Substituted pyrazolopyridine amides and their use as GLUN2B receptor modulators

Abstract

This invention discloses substituted pyrazolopyridine as a GluN2B receptor ligand. Such compounds can be used in pharmaceutical compositions and methods for treating disease states, disorders, and conditions mediated by GluN2B receptor activity, including those involving GluN2B receptor modulation and neutralization.

Description

[0001] This application is a divisional application of the invention patent filed on June 12, 2020, with application number 202080043675.8 (PCT / EP2020 / 066392) and entitled "Substituted pyrazolopyridine amides and their use as GLUN2B receptor modulators".

[0002] Cross-reference to related applications This application claims priority to U.S. Provisional Application No. 62 / 861,656, filed June 14, 2019, and Argentine Application No. P 20 01 01623, filed June 9, 2020, the contents of each of which are incorporated herein by reference in their entirety. Technical Field

[0003] This invention relates to compounds having GluN2B regulatory properties, pharmaceutical compositions comprising these compounds, chemical methods for preparing these compounds, and their use in treating diseases related to GluN2B receptor activity in animals (particularly humans). Background Technology

[0004] Glutamate is one of the major excitatory neurotransmitters that circulates widely in the brain. Its first indication as an excitatory messenger was observed in the 1950s when intravenous glutamate injection induced seizures. However, prior to the 1970s and 1980s, the entire glutamatergic neurotransmitter system and its various receptors were not investigated, leading to the development of numerous antagonists, or at best, those identified as antagonists in the cases of PCP and ketamine. Finally, in the 1990s, molecular biology provided tools for classifying glutamatergic receptors.

[0005] N-methyl-D-aspartate (NMDA) receptors are a subtype of ionotropic glutamate receptors that mediate excitatory synaptic transmission in the brain. NMDA receptors are widely distributed throughout the brain and play crucial roles in synaptic plasticity, synapsis, excitotoxicity, memory acquisition, and learning. NMDA receptors differ from other major subtypes of ionotropic glutamate receptors (AMPA and phycocyanin receptors) in that they are mediated by Mg2+ at resting membrane potential. 2+ Blocking is a high-level Ca 2+ It is permeable and requires activation by two different neurotransmitters: glutamate and glycine (or D-serine) (Traynelis SF et al., Pharmacol Rev. 2010; 62(3):405-96). Ca 2+NMDA receptor influx triggers a signaling cascade and regulates gene expression crucial for different forms of synaptic plasticity, including long-term potentiation of synaptic effects (LTP) (Berberich S et al., Neuropharmacology 2007;52(1):77-86) and long-term suppression (LTD) (Massey, PV et al., J Neurosci. September 8, 2004; 24(36):7821-8).

[0006] The vast majority of mammalian NMDA receptors form heterotetramers, which consist of two obligate GluN1 units and two variable GluN2 receptor subunits, encoded by the GRIN1 gene and one of four GRIN2 genes, respectively. One or both GRIN2 subunits can be potentially replaced by GluN3A or GluN3B subunits. The GRIN1 gene product has eight splice variants; however, four distinct GRIN2 genes (GRIN2A-D) encode four distinct GluN2 subunits. Glycine-binding sites are located on the GluN1 subunits, and glutamate-binding sites are located on the GluN2 subunits.

[0007] The GluNR2 subunit plays a major role in determining the functional and pharmacological properties of NMDA receptor components and exhibits varying distributions in different brain regions. For example, the GluN2B subunit is primarily expressed in the forebrain of the adult mammalian brain (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 involves learning, memory processing, emotion, attention, feeling and pain perception (Cull-Candy S et al., Curr Opin Neurobiol . 2001;11(3):327-35).

[0008] Compounds that modulate the function of GluN2B-containing NMDA receptors can be used to treat a variety of neurological and psychiatric disorders, including but not limited to bipolar disorder (Martucci L et al.). Schizophrenia Res , 2006;84(2-3):214-21), major depressive disorder (Miller OH et al., 2006;84(2-3):214-21), 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 (including schizophrenia (Grimwood S et al., Neuroreport. 1999;10(3):461-5;Weickert CS et al. Molecular Psychiatry (2013) 18, 1185–1192), prenatal 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 dementias (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 disease (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 injury (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. June 2012; 100(1-2):12-9), movement disorders (e.g., difficulty in movement) (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 neurodegenerative changes associated with bacteria or chronic infection), glaucoma (Naskar R et al., Semin Ophthalmol.September 1999; 14(3):152-8), pain (e.g., chronic pain, cancer pain, postoperative pain, 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 disabilities (Tang, YP et al., Nature. 1999;401(6748):63-9), obsessive-compulsive 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; HuSS et al., 2016; 273(2): 325-332), sleep disorders (such as narcolepsy or excessive daytime sleepiness, patent WO2009058261 A1), vertigo and nystagmus (Straube A. et al., Curr Opin Neurol. 2005; 18(1):11-4; Starck M et al., Neurol. January 1997; 244(1):9-16), anxiety-related autoimmune diseases such as neurological lupus (Kowal C et al., Proc. Natl. Acad. Sci. USA 2006; 103, 19854–19859) and addictive disorders (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).

[0009] Given the clinical importance of GluN2B, the identification of compounds that modulate GluN2B receptor function is of great interest in the development of novel therapeutics. This article presents such compounds. Summary of the Invention

[0010] This invention relates to general and preferred embodiments, which are defined respectively by the independent and dependent claims appended herein and incorporated herein by reference. One aspect of the invention relates to compounds of formula (I) and pharmaceutically acceptable salts of compounds of formula (I). in R 1 It can be H, halogen, or CH3; Ar 1 Selected from: (a) A phenyl group substituted with one member selected from: halogens, C 1-6 Alkyl, OC 1-6 Alkyl, C 1-6 Fully halogenated alkyl, OC 1-6 Fully halogenated alkyl groups, CN and C 3-6 cycloalkyl; (b) A phenyl group substituted with two or three members, each of which is independently selected from: halogens, C 1-6 Alkyl, C 1-6 Fully halogenated alkyl, OC 1-6 Alkyl, OC 1-6 All-halogenated alkyl groups and (C=O)CH3; and (c) A thiophene group independently substituted by one or two members selected from: halogens, C 1-6 Alkyl and C 1-6 Perhalogenated alkyl groups; and pyridines substituted with CF3; R 2 Selected from: (d) ;in R a Each is independently selected from: H, halogen, 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 Halogenated alkyl, 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 pyrrolidone-2-one; or two R a Members combine to form C 3-6 Cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one or two F members; (e) ;in R b Each is independently selected from: H, OH, F, OCH3, CH2OCH3, and NHC(=O)CH3; or two Rs. b The members come together to form =O; (f) and (g) ,in R d Selected from: C 1-6 Alkyl; C 2-6 alkenyl; C 1-6 Alkyl halide; CH2CH2OCH3; CH2CH2OH; CH2CN; NH2; NH-C(=O)CH3; C 3-6 cycloalkyl; C substituted with two F members 3-6 cycloalkyl; 1-methylazacyclobutane-3-yl; and oxacyclobutane-3-yl; R e It is H or CH3; n is 1 or 2; and m is 1 or 2; And pharmaceutically acceptable salts, stereoisomers, isotopic variants, N-oxides or solvates of compounds of formula (I); Other embodiments involve 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).

[0011] In some embodiments, the compound of formula (I) is selected from those kinds of compounds described or exemplified in the detailed embodiments below.

[0012] In another aspect, the present invention relates to enantiomers and diastereomers of compounds of formula (I), as well as pharmaceutically acceptable salts.

[0013] In another aspect, the present invention relates to a pharmaceutical composition for treating diseases, disorders or medical conditions 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).

[0014] The pharmaceutical compositions according to the present invention may also contain one or more pharmaceutically acceptable excipients.

