CH ３ phenyl substituted with two or three members each independently selected from the group consisting of: (c) Halo, C １～６ Alkyl, and C １～６ thienyl substituted with one or two members independently selected from perhaloalkyl; and CF ３ Pyridine substituted with selected from the group consisting of: R ａ are H, halo, OH, and C, respectively. １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, CH ２ OH, CH(OH)(CH ３ ), C.H. ２ OCH ３ , O.C. １～６ Haloalkyl, O.C. １～６ Alkyl, NH(CH ３ ), N.H.C.O. ２ CH ３ ,NHC(=O)CH ３ ,NHC(=O)CF ３ , NHC(=O)cyclopropyl, N(CH ３ )C(=O)CH ３ , C(=O)N(CH ３ ) ２ , C(=O)CH ３ , C.N., N.H.S.O. ２ CH ３ , S.O. ２ CH ３ , 1H-imidazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidin-4-yl, and pyrrolidin-2-one-1-yl, or two R ａ The members join together to form C ３～６ Form a cycloalkyl or heterocycloalkyl; ３～６ cycloalkyl and heterocycloalkyl are optionally substituted with 1 or 2 F atoms; n is 1 or 2.

2. The compound of claim 1 having the structure: or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

24. Formula (IA): 【Chemistry 20-2】 (In the formula, R １ is H, F, or CH ３ and Ar １ But, Halo, C １～４ Alkyl, C １～４ Perhaloalkyl, OC １～４ Alkyl and O.C. １～４ perhaloalkyl; R ａ are H, Cl, F, OH, and CH ３ , C.H. ２ CH ３ , C.H. ２ F, C.H.F. ２ , C.F. ３ , =CH ２ , CH=CH ２ , CH=CH(CH ３ ), CH=CH(F), CH=CF(F), C=CH, CH ２ OH, CH(OH)(CH ３ ), C.H. ２ OCH ３ , O.C.H.F. ２ , O.C.F. ３ , O.C.H. ３ , O.C.H. ２ CH ３ , NH(CH ３ ), N.H.C.O. ２ CH ３ ,NHC(=O)CH ３ ,NHC(=O)CF ３ , NHC(=O)cyclopropyl, N(CH ３ )C(=O)CH ３ , C(=O)CH ３ , C.N., N.H.S.O. ２ CH ３ , 1H-imidazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidin-4-yl, and pyrrolidin-2-one; or two R ａ members join to form a cyclopropyl, cyclobutyl, or oxetanyl, said cyclopropyl being optionally substituted with one or two F atoms; n is 1 or 2. or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

25. R １ is H, or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

26. Formula (IB): 【Chemistry 21】 (In the formula, Ar １ but, (d) halo and C １～６ phenyl substituted with one member selected from the group consisting of perhaloalkyl; (e) Halo, C １～６ Alkyl, C １～６ Perhaloalkyl, OC １～６ phenyl substituted with two or three members each independently selected from the group consisting of perhaloalkyl; and (f) Halo, C １～６ Alkyl, C １～６ thienyl independently substituted with one or two members selected from the group consisting of perhaloalkyl; and pyridine substituted with CF3. selected from the group consisting of: ring 【Chemical 22】 but, 【Chemistry 23】 selected from the group consisting of: R ｂ are H, OH, F, and OCH, respectively. ３ , C.H. ２ OCH ３ and NHC(=O)CH ３ or two R ｂ The members together form =O; n is 1 or 2; m is 1 or 2.

2. The compound of claim 1 having the structure: or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

27. ring 【Chemistry 24】 but, 【Chemistry 25】 27. The compound of claim 26, wherein:

28. Formula (IC): 【Chemistry 26】 (In the formula, R １ is H, F, or CH ３ and Ar １ but, (d) halo and C １～６ phenyl substituted with one member selected from the group consisting of perhaloalkyl; (e) Halo, C １～６ Alkyl, C １～６ Perhaloalkyl, OC １～６ phenyl substituted with two or three members each independently selected from the group consisting of perhaloalkyl; and (f) Halo, C １～６ Alkyl, and C １～６ thienyl independently substituted with one or two members selected from perhaloalkyl; and CF ３ Pyridine selected from the group consisting of: R ｄ But, C １～６ Alkyl, CH ２ CH=CH ２ , C １～６ Haloalkyl, CH ２ CH ２ OCH ３ , C.H. ２ CH ２ O.H., C.H. ２ CN;NH ２ ,NH-C(=O)CH ３ , cyclopropyl, cyclobutyl, 3-bicyclo[1.1.1]pentanyl, 3,3-difluorocyclobutyl, 1-methylazetidin-3-yl, and oxetan-3-yl; R ｅ is H or CH ３ It is.) 2. The compound of claim 1 having the structure: or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.

29. Ar １ but, 【Chemistry 27】 29. The compound of claim 28, or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, which is:

30. 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methyleneazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(methylamino)azetidin-1-yl]ethanone; N-[1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]azetidin-3-yl]-N-methyl-acetamide; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; N,N-dimethyl-2-[6-[6-(trifluoromethyl)-2-pyridyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide; 2-[6-[4-chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[4-chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; N,N-dimethyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-morpholino-ethanone; 1-morpholino-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; N-cyclopropyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide; N-(1-methylazetidin-3-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide; 1-(3-fluoroazetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3,3-difluoroazetidin-1-yl)-2-[6-(2,4-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-(5-chloro-2-thienyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-[5-(difluoromethyl)-2-thienyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[3-fluoro-6-[5-(trifluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-(3-chlorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-[3-(fluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-[3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-[3-(1,1-difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-[3-(1,1-difluoroethyl)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[3-methyl-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone, 1-(azetidin-1-yl)-2-[6-(3,4-dichlorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-(2,3-dichlorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-(3-chloro-2-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-(3,4-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-[2-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-methyl-pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-(4-chloro-3-methylphenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-(4-chloro-3-methylphenyl)-3-methyl-pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-(2-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-[4-chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-[4-chloro-3-(difluoromethoxy)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-(4-fluoro-2-methoxy-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-(3-acetyl-4-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(azetidin-1-yl)ethanone, 1-(azetidin-1-yl)-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-[2-(trifluoromethyl)-4-pyridyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-(5-chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-(5-chloro-2-thienyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[5-(difluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[5-(difluoromethyl)-2-thienyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 1-(3-fluoroazetidin-1-yl)-2-[6-5-(trifluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3-fluoroazetidin-1-yl)-2-[3-fluoro-6-[5-(trifluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3-fluoroazetidin-1-yl)-2-[6-(3-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3-fluoroazetidin-1-yl)-2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-(3-chlorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 1-(3-fluoroazetidin-1-yl)-2-[6-(m-tolyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3-fluoroazetidin-1-yl)-2-[6-[3-(fluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[3-(1,1-difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-(2,3-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-(2,4-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-(3,4-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-(3,5-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-(3-chloro-2-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-(3-chloro-4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 1-(3-chloroazetidin-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-methyl-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[4-chloro-3-(1,1-difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[4-chloro-3-(1,1-difluoroethyl)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[4-chloro-3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-(4-chloro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 1-(3-fluoroazetidin-1-yl)-2-[6-(4-fluoro-2-methoxy-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[4-chloro-3-(difluoromethoxy)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-(2,4-difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-(3,4-difluoro-5-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 1-(3-fluoroazetidin-1-yl)-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3-fluoroazetidin-1-yl)-2-[6-2-(trifluoromethyl)-4-pyridyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3-methylazetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate; (racemic) 1-(2-methylazetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methylazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methylazetidin-1-yl)ethanone; (racemic) 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(2-methylazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methylazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methylazetidin-1-yl)ethanone; 2-[6-[4-chloro-3-(difluoromethoxy)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methylazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-ethynylazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-vinylazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-3-(Z)-prop-1-enyl]azetidin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(fluoromethyl)azetidin-1-yl]ethanone; 1-[3-(difluoromethyl)azetidin-1-yl]-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-[3-(trifluoromethyl)azetidin-1-yl]-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(trifluoromethyl)azetidin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-3-(Z)-2-fluorovinyl]azetidin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-3-(2,2-difluorovinyl)azetidin-1-yl]ethanone; 1-(3-methoxyazetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methoxyazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-ethoxyazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(methoxymethyl)azetidin-1-yl]ethanone 1-[3-(methoxymethyl)azetidin-1-yl]-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; (racemic) 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(1-hydroxyethyl)azetidin-1-yl]ethanone, 1-[3-(difluoromethoxy)azetidin-1-yl]-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(trifluoromethoxy)azetidin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-hydroxyazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-hydroxyazetidin-1-yl)ethanone; 1-(3-hydroxyazetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(hydroxymethyl)azetidin-1-yl]ethanone; 1-(3,3-difluoroazetidin-1-yl)-2-[6-(4-methyl-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3,3-difluoroazetidin-1-yl)-2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-(3-chlorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3,3-difluoroazetidin-1-yl)ethanone; 1-(3,3-difluoroazetidin-1-yl)-2-[6-(m-tolyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3,3-difluoroazetidin-1-yl)-2-[6-[3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3,3-difluoroazetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate; 3-[1-[2-(3,3-difluoroazetidin-1-yl)-2-oxo-ethyl]pyrazolo[4,3-b]pyridin-6-yl]benzonitrile; 1-(3,3-difluoroazetidin-1-yl)-2-[6-[6-(trifluoromethyl)-2-pyridyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate; 1-(3,3-difluoroazetidin-1-yl)-2-[6-[2-(trifluoromethyl)-4-pyridyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3,3-difluoroazetidin-1-yl)-2-[6-[5-(trifluoromethyl)-3-pyridyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3,3-difluoroazetidin-1-yl)-2-[6-(3,4-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3,3-difluoroazetidin-1-yl)-2-[6-(3,5-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-(3-chloro-4-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3,3-difluoroazetidin-1-yl)ethanone; 2-[6-(3-chloro-2-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3,3-difluoroazetidin-1-yl)ethanone; 1-(3,3-difluoroazetidin-1-yl)-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate; 1-(3,3-difluoroazetidin-1-yl)-2-[6-(4-fluoro-2-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate; 1-(3,3-difluoroazetidin-1-yl)-2-[6-(2-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3,3-difluoroazetidin-1-yl)-2-[6-[2-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3,3-difluoroazetidin-1-yl)-2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3,3-difluoroazetidin-1-yl)-2-[6-[2-fluoro-5-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3,3-difluoroazetidin-1-yl)-2-[6-[2-methyl-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3,3-difluoroazetidin-1-yl)-2-[6-(4-fluoro-2-methoxy-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3,3-difluoroazetidin-1-yl)-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(3,3-dimethylazetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate; 1-(3-fluoro-3-methyl-azetidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3,3-dimethylazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoro-3-methyl-azetidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-ethyl-3-fluoro-azetidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-fluoro-3-(fluoromethyl)azetidin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methoxy-3-methyl-azetidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-ethyl-3-hydroxy-azetidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-hydroxy-3-methyl-azetidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-fluoro-3-(hydroxymethyl)azetidin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-fluoro-3-(methoxymethyl)azetidin-1-yl]ethanone; [6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-hydroxy-2-methyl-azetidin-1-yl)ethanone; 1-[2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]azetidine-3-carbonitrile; 1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]azetidine-3-carbonitrile; 1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]-3-methyl-azetidine-3-carbonitrile; 1-(3-acetylazetidin-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; N-[1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]azetidin-3-yl]acetamide; 1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]-N,N-dimethyl-azetidine-3-carboxamide; Methyl N-[1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]azetidin-3-yl]carbamate; N-[1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]azetidin-3-yl]-2,2,2-trifluoro-acetamide; N-[1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]azetidin-3-yl]cyclopropanecarboxamide; N-[1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]azetidin-3-yl]methanesulfonamide; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methylsulfonylazetidin-1-yl)ethanone; 1-[1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]azetidin-3-yl]pyrrolidin-2-one; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(1H-imidazol-2-yl)azetidin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[3-(4-pyridyl)azetidin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-pyrimidin-4-ylazetidin-1-yl)ethanone; 1-(5-azaspiro[2.3]hexan-5-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(6-azaspiro[3.3]heptan-6-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-oxa-6-azaspiro[3.3]heptan-6-yl)ethanone; 1-(6-oxa-2-azaspiro[3.3]heptan-2-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-pyrrolidin-1-yl-ethanone; 1-pyrrolidin-1-yl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-(3-cyclopropylphenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-pyrrolidin-1-yl-ethanone; 2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-pyrrolidin-1-yl-ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-pyrrolidin-1-yl-ethanone; 2-[6-(3,5-difluoro-4-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-pyrrolidin-1-yl-ethanone trifluoroacetate; 1-[(3R)-3-fluoropyrrolidin-1-yl]-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethano; 1-[(3S)-3-fluoropyrrolidin-1-yl]-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; (racemic)(R,S)-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoropyrrolidin-1-yl)ethanone; (racemic)(R,S)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoropyrrolidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[(3S)-3-fluoropyrrolidin-1-yl]ethanone; (racemic)(R,S)-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-hydroxypyrrolidin-1-yl)ethanone; (racemic)(R,S)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-hydroxypyrrolidin-1-yl)ethanone; (racemic) 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methoxypyrrolidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]ethanone; N-[(3S)-1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]pyrrolidin-3-yl]acetamide; N-[(3R)-1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]pyrrolidin-3-yl]acetamide; 1-(3,3-difluoropyrrolidin-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-[3-difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3,3-difluoropyrrolidin-1-yl)ethanone; 2-[6-[3-difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3,3-difluoropyrrolidin-1-yl)ethanone; (racemic) 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-hydroxy-3-methyl-pyrrolidin-1-yl)ethanone; (racemic) trans-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoro-4-hydroxy-pyrrolidin-1-yl)ethanone; 1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]pyrrolidin-3-one; 1-[2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]pyrrolidin-3-one; 1-(1-piperidine)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone trifluoroacetate; 1-(4,4-difluoro-1-piperidyl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; N-[1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]-4-piperidyl]acetamide; 2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-morpholino-ethanone; 1-[(1R,5S)-3-Azabicyclo[3.1.0]hexan-3-yl]-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]ethanone; (racemic)cis-5-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]-3a,4,6,6a-tetrahydro-3H-pyrrolo[3,4-d]oxazol-2-one; (racemic)cis-5-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]-1,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-2-one; 2-[6-[5-difluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; N,N-dimethyl-2-[6-[5-(trifluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide; 2-[6-(5-chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-(5-chloro-4-methyl-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-[3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-[3-difluoromethyl)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[3-fluoro-6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[3-fluoro-6-(3-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]N,N-dimethyl-acetamide; 2-[6-(3-chlorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; N,N-dimethyl-2-[6-[2-(trifluoromethyl)-4-pyridyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N-methyl-acetamide; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N-ethyl-acetamide; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N-ethyl-N-methyl-acetamide; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-methyl-pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-[4-chloro-3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-N-methyl-acetamide; 2-[3-fluoro-6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-(4-chloro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-(3-chloro-4-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-3,4-dichlorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-(3,5-difluorophenyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-(3,4-difluorophenyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-[3-(1,1-difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-[3-(1,1-difluoroethyl)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-[2-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N-(2-methoxyethyl)-N-methyl-acetamide; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N-(2-hydroxyethyl)-N-methyl-acetamide; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide; N-(cyanomethyl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N-methyl-acetamide; N-allyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N-methyl-acetamide; N,N-dimethyl-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]acetamide; 2-[6-(3,4-difluoro-5-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-(2,4-difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; N-cyclopropyl-N-methyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide; N-cyclopropyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide; N-cyclopropyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N-methyl-acetamide; N-cyclopropyl-2-[3-methyl-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide; N-cyclopropyl-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide; N-cyclobutyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide; N-cyclobutyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N-methyl-acetamide; N-cyclobutyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide; N-(3,3-difluorocyclobutyl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide; N-(3,3-difluorocyclobutyl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide; N-(3-bicyclo[1.1.1]pentanyl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N-methyl-acetamide; N-(oxetan-3-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetamide; 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-(pyridin-3-yl)azetidin-1-yl)ethan-1-one; 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-(pyridin-2-yl)azetidin-1-yl)ethan-1-one; Methyl (1-(2-(6-(3-(difluoromethyl)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)acetyl)azetidin-3-yl)carbamate; (S)—N-(1-(2-(6-(3-(difluoromethyl)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)acetyl)pyrrolidin-3-yl)acetamide; (R)—N-(1-(2-(6-(3-(difluoromethyl)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)acetyl)pyrrolidin-3-yl)acetamide; and 1-(3-(fluoro-18F)azetidin-1-yl)-2-(6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one and pharma- ceutically acceptable salts, solvates, stereoisomers, isotopic variants, and N-oxides thereof.

31. 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethyl-acetamide; 2-[6-[4-chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 1-(azetidin-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 1-(azetidin-1-yl)-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[4-chloro-3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; 2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone; and 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoro-3-methyl-azetidin-1-yl)ethanone and pharma- ceutically acceptable salts, solvates, stereoisomers, isotopic variants, and N-oxides thereof.

32. 32. A pharmaceutical composition comprising a compound according to any one of claims 1 to 31, or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide of said compound, and a pharma- ceutically acceptable excipient.

33. 32. A pharmaceutical composition for use in a method of treating a subject suffering from or diagnosed as having a disease, disorder, or condition mediated by GluN2B receptor activity, said pharmaceutical composition comprising a compound according to any one of claims 1 to 31, or a pharma- ceutical acceptable salt, solvate, stereoisomer, isotope, or N-oxide thereof.

34. 34. The pharmaceutical composition of claim 33, wherein the disease, disorder or condition mediated by the GluN2B receptor activity is selected from the group consisting of bipolar disorder, major depressive disorder, treatment-resistant depression, postpartum depression, seasonal affective disorder, Alzheimer's disease, Parkinson's disease, Huntington's chorea, multiple sclerosis, cognitive disorders, head trauma, spinal cord injury, stroke, epilepsy, dyskinesia, amyotrophic lateral sclerosis, neurodegeneration associated with bacterial or chronic infections, pain, diabetic neuropathy, migraine, cerebral ischemia, schizophrenia, encephalitis, autism and autism spectrum disorders, memory disorders and learning disorders, obsessive-compulsive disorder, attention deficit hyperactivity disorder (ADHD), and addictive disorders.

35. 34. The pharmaceutical composition of claim 33, wherein the disease, disorder, or condition is selected from the group consisting of treatment-resistant depression, major depressive disorder, and bipolar disorder.

36. 32. Use of a compound according to any one of claims 1 to 31, or a pharma- ceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, in the manufacture of a medicament for treating a disease, disorder, or medical condition mediated by GluN2B receptor activity.

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