[0015] In another aspect, the chemical embodiments of the present invention can be used as GluN2B receptor modulators. Therefore, the present invention relates to a method for modulating GluN2B receptor activity, comprising exposing the GluN2B receptor to an effective amount of at least one compound selected from the group consisting of: 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).

[0016] On another aspect, the present invention relates to a method for treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by GluN2B receptor activity, comprising administering to the subject requiring such treatment 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). Further embodiments of the treatment method are shown in the detailed description.

[0017] On the other hand, in metabolic studies (preferably using...) 14 C) Reaction kinetic studies (e.g., using...) 2 H or 3 H) Detection or imaging techniques, including methods for determining the tissue distribution of drugs or substrates [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)], and methods for studying isotopically labeled compounds during a patient's radiotherapy. For example, 18 F or 11 C-labeled compounds may be particularly preferred for PET or SPECT studies.

[0018] Another embodiment of the present invention includes a method for preparing the following substances: 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] One object of the present invention is to overcome or improve at least one disadvantage of conventional methods and / or prior art, or to provide alternative methods available thereto.

[0020] Additional embodiments, features, and advantages of the present invention will become apparent from the following detailed description and by practicing the invention. Detailed Implementation

[0021] In one respect, this article provides compounds of formula (I) and their pharmaceutically acceptable salts, stereoisomers, isotopic variants, N-oxides, or solvates. in R 1 It can be H, halogen, or CH3; Ar 1 Selected from: (a) A phenyl group substituted with one member selected from: halogens, C 1-6 Alkyl, OC 1-6 Alkyl, C 1-6 Fully halogenated alkyl, OC 1-6 Fully halogenated alkyl groups, CN and C 3-6 cycloalkyl; (b) A phenyl group substituted with two or three members, each of which is independently selected from: halogens, C 1-6 Alkyl, C 1-6 Fully halogenated alkyl, OC 1-6 Alkyl, OC 1-6 All-halogenated alkyl groups and (C=O)CH3; and (c) A thiophene group independently substituted by one or two members selected from: halogens, C 1-6 Alkyl and C 1-6 Perhalogenated alkyl groups; and pyridines substituted with CF3; R 2 Selected from: (d) ;in R a Each is independently selected from: H, halogen, 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 Halogenated alkyl, 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 pyrrolidone-2-one; or two R a Members combine to form C 3-6 Cycloalkyl or heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one or two F members; (e) ;in R b Each is independently selected from: H, OH, F, OCH3, CH2OCH3, and NHC(=O)CH3; or two Rs. b The members come together to form =O; (f) and (g) ,in R d Selected from: C 1-6 Alkyl; C 2-6 alkenyl; C 1-6 Alkyl halide; CH2CH2OCH3; CH2CH2OH; CH2CN; NH2; NH-C(=O)CH3; C 3-6 cycloalkyl; C substituted with two F members 3-6 cycloalkyl; 1-methylazacyclobutane-3-yl; and oxacyclobutane-3-yl; R e It is H or CH3; n is 1 or 2; and m is 1 or 2.

[0022] Another embodiment of the present invention is a compound of formula (I), wherein R 1 For H.

[0023] Another embodiment of the present invention is a compound of formula (I), wherein R 1 It is F.

[0024] Another embodiment of the present invention is a compound of formula (I), wherein R 1 It is CH3.

[0025] Another embodiment of the present invention is a compound of formula (I), wherein Ar 1The phenyl group is a phenyl group substituted by one member selected from: Cl, F, CH3, OCH3, CH2F, CHF2, CF3, CHF2CH3, OCHF2, CN, and cyclopropyl.

[0026] Another embodiment of the present invention is a compound of formula (I), wherein Ar 1 Selected from: Another embodiment of the present invention is a compound of formula (I), wherein Ar 1 The phenyl group is substituted by two members, each independently selected from: Cl, F, CH3, CHF2, CF3, CHF2CH3, OCH3, OCHF2 and (C=O)CH3.

[0027] Another embodiment of the present invention is a compound of formula (I), wherein Ar 1 Selected from: Another embodiment of the present invention is a compound of formula (I), wherein Ar 1 The phenyl group is replaced by three members, each independently selected from halogens and CH3.

[0028] Another embodiment of the present invention is a compound of formula (I), wherein Ar 1 Selected from: Another embodiment of the present invention is a compound of formula (I), wherein Ar 1 A thiophene group substituted by one or two members, which are independently selected from: Cl, CH3, CF3 and CHF2.

[0029] Another embodiment of the present invention is a compound of formula (I), wherein Ar 1 Selected from: Another embodiment of the present invention is a compound of formula (I), wherein Ar 1 Selected from: Another embodiment of the present invention is a compound of formula (I), wherein R 2 for ;in R aEach of the following is independently selected from: H, Cl, F, OH, CH3, CH2CH3, CH2F, CHF2, CF3, =CH2, CH=CH2, CH=CH(CH3), CH=CH(F), CH=CF(F), C = CH, CH2OH, CH(OH)(CH3), CH2OCH3, 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 pyrrolidone-2-one; or two R a The members are combined to form cyclopropyl, cyclobutyl, or oxacyclobutane; wherein the cyclopropyl group is optionally substituted with one or two F members; And n is 1 or 2.

[0030] Another embodiment of the present invention is a compound of formula (I), wherein R 2 Selected from: Another embodiment of the present invention is a compound of formula (I), wherein R 2 Selected from: Another embodiment of the present invention is a compound of formula (I), wherein R 2 Selected from: Another embodiment of the present invention is a compound of formula (I), wherein R 2 Selected from: Another embodiment of the present invention is a compound of formula (I), wherein R 2 Selected from: Another embodiment of the present invention is a compound of formula (I), wherein R 2 Selected from: Another embodiment of the present invention is a compound of formula (I), wherein R 2 Selected from: Another embodiment of the present invention is a compound of formula (I), wherein R 2Selected from: Another embodiment of the present invention is a compound of formula (I), wherein n is 1.

[0031] Another embodiment of the present invention is a compound of formula (I), wherein n is 2.

[0032] Another embodiment of the present invention is a compound of formula (I), wherein m is 1.

[0033] Another embodiment of the present invention is a compound of formula (I), wherein m is 2.

[0034] Another embodiment of the present invention is a compound of formula (I) having the structure of formula (IA): in R 1 It can be H, F, or CH3; Ar 1 Selected from: (a) A phenyl group substituted with a member selected from: halogens, C 1-6 Alkyl, OC 1-6 Alkyl, C 1-6 Fully halogenated alkyl, OC 1-6 Fully halogenated alkyl groups, CN and C 3-6 cycloalkyl; (b) A phenyl group substituted with two or three members, each of which is independently selected from: halogens, C 1-6 Alkyl, C 1-6 Fully halogenated alkyl, OC 1-6 Alkyl, OC 1-6 All-halogenated alkyl groups and (C=O)CH3; and (c) A thiophene group independently substituted by one or two members selected from: halogens, C 1-6 Alkyl and C 1-6 Perhalogenated alkyl groups; and pyridines substituted with CF3; R a Each is independently selected from: H, halogen, 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 Halogenated alkyl, 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 pyrrolidone-2-one; or two R a Members combine to form C 3-6 cycloalkyl or heterocycloalkyl, wherein the C 3-6 Cycloalkyl and heterocycloalkyl groups are optionally substituted with one or two F members; and n It can be 1 or 2.

[0035] Another embodiment of the present invention is a compound of formula (IA), wherein R 1 It can be H, F, or CH3; Ar 1 A phenyl group substituted with two or three members, each independently selected from: halogens, C 1-4 Alkyl, C 1-4 Fully halogenated alkyl, OC 1-4 Alkyl and OC 1-4 Fully halogenated alkyl groups; R a Each of the following is independently selected from: H, Cl, F, OH, CH3, CH2CH3, CH2F, CHF2, CF3, =CH2, CH=CH2, CH=CH(CH3), CH=CH(F), CH=CF(F), C = CH, CH2OH, CH(OH)(CH3), CH2OCH3, OCHF2, OCF3, OCH3, OCH2CH3, NH(CH3), NHCO2CH3, NHC(=O)CH3, NHC(=O)CF3, NHC(=O)cyclopropyl, N(CH3)C(=O)CH3, C(=O)CH3, CN, NHSO2CH3, 1H-imidazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidin-4-yl, and pyrrolidone-2-one; or two R a The members are combined to form cyclopropyl, cyclobutyl, or oxacyclobutane; wherein the cyclopropyl group is optionally substituted with one or two F members; And n is 1 or 2.

[0036] Another embodiment of the present invention is a compound of formula (IA), wherein R 1 For H.

[0037] Another embodiment of the present invention is a compound of formula (I) having formula (IB): in Ar 1 Selected from: (a) A phenyl group substituted with a member selected from: halogens and C 1-6 Fully halogenated alkyl groups; (b) A phenyl group substituted with two or three members, each of which is independently selected from: halogens, C 1-6 Alkyl, C 1-6 Fully halogenated alkyl, OC 1-6 All-halogenated alkyl groups; and (c) A thiophene group independently substituted by one or two members selected from: halogens, C 1-6 Alkyl and C 1-6 Perhalogenated alkyl groups; and pyridines substituted with CF3; ring Selected from: R b Each is independently selected from: H, OH, F, OCH3, CH2OCH3, and NHC(=O)CH3; or two Rs. b The members come together to form =O; n is 1 or 2; and m It can be 1 or 2.

[0038] Another embodiment of the invention is a compound of formula (IB), wherein the ring for Another embodiment of the present invention is a compound of formula (I) having formula (IC): in R 1 It can be H, F, or CH3; Ar 1 Selected from: (a) A phenyl group substituted with a member selected from: halogens and C 1-6 Fully halogenated alkyl groups; (b) A phenyl group substituted with two or three members, each of which is independently selected from: halogens, C 1-6 Alkyl, C 1-6 Fully halogenated alkyl, OC 1-6 All-halogenated alkyl groups; and (c) A thiophene group independently substituted by one or two members selected from: halogens, C 1-6 Alkyl and C 1-6 Perhalogenated alkyl groups; and pyridines substituted with CF3; R d Selected from: C 1-6 Alkyl; CH2CH=CH2; C 1-6 Haloalkyl; CH2CH2OCH3; CH2CH2OH; CH2CN; NH2; NH-C(=O)CH3; cyclopropyl; cyclobutyl; 3-bicyclo[1.1.1]pentyl; 3,3-difluorocyclobutyl; 1-methylazacyclobutane-3-yl; and oxacyclobutane-3-yl; and R e It can be H or CH3.

[0039] Another embodiment of the invention is a compound of formula (IC), wherein Ar 1 for Another embodiment of the present invention is a compound shown in Table 1 below. And its pharmaceutically acceptable salts, N-oxides or solvates.

[0040] Another embodiment of the present invention comprises compounds selected from the following: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazacyclobutan-1-yl)acetone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-N,N-dimethylacetamide; 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-fluorozahexacyclic butan-1-yl)acetone; 1-(azacyclobutan-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetone; 1-(azacyclobutan-1-yl)-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetone; 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazacyclobutan-1-yl) ethyl ketone; 2-[6-[4-chloro-3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazacyclobutan-1-yl)acetone; 2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazacyclobutan-1-yl)acetone; and 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoro-3-methyl-azacyclobutan-1-yl)acetone; And its pharmaceutically acceptable salts, solvates, stereoisomers, isotopic variants, or N-oxides.

[0041] Another embodiment of the present invention is a pharmaceutical composition comprising: (A) An effective amount is selected from at least one compound of formula (I): in R 1 It can be H, halogen, or CH3; Ar 1 Selected from: (a) A phenyl group substituted with a member selected from: halogens, C 1-6 Alkyl, OC1-6 Alkyl, C 1-6 Fully halogenated alkyl, OC 1-6 Fully halogenated alkyl groups, CN and C 3-6 cycloalkyl; (b) A phenyl group substituted with two or three members, each of which is independently selected from: halogens, C 1-6 Alkyl, C 1-6 Fully halogenated alkyl, OC 1-6 Alkyl, OC 1-6 All-halogenated alkyl groups and (C=O)CH3; and (c) A thiophene group independently substituted by one or two members selected from: halogens, C 1-6 Alkyl and C 1-6 Perhalogenated alkyl groups; and pyridines substituted with CF3; R 2 Selected from: (d) ;in R a Each is independently selected from: H, halogen, 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 Halogenated alkyl, 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 pyrrolidone-2-one; or two R a Members combine to form C 3-6 Cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by one or two F members; (e) ;in R b Each is independently selected from: H, OH, F, OCH3, CH2OCH3, and NHC(=O)CH3; or two Rs. b The members come together to form =O; (f) and (g) ,in R d Selected from: C 1-6 Alkyl; C 2-6 alkenyl; C 1-6 Alkyl halide; CH2CH2OCH3; CH2CH2OH; CH2CN; NH2; NH-C(=O)CH3; C 3-6 cycloalkyl; C substituted with two F members 3-6 cycloalkyl; 1-methylazacyclobutane-3-yl; and oxacyclobutane-3-yl; R e It is H or CH3; n is 1 or 2; and m is 1 or 2; And pharmaceutically acceptable salts, stereoisomers, isotopic variants, N-oxides or solvates of compounds of formula (I); (B) at least one pharmaceutically acceptable excipient.

[0042] Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one compound of formula (IA), and a pharmaceutically acceptable salt, N-oxide or solvate of the compound of formula (IA), a pharmaceutically acceptable prodrug of the compound of formula (IA), and a pharmaceutically active metabolite of formula (IA); and at least one pharmaceutically acceptable excipient.

[0043] Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one compound of formula (IB), and a pharmaceutically acceptable salt, N-oxide or solvate of the compound of formula (IB), a pharmaceutically acceptable prodrug of the compound of formula (IB), and a pharmaceutically active metabolite of formula (IB); and at least one pharmaceutically acceptable excipient.

[0044] Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one compound of formula (IC), and a pharmaceutically acceptable salt, N-oxide or solvate of the compound of formula (IC), a pharmaceutically acceptable prodrug of the compound of formula (IC), and a pharmaceutically active metabolite of formula (IC); and at least one pharmaceutically acceptable excipient.

[0045] Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one compound from Table 1, and a pharmaceutically acceptable salt, N-oxide or solvate of a compound from Table 1, a pharmaceutically acceptable prodrug of a compound from Table 1, and a pharmaceutically active metabolite from Table 1; and at least one pharmaceutically acceptable excipient.

[0046] Also within the scope of this invention are enantiomers and diastereomers of compounds of formula (I) (and formulas (IA), (IB), and (IC)). This invention also covers pharmaceutically acceptable salts, N-oxides, or solvates of compounds of formula (I) (and formulas (IA), (IB), and (IC)). Also within the scope of this invention are pharmaceutically acceptable prodrugs of compounds of formula (I) (and formulas (IA), (IB), and (IC)), and pharmaceutically active metabolites of compounds of formula (I) (and formulas (IA), (IB), and (IC)).

[0047] Also within the scope of this invention are isotopic variants of compounds of formula (I) (and formulas (IA), (IB), and (IC)), such as deuterated compounds of formula (I). Also within the scope of this invention are pharmaceutically acceptable salts, N-oxides, or solvates of isotopic variants of compounds of formula (I) (and formulas (IA), (IB), and (IC)). Also within the scope of this invention are pharmaceutically acceptable prodrugs of isotopic variants of formula (I) (and formulas (IA), (IB), and (IC)), and pharmaceutically active metabolites of isotopic variants of compounds of formula (I) (and formulas (IA), (IB), and (IC)).

[0048] Another embodiment of the present invention is a method for treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by GluN2B receptor activity, the method comprising administering to the subject requiring such treatment an effective amount of at least one compound selected from compounds of formula (I): in R 1 It can be H, halogen, or CH3; Ar 1 Selected from: (a) A phenyl group substituted with a member selected from: halogens, C 1-6 Alkyl, OC 1-6 Alkyl, C 1-6 Fully halogenated alkyl, OC 1-6 Fully halogenated alkyl groups, CN and C 3-6 cycloalkyl; (b) A phenyl group substituted with two or three members, each of which is independently selected from: halogens, C 1-6 Alkyl, C 1-6 Fully halogenated alkyl, OC 1-6 Alkyl, OC 1-6 All-halogenated alkyl groups and (C=O)CH3; and (c) A thiophene group independently substituted by one or two members selected from: halogens, C1-6 Alkyl and C 1-6 Perhalogenated alkyl groups; and pyridines substituted with CF3; R 2 Selected from: (d) ;in R a Each is independently selected from: H, halogen, 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 Halogenated alkyl, 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 pyrrolidone-2-one; or two R a Members combine to form C 3-6 Cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by one or two F members; (e) ;in R b Each is independently selected from: H, OH, F, OCH3, CH2OCH3, and NHC(=O)CH3; or two Rs. b The members come together to form =O; (f) and (g) ,in R d Selected from: C 1-6 Alkyl; C 2-6 alkenyl; C 1-6 Alkyl halide; CH2CH2OCH3; CH2CH2OH; CH2CN; NH2; NH-C(=O)CH3; C 3-6 cycloalkyl; C substituted with two F members 3-6 cycloalkyl; 1-methylazacyclobutane-3-yl; and oxacyclobutane-3-yl; R e It is H or CH3; n is 1 or 2; and m is 1 or 2; And pharmaceutically acceptable salts, stereoisomers, isotopic variants, N-oxides or solvates thereof, given to subjects in need.

[0049] Another embodiment of the invention is a method for treating a subject who has or is diagnosed with a disease, disorder, or medical condition mediated by GluN2B receptor activity, comprising administering to the subject in need of such treatment an effective amount of at least one compound selected from the group consisting of: compounds of formula (I) (and formulas (IA), (IB), and (IC)), enantiomers and diastereomers of compounds of formula (I), isotopic variants of compounds of formula (I), and all pharmaceutically acceptable salts of the foregoing substances.

[0050] In a preferred embodiment of the method of the present invention, the disease, disorder, or medical condition is selected from: neurological and mental disorders, including but not limited to: (1) mood disorders and affective disorders; (2) neurotic, stress-related, and somatic symptom disorders, including anxiety disorders; (3) psychodevelopmental disorders; (4) behavioral syndromes associated with physiological disorders and physical factors; (5) extrapyramidal and motor disorders; (6) epilepsy, an episodic or paroxysmal disease; (7) pain; (8) forms of neurodegenerative diseases; (9) cerebrovascular diseases, acute and chronic; and any sequelae of cerebrovascular diseases.

[0051] Examples of mood disorders and affective disorders that can be treated according to the present invention include, but are not limited to, type I bipolar disorder (depression, hypomania, mania, and mixed type); type II bipolar disorder; depressive disorders such as single depression or recurrent major depressive disorder, mild depression, treatment-resistant depression, postpartum depression, depression with psychotic symptoms; persistent mood disorders such as cyclical psychosis, dysphoric mood, and normal affective mood; and premenstrual anxiety disorder.

[0052] Examples of neurotic, stress-related, and somatic symptom disorders treatable according to 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; responses to severe stress and adjustment disorders, such as post-traumatic stress disorder (PTSD); and other neurotic disorders, such as depersonalization-loss of reality syndrome.

[0053] Examples of psychodevelopmental disorders that can be treated according to the present invention include, but are not limited to, pervasive developmental disorders, including but not limited to Asperger's syndrome and Rett syndrome, autism, and childhood autism and ADHD associated with intellectual disability and stereotyped movements, specific developmental disorders of motor function, and specific developmental disorders of learning skills.

[0054] Examples of behavioral syndromes related to physiological disorders and 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) and prenatal depression; and eating disorders, including, but not limited to, anorexia nervosa, bulimia nervosa, pica, and bulimia nervosa.

[0055] Examples of extrapyramidal and motor disorders treatable according to the present invention include, but are not limited to, Parkinson's disease; secondary Parkinsonian syndromes, such as post-encephalitis Parkinson's syndrome; Parkinsonian syndromes included in other disorders; Lewis body disease; degenerative diseases of the basal ganglia; other extrapyramidal and motor disorders, including but not limited to tremor, essential tremor and drug-induced tremor, myoclonus, chorea and drug-induced chorea, drug-induced convulsions and organic convulsions, drug-induced acute dystonia, drug-induced tardive dyskinesia, levodopa-induced motor disorders; benzodiazepine-induced motor disorders, including but not limited to benzodiazepine malignant syndrome (NMS), benzodiazepine-induced Parkinson's syndrome, benzodiazepine-induced early-onset or acute motor disorders, benzodiazepine-induced acute dystonia, benzodiazepine-induced acute akathisia, benzodiazepine-induced tardive dyskinesia, benzodiazepine-induced tremor; restless legs syndrome, rigidity syndrome.

[0056] Other examples of motor disorders with basal ganglia dysfunction and / or degeneration that can be treated according to the present invention include, but are not limited to, dystonia, including but not limited to focal dystonia, multifocal or segmental dystonia, torsional dystonia, hemispheric, generalized and tardive dystonia (induced by psychopharmacological drugs). Focal dystonia includes cervical dystonia (torticollis), blepharospasm, appendiceal dystonia (limb spasticity, such as writer's cramp), oromandibular dystonia and spasmodic dysphonia (vocal cord spasm).

[0057] Examples of occasional or paroxysmal diseases that can be treated according to the present invention include, but are not limited to, epilepsy, including localization-related (focal) (local) idiopathic epilepsy and epilepsy syndromes with focal seizures, localization-related (focal) (local) symptomatic epilepsy and epilepsy syndromes with simple focal seizures, localization-related (focal) (local) symptomatic epilepsy and epilepsy syndromes with complex focal seizures, and generalized idiopathic epilepsy and epilepsy syndromes, including but not limited to, infantile myoclonic epilepsy, neonatal seizures (familial), childhood epilepsy (epileptic seizures), epilepsy with grand mal seizures during awakening, absence epilepsy, myoclonic epilepsy (impulsive petit mal), and nonspecific atonic, clonic, myoclonic, tonic, and tonic-clonic seizures.

[0058] Other examples of epilepsy that can be treated according to the present invention include, but are not limited to, epilepsy with myoclonic absence, myoclonic unstable epilepsy, infantile spasms, Lennox-Jackson syndrome, forehead-palpitation seizures, early symptomatic myoclonic encephalopathy, Wester syndrome, petit mal and grand mal seizures; status epilepticus.

[0059] Examples of pain include, but are not limited to, pain disorders related to psychological factors, such as persistent somatic symptom disorder; acute, chronic, and chronic intractable pain, headache; acute and chronic pain related to physiological processes and physical discomfort, including but not limited to back pain, toothache, abdominal pain, lower back pain, joint pain; acute and chronic pain related to diseases of the musculoskeletal system and connective tissue, including but not limited to rheumatism, myalgia, neuralgia, and fibromyalgia; acute and chronic pain related to diseases of the nerves, nerve roots, and nerve plexuses, such as trigeminal neuralgia, postherpetic neuralgia, phantom limb pain syndrome with pain, carpal tunnel syndrome, sciatic nerve injury, and diabetic mononeuropathy; and acute and chronic pain related to polyneuropathy of the peripheral nervous system and other diseases, such as hereditary and idiopathic neuropathy, inflammatory polyneuropathy, drug-induced polyneuropathy, polyneuropathy in oncological diseases, and diabetic polyneuropathy.

[0060] Examples of diseases that include forms of neurodegenerative disorders include, but are not limited to, acute neurodegenerative disorders such as intracranial brain injury, such as stroke, diffuse and focal brain injury, epidural, subdural and subarachnoid hemorrhage, and chronic neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, multiple sclerosis and ALS.

[0061] 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 of the anterior cerebral arteries and cerebral arteries that do not lead to cerebral infarction, 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 diseases.

[0062] In some embodiments, application of the compounds of the present invention, or pharmaceutically acceptable salts thereof, effectively prevents disease; for example, it prevents disease, condition, or disorder in individuals who may be susceptible to disease, symptom, or disorder but have not yet experienced or shown the pathology or symptoms of disease.

[0063] Additional embodiments, features, and advantages of the present invention will become apparent from the following detailed description and by practicing the invention.

[0064] The invention can be more fully understood by referring to the following description, including the glossary of terms and concluding examples. For the sake of brevity, the disclosures of publications (including patents) referenced in this specification are incorporated herein by reference.

[0065] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-restrictive sense.

[0066] The term "alkyl" refers to a straight-chain or branched alkyl group having 1 to 12 carbon atoms in its chain. Examples of alkyl groups include methyl (Me, which may also be represented structurally by the symbol " / "), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that, based on ordinary skill in the art and the teachings provided herein, would be considered equivalent to any of the foregoing examples. The term "C" as used herein... 1-6 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 4 carbon atoms in its chain. As used herein, the term "C1-6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms in its chain.

[0067] The term "halogen" refers to chlorine, fluorine, bromine, or iodine.

[0068] The term "perhaloalkyl" or "haloalkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms in its chain, which optionally substitutes hydrogen with a halogen. As used herein, the term "C" is similar. 1-3 "Hyperhaloalkyl" refers to a straight-chain or branched alkyl group having 1 to 3 carbon atoms in its chain, which optionally replaces hydrogen with a halogen. As used herein, the term "C"... 1-6 "Haloalkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms in its chain, which optionally replaces hydrogen with a halogen. Examples of "per-haloalkyl" or "haloalkyl" include trifluoromethyl (CF3), difluoromethyl (CF2H), monofluoromethyl (CH2F), pentafluoroethyl (CF2CF3), tetrafluoroethyl (CHFCF3), monofluoroethyl (CH2CH2F), trifluoroethyl (CH2CF3), tetrafluorotrifluoromethylethyl (CF(CF3)2), chloropropyl (CH2CH2CH2Cl), and groups that, based on ordinary skill in the art and the teachings provided herein, would be considered equivalent to any of the foregoing examples.

[0069] The term "alkoxy" refers to a straight-chain or branched alkyl group that connects the alkyl group to other parts of a molecule via a terminal oxygen atom. Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, and so on.

[0070] The term "cyano" refers to the -CN group.

[0071] The term "aryl" refers to a monocyclic aromatic carbon ring (a ring structure with all ring atoms being carbon) having six atoms per ring. (The carbon atom located in the aryl group is sp.) 2 Hybrid. The term "phenyl" represents the following part: .

[0072] The term "thiophene group" represents the following part: .

[0073] The term "heteroaryl" refers to a monocyclic or fused bicyclic heterocycle (having a ring structure with 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. Exemplary examples of heteroaryl groups include the following entities appearing in the form of suitable bonded portions: Those skilled in the art will recognize that the heteroaryl, cycloalkyl, aryl, and heterocycloalkyl groups listed or illustrated above are not exhaustive, and other substances within the scope of these defined terms may also be selected.

[0074] "Heterocyclic alkyl" refers to a monocyclic or bicyclic (fused or spirocyclic) ring structure that is saturated or partially saturated, each ring structure having 4 to 7 ring atoms selected from carbon atoms and up to two heteroatoms selected from nitrogen, oxygen, and sulfur. The ring structure may optionally contain up to two oxo groups on the sulfur ring member. Exemplary entities appearing in the form of suitable bonded portions include: The term "cycloalkyl" refers to a saturated or partially saturated monocyclic, fused polycyclic, or spiropolycyclic carbon ring having 3 to 12 ring atoms per carbon ring. Exemplary examples of cycloalkyl groups include the following entities appearing in the form of a suitable bonded moiety: The term "pyridyl" or "pyridyl group" refers to the following part: The pyridyl or pyridyl moiety can be linked by any carbon atom at the 2-, 3-, 4-, 5-, or 6-position.

[0075] The term "pyrimidinyl" refers to the following part: The pyrimidine moiety can be attached to any of the carbon atoms at the 2-, 4-, 5-, or 6-positions.

[0076] The term "thiophene group" refers to the following part: The pyrazolium moiety can be linked to any one of the carbon atoms at the 1-, 2-, 3-, 4-, or 5-position.

[0077] The term "piperidinyl" refers to the following part: When the piperidinyl moiety is a substituent, it can be connected by any one of the 1-, 2-, 3-, 4-, 5-, or 6-position atoms, if permitted.

[0078] The term "pyrrolidinyl" represents the following part: When the pyrroloalkyl moiety is substituent, it can be connected by any one of the 1-, 2-, 3-, 4-, or 5-position atoms, if permitted.

[0079] The term "azacyclobutane" refers to a four-membered heterocyclic alkyl moiety having a nitrogen atom in its ring. When the azacyclobutane moiety is substituent, it can be connected via any carbon atom or via a nitrogen atom, as permitted.

[0080] The term "morpholino" represents the following part: When the morpholino group is a substituent, it can be connected by any of the 2-, 3-, 4-, 5-, or 6-position atoms, if permitted.

[0081] The term "substituted" means that the specified group or part contains one or more substituents. The term "unsubstituted" means that the specified group does not contain any substituents. The term "optionally substituted" means that a particular group is either unsubstituted or substituted by one or more substituents. If the term "substituted" is used to describe a structural system, it means that substitution occurs at any position permitted by any valence in that system. Where a specified part or group is not explicitly indicated to be optionally substituted or replaced by any specified substituents, it should be understood that such part or group is intended to represent unsubstituted.

[0082] The terms “para,” “meta,” and “ortho” have the meanings as understood in the art. Thus, for example, a fully substituted phenyl group has substituents at two “ortho” (o) positions, two “meta” (m) positions, and one “para” (p) position opposite the connection point on the benzene ring. To further clarify the positions of the substituents on the benzene ring, the two distinct ortho positions will be designated “ortho and ortho’”, and the two distinct meta positions will be designated “meta and meta’”.

[0083] When referring to substituents on a pyridyl group, the terms "para," "meta," and "ortho" refer to the position of the substituent relative to the pyridyl ring connection point. For example, the structure below is described as having an X at the ortho position. 1 Substituents, X at the meta position 2 The 3-pyridyl substituent and the X at the para position 3 3-pyridyl substituent: .

[0084] To provide a more concise description, some of the quantitative expressions given herein are not modified by the term "about". It should be understood that, whether or not the term "about" is explicitly used, each quantity given herein is intended to refer to an actual given value, and also to an approximation of such given values ​​that can be reasonably inferred from the general art, including equivalent and approximate values ​​of such given values ​​caused by experimental and / or measurement conditions. When yield is given as a percentage, it refers to the ratio of the mass of the entity to which the yield is given to the maximum amount of the same entity available under the given stoichiometric conditions. Unless otherwise specified, concentrations given as percentages refer to mass ratios.

[0085] The terms “buffered” solution or “buffer” are used interchangeably herein, according to their standard meanings. Buffers are used to control the pH of media, and their selection, use, and function are known to those skilled in the art. See, for example, the description in GD Considine, ed., Van Nostrand's Encyclopedia of Chemistry, page 261, fifth edition (2005), in particular, how buffer solutions and the concentrations of buffer components relate to the pH of buffer solutions. For example, a buffered solution is obtained by adding MgSO4 and NaHCO3 to a solution in a 10:1 weight / weight ratio to maintain the pH of said solution at approximately 7.5.

[0086] Any formula given herein is intended to represent compounds having the structure shown in the formula, as well as certain variations or forms. Specifically, compounds of any formula given herein may have an asymmetric center and thus exist in different enantiomeric forms. All optical isomers of the compounds represented by the general formula and mixtures thereof are considered to be within the scope of the formula. Therefore, any formula given herein is intended to represent racemic mixtures, one or more enantiomeric forms, one or more diastereomeric forms, one or more transisomers, and mixtures thereof. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as transisomers.

[0087] It should also be understood that compounds with the same molecular formula but differing in the nature or sequence of their atomic bonds or in the spatial arrangement of their atoms are called "isomers". Isomers that differ in their atomic spatial arrangement are called "...".

[0088] Stereoisomers that are not mirror images of each other are called "diastereomers," while stereoisomers that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetry center and are described by the R- and S-sequence rules of Cahn and Prelog, or by rotating the molecule in a plane of polarized light and naming it dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as their individual enantiomers or as mixtures thereof. A mixture containing enantiomers in equal proportions is called a "racemic mixture."

[0089] "Tautomers" are compounds that are interchangeable forms of a given compound structure, with the positions of hydrogen atoms and electrons changing. Thus, the two structures can be in equilibrium via the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they rapidly interconvert by treatment with an acid or base. Another example of tautomerism is the "acid-" and "nitro-" forms of phenylnitromethane, also formed by treatment with an acid or base.

[0090] Tautomerism may be related to the attainment of optimal chemical and biological activity of the compound of interest.

[0091] The compounds of this invention may have one or more asymmetric centers; therefore, such compounds can be used as individual ( R )-or( S )- Stereoisomes or as mixtures thereof are prepared.

[0092] Unless otherwise specified, the description or naming of a particular compound in the specification and claims is intended to include its individual enantiomers and mixtures, said mixtures being racemic mixtures or other mixtures. Methods for the determination of stereochemical properties and the separation of stereoisomers are well known in the art.

[0093] Some examples contain chemical structures described as absolute enantiomers, but are intended to represent enantiomeric pure substances with unknown configurations. In these cases, (R * ) or (S * The absolute stereochemistry of the corresponding stereocenter used in the name is unknown. Therefore, it is named (R). *A compound with (R) or (S) is an enantiomerically pure compound having an absolute configuration of (R) or (S). When the absolute stereochemistry has been confirmed, the structure is named using (R) and (S).

[0094] symbol and The same spatial arrangement is used to represent the chemical structures shown in this article. Similarly, the symbol... and It is used to represent the same spatial arrangement in the chemical structures shown in this article.

[0095] Furthermore, any formula given herein is intended to also refer to hydrates, solvates, and polymorphs of such compounds, as well as mixtures thereof, even if these forms are not explicitly listed. 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)) are available as solvates. Solvates include those formed by the interaction or complexation of the compounds of the present invention with one or more solvents, which are in solution or solid or crystalline form. In some embodiments, the solvent is water and the solvate is a hydrate. Additionally, 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)) are available as eutectic forms. In some embodiments of the present invention, the compounds of formula (I) are obtained in some crystalline form. In other embodiments, the crystalline form of the compounds of formula (I) is cubic in nature. In other embodiments, a pharmaceutically acceptable salt of the compound of formula (I) is obtained in a crystalline form. In other embodiments, the compound of formula (I) is obtained as one of several polymorphs, as a mixture of crystalline forms, as a polymorph, or as an amorphous form. In other embodiments, the compound of formula (I) transforms in solution between one or more crystalline forms and / or polymorphs.

[0096] References to compounds herein represent references to any of the following: (a) the actual form in which the compound is described, and (b) any form of the compound in the medium in which the compound is considered when it is mentioned. For example, references to compounds such as R-COOH herein cover references to, for example, any of the following: R-COOH(s), R-COOH( sol) and R-COO- (sol) In this example, R-COOH(s) refers to a solid compound, which may be in the form of tablets or certain other solid pharmaceutical compositions or formulations; R-COOH(sol) refers to the undissociated form of the compound in a solvent; and R-COO-(sol) This refers to the dissociation form of a compound in a solvent, such as the dissociation form of a compound in an aqueous environment, regardless of whether such dissociation form is derived from R-COOH, its salt, or any other entity that, upon dissociation in the medium under consideration, produces R-COO-. In another example, a statement such as “exposing an entity to a compound of formula R-COOH” means exposing the entity to one or more forms of compound R-COOH present in the medium in which the exposure occurs. In yet another example, a statement such as “reacting an entity with a compound of formula R-COOH” means reacting (a) the entity (for one or more chemically related forms of the entity present in the medium in which the reaction occurs) with (b) one or more chemically related forms of compound R-COOH present in the medium in which the reaction occurs. In this respect, if the entity is, for example, in an aqueous environment, it should be understood that compound R-COOH is in that same medium, and therefore the entity is being exposed to substances such as R-COOH. (aq) and / or R-COO - (aq) Substances such as these, where the subscript "(aq)" stands for "aqueous" according to its conventional meaning in chemistry and biochemistry. The carboxylic acid functional group has been chosen in these naming examples; however, this choice is not intended to be limiting, but merely illustrative. It should be understood that similar examples can be provided with other functional groups, including but not limited to hydroxyl groups, basic nitrogen members (such as those in amines), and any other groups that interact or transform in a medium containing the compound in a known manner. Such interactions and transformations include, but are not limited to, dissociation, association, tautomerism, solvent decomposition including hydrolysis, solvation including hydration, protonation, and deprotonation. No further examples are provided here, as these interactions and transformations in a given medium are known to any person skilled in the art.

[0097] In another example, this article covers zwitterionic compounds by referring to compounds known to form zwitterions, even if they are not explicitly mentioned in their zwitterionic form. Terms such as one or more zwitterions and their synonyms zwitterionic compounds are standard names recognized by IUPAC; these names are well-known and part of a standard set of defined scientific names. In this respect, the name zwitterion is assigned the identifier CHEBI:27369 by the molecular entity dictionary of the Chemical Entities of Biological Inerest (ChEBI) database. Zwitterions or zwitterionic compounds are known to be neutral compounds with a single charge in the form of opposite signs. Sometimes, these compounds are referred to by the term "internal salt." Other sources refer to these compounds as "dipolar ions," although this term is considered misnomer by other sources. For a concrete example, aminoacetic acid (i.e., the amino acid glycine) has the formula H₂NCH₂COOH and forms zwitterions in some media (in this case, neutral media). + H3NCH2COO - The terms zwitterions, zwitterionic compounds, inner salts, and dipolar ions fall within the scope of this invention in their known and established meanings, as will be understood by those skilled in the art in any event. Since it is not necessary to name every embodiment that would be recognized by those of ordinary skill in the art, the structures of zwitterionic compounds associated with the compounds of this invention are not explicitly given herein. However, they are part of the embodiments of this invention. No further examples are provided in this regard, as the various forms of interactions and transformations leading to the production of a given compound in a given medium are known to any person of ordinary skill in the art.

[0098] Any formulas given herein are also intended to represent both the unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structures depicted by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as... 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 and125 I. These isotope-labeled compounds can be used for metabolic studies (preferably utilizing...) 14 C), reaction kinetic studies (using, for example, 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 determination, or in the context of a patient's radiation therapy. Specifically, 18 F or 11 C-labeled compounds may be particularly preferred for PET or SPECT studies. Furthermore, heavier isotopes such as deuterium (i.e., 2 H) Substitution can provide certain therapeutic advantages due to greater metabolic stability, such as prolonged in vivo half-life or reduced required dose. Isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents to perform the procedures disclosed in the “Schemes” or “Examples and Preparations” described below.

[0099] When referring to any formula given herein, the selection of a specific part from the list of possible categories for a given variable is not intended to limit the selection of the same category when the variable appears elsewhere. In other words, unless otherwise specified, the selection of a category from the specified list when a variable appears more than once is irrelevant to the selection of that category for the same variable elsewhere in the formula.

[0100] Based on the above explanation of assignment and naming, it should be understood that when a set is chemically meaningful and unless otherwise stated, when this document explicitly refers to a set, it means that the various embodiments of that set are referred to independently, and that each and every possible embodiment of the various subsets of the explicitly referred set is referred to.

[0101] Regarding the first example of the substituent term, if the substituent S 1 实施例 It is one of S1 and S2, and it substitutes for base S. 2 实施例 If it is one of S3 and S4, then these assignments refer to embodiments of the invention resulting from the following selections: S 1 实施例 For S1 and S 2 实施例 S3; S 1 实施例 For S1 and S 2 实施例 S4; S 1 实施例 For S2 and S 2实施例 S3; S 1 实施例 For S2 and S 2 实施例 S4; and equivalent assignments to each of these choices. Therefore, for the sake of brevity, this paper uses the shorter term "S". 1 实施例 It is one of S1 and S2, and S 2 实施例 "One of S3 and S4", but not restrictively. The first example of the terminology regarding substituents stated above in general terms is intended to illustrate the different substituent assignments described herein. Where applicable, the aforementioned substituent conventions given herein extend to such as R 1 R 2 R a R b R d R e Ar 1 Members of ring A, n, m, X, and any other general substituent symbols used herein.

[0102] Furthermore, when more than one assignment is given to any member or substituent, embodiments of the invention include a variety of groupings that can be independently selected from the enumerated assignments, and their equivalents. As for the second example of the term "substituent," if it describes substituent S herein... 实施例 If S1, S2, and S3 are one of them, then the enumeration refers to the following embodiments of the present invention: S 实施例 S1; S 实施例 S2; S 实施例 S3; S 实施例 It is one of S1 and S2; S 实施例 It is one of S1 and S3; S 实施例 S is one of S2 and S3; S embodiment is one of S1, S2 and S3; and S 实施例 For each of these choices, any equivalent assignment is made. Therefore, for the sake of brevity, this paper uses the shorter term "S". 实施例 "One of S1, S2, and S3", but not restrictively. The second example of the substituent terminology stated above in a generally accepted manner is intended to illustrate the various substituent assignments described herein. Where applicable, the aforementioned substituent conventions given herein extend to, for example, R... 1 R 2 R a R b R d R e Ar 1 Members of ring A, n, m, X, and any other general substituent symbols used herein.

[0103] Term "C" i-j "(j>i)," when applied herein to a set of substituents, is intended to refer to an embodiment of the invention in which each and every one of the carbon members from i to j (inclusive) is implemented independently. By way of example only, the term C 1-6 Independently, it refers to an implementation scheme with one carbon member (C1), an implementation scheme with two carbon members (C2), an implementation scheme with three carbon members (C3), and an implementation scheme with four carbon members (C4).

[0104] Term C n-m Alkyl refers to an aliphatic chain (whether straight or branched) in which the total number N of carbon members in the chain satisfies n ≤ N ≤ m, and m > n. Any disubstituent mentioned herein refers to a disubstituent containing various connection possibilities when more than one such possibility is permitted. For example, when the disubstituent –AB- (where A ≠ B) is mentioned herein, it refers to a disubstituent in which A is connected to a first substituted member and B is connected to a second substituted member; it also refers to a disubstituent in which A is connected to a second substituted member and B is connected to a first substituted member.

[0105] The present invention also includes pharmaceutically acceptable salts of compounds of formula (I) (and formulas (IA), (IB) and (IC)), preferably pharmaceutically acceptable salts of those compounds described above and pharmaceutically acceptable salts of the specific compounds exemplified herein, and methods of treatment with such salts.

[0106] The term "pharmaceutically acceptable" means approved or permitted by a federal or state regulatory agency or by an appropriate agency in a country outside the United States, or listed in the United States Pharmacopeia or other recognized pharmacopoeia for use in animals, especially humans.

[0107] "Pharmaceutically acceptable salt" is intended to represent a salt of the free acid or base of a compound represented by formula (I) (and formulas (IA), (IB), and (IC)), which is non-toxic, biologically tolerable, or in other words, biologically suitable for administration to a subject. It should possess the desired pharmacological activity of the parent compound. Generally, see 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, SM 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 those that are pharmacologically effective and suitable for contact with patient tissues without undue toxicity, irritation, or anaphylactic reactions. Compounds of formula (I) (and formulas (IA), (IB), and (IC)) may have sufficiently acidic groups, sufficiently basic groups, or both types of functional groups, thereby allowing them to react with a variety of inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts.

[0108] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanates, propynates, oxalates, malonates, succinates, octanoates, sebates, fumarates, maleates, butyn-1,4-dicitates, hexyn-1,6-dicitates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0109] When the compounds of formula (I) (and formulas (IA), (IB) and (IC)) contain basic nitrogen, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art. For example, the free base can be treated with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, etc., or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, hydroxyethanesulfonic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, or pyranoside (such as glucuronic acid or galactoside). Glucuronic acids, α-hydroxy acids (such as mandelic acid, citric acid, or tartaric acid), amino acids (such as aspartic acid, glutaric acid, or glutamic acid), aromatic acids (such as benzoic acid, 2-acetoxybenzoic acid, naphtholic acid, or cinnamic acid), sulfonic acids (such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid), any compatible mixtures of those acids given by way of example herein, and any other acids and mixtures thereof that are considered equivalents or acceptable substitutes according to the ordinary skill level in this art.

[0110] When the compound of formula (I) (and formulas (IA), (IB) and (IC)) is an acid, such as a carboxylic acid or a sulfonic acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example by treating the free acid with an inorganic or organic base such as amines (primary, secondary, or tertiary amines), alkali metal hydroxides, alkaline earth metal hydroxides, any compatible mixtures of bases such as those given by way of example herein, and any other bases and mixtures thereof that are regarded as equivalents or acceptable substitutes by those skilled in the art. Exemplary examples of suitable salts include organic salts derived from substances such as amino acids (e.g., N-methyl-D-glucosamine, lysine, choline, glycine, and arginine), ammonia, carbonates, bicarbonates, primary amines, secondary amines, tertiary amines, and cyclic amines (e.g., aminobutanetriol, benzylamine, pyrrolidine, piperidine, morpholine, and piperazine), and inorganic salts derived from substances such as sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0111] This invention also relates to pharmaceutically acceptable prodrugs of compounds of formula (I) (and formulas (IA), (IB), and (IC)), and to treatment methods using such pharmaceutically acceptable prodrugs. The term "prodrug" means a precursor of a specified compound that, upon administration to a subject, is produced in vivo through a chemical or physiological process such as solvent degradation or enzymatic cleavage, or under physiological conditions (e.g., the prodrug is converted to a compound of formula (I) upon exposure to physiological pH). A "pharmaceuticalally acceptable prodrug" is a non-toxic, biologically tolerable, and in other words, biologically suitable for administration to a subject. Exemplary methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs," edited by H. Bundgaard, Elsevier, 1985.

[0112] 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 linked by an amide or ester bond to a compound of formula (I) (and formulas (IA), (IB), and (IC))). Examples of amino acid residues include twenty naturally occurring amino acids typically identified by three-letter symbols, as well as 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, valine, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone.

[0113] Other types of prodrugs can be prepared, for example, by deriving the free carboxyl group of the structure of formula (I) (and formulas (IA), (IB), and (IC)) into an amide or alkyl ester. Examples of amides include those derived from ammonia, primary C 1-6 Alkylamines and secondary di(C) 1-6 Alkylamines. Secondary amines include 5- or 6-membered heterocyclic alkyl or heteroaryl ring moieties. Examples of amides include those derived from ammonia, C... 1-3 Alkyl primary amines and di(C) 1-2 Those alkylamines. Examples of esters of the present invention include C. 1-7 Alkyl, C 5-7 Cycloalkyl, phenyl and phenyl (C 1-6 Alkyl esters. Preferred esters include methyl esters. Free hydroxyl groups can also be derived using groups including hemisuccinate, phosphate ester, dimethylaminoacetate, and phosphoryloxymethoxycarbonyl groups, and then, for example, by Fleisher et al. in Adv. Drug Delivery Review. 1996, 19 The methods outlined in pp. 115-130 are used to prepare prodrugs. Carbamate derivatives of hydroxyl and amino groups can also produce prodrugs. Carbonate derivatives, sulfonates, and sulfate esters of hydroxyl groups can also provide prodrugs. Derivatization of the hydroxyl group into (acyloxy)methyl esters and (acyloxy)ethyl esters, wherein the acyl group may optionally be an alkyl ester substituted with one or more ether, amine, or carboxylic acid functional groups, or wherein the acyl group is an amino acid ester as described above, can also be used to produce prodrugs. Prodrugs of this type, such as those by Robinson et al., J Med Chem. 1996, 39 (1), as described in 10-18. The free amine can also be derived into amides, sulfonamides, or phosphonamides. All of these prodrug moieties can be incorporated with groups including ether, amine, and carboxylic acid functional groups.

[0114] This invention also relates to pharmaceutically active metabolites of compounds of formula (I) (and, if applicable, formulas (IA), (IB), and (IC)), which can also be used in the methods of this invention. "Pharmaceutically active metabolite" refers to the pharmaceutically active product of a compound of formula (I) (and, if applicable, formulas (IA), (IB), and (IC)) or its salts, during metabolism in vivo. The prodrugs and active metabolites of the compounds can be identified using conventional techniques 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 (Edited by Krogsgaard-Larsen et al., Harwood Academic Publishers, 1991).

[0115] Compounds of formula (I) (and formulas (IA), (IB) and (IC)) of the present invention, as well as their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites, can be used as modulators of the GluN2B receptor in the methods of the present invention. As such modulators, these compounds may act as antagonists, agonists, or inverse agonists. The term "modulator" includes inhibitors and activators, wherein an "inhibitor" refers to a compound that reduces, prevents, inactivates, desensitizes, or downregulates the expression or activity of the GluN2B receptor, and an "activator" refers to a compound that increases, activates, promotes, sensitizes, or upregulates the expression or activity of the GluN2B receptor.

[0116] As used herein, the term "treatment" is intended to mean administering the active agent or composition of the present invention to a subject with the aim of achieving a therapeutic or preventive effect by modulating GluN2B receptor activity. Treatment includes reversing, improving, alleviating, inhibiting the progression of, reducing the severity of, or preventing one or more symptoms of a disease, disorder, or condition mediated by the modulation of GluN2B receptor activity. The term "subject" refers to a mammalian patient, such as a human, who requires such treatment.

[0117] Therefore, this invention relates to methods of treating subjects diagnosed with or suffering from diseases, disorders, or conditions mediated by GluN2B receptor activity using the compounds described herein, such as: type I bipolar disorder (depression, hypomania, mania, and mixed forms); type II bipolar disorder; depression, such as single depression or recurrent major depressive disorder, mild depression, treatment-resistant depression, postpartum depression, disruptive mood disorder, depression with psychotic symptoms; persistent mood disorders, such as cyclical mood disorder, dysphoric mood, and normal affective mood; and premenstrual anxiety disorder; Anxiety disorders, generalized anxiety disorder, panic disorder with or without agoraphobia, specific phobias, social anxiety disorder, chronic anxiety disorder; obsessive-compulsive disorder; responses to severe stress and adjustment disorders, such as post-traumatic stress disorder (PTSD); other neurotic disorders, such as depersonalization-loss of reality syndrome; pervasive developmental disorders, including but not limited to Asperger's syndrome and Rett syndrome, autism, and childhood autism and ADHD associated with intellectual disability and stereotyped movements, specific developmental disorders of motor function, specific developmental disorders of learning skills; postnatal (postnatal) ) and prenatal depression; eating disorders, including but not limited to anorexia nervosa, bulimia nervosa, pica, and bulimia nervosa; Parkinson's disease; secondary Parkinsonian syndromes, such as post-encephalitis Parkinson's syndrome; Parkinsonian syndromes included in other disorders; Lewis body disease; degenerative diseases of the basal ganglia; other extrapyramidal and motor disorders, including but not limited to tremor, essential tremor and drug-induced tremor, myoclonus, chorea and drug-induced chorea, drug-induced convulsions and organic convulsions, drug-induced acute dystonia, drug-induced tardive dyskinesia, levodopa-induced dyskinesia; benzodiazepine-induced dyskinesia. Movement disorders, including but not limited to benzodiazepine malignant syndrome (NMS), benzodiazepine-induced Parkinson's syndrome, benzodiazepine-induced early-onset or acute movement disorders, benzodiazepine-induced acute dystonia, benzodiazepine-induced acute akathisia, benzodiazepine-induced tardive dyskinesia, benzodiazepine-induced tremor; restless legs syndrome, rigidity syndrome; dystonia, including but not limited to focal dystonia, multifocal or segmental dystonia, torsional dystonia, hemispheric, generalized and tardive dystonia (induced by psychopharmacological drugs).Focal dystonia includes cervical dystonia (torticollis), blepharospasm, appendiceal dystonia (limb spasms, such as writer's cramp), oromandibular dystonia, and spasmodic dysphonia (vocal cord spasm); epilepsy includes focal idiopathic epilepsy and epilepsy syndromes with focal seizures, focal symptomatic epilepsy and epilepsy syndromes with simple focal seizures, focal symptomatic epilepsy and epilepsy syndromes with complex focal seizures, and generalized idiopathic epilepsy and epilepsy syndromes, including but not limited to myoclonic epilepsy in infancy, neonatal seizures (familial), childhood epilepsy (epileptic seizures), and grand mal seizures with awakening. Seizures including: absence epilepsy, myoclonic epilepsy (impulsive petit mal epilepsy), and nonspecific atonic, clonic, myoclonic, tonic, and tonic-clonic seizures; epilepsy with myoclonic absence, myoclonic unstable epilepsy, infantile spasms, Lennox-Weber syndrome, forehead-sparring seizures, early-symptom myoclonic encephalopathy, Wester's syndrome, petit mal and grand mal seizures; status epilepticus; persistent somatic symptom disorder; acute, chronic, and chronic intractable pain, headache; acute and chronic pain related to physiological processes and physical discomfort, including but not limited to back pain, toothache, abdominal pain, lower back pain, and joint pain; acute and chronic pain related to musculoskeletal and connective tissue diseases, including but not limited to rheumatism, myalgia, and neuralgia. And fibromyalgia; acute and chronic pain associated with nerve, nerve root, and nerve plexus disorders, such as trigeminal neuralgia, postherpetic neuralgia, phantom limb pain syndrome with pain, carpal tunnel syndrome, sciatic nerve injury, and diabetic mononeuropathy; acute and chronic pain associated with polyneuropathy and other diseases of the peripheral nervous system, such as hereditary and idiopathic neuropathy, inflammatory polyneuropathy, drug-, alcohol-, or toxic polyneuropathy, polyneuropathy in oncological diseases, and diabetic polyneuropathy; as well as acute neurodegenerative diseases, such as intracranial brain injury, such as stroke, diffuse and focal brain injury, epidural, subdural, and subarachnoid hemorrhage, and chronic neurodegenerative diseases, such as Alzheimer's disease. Alzheimer's disease, Huntington's disease, multiple sclerosis, and ALS; subarachnoid hemorrhage, intracerebral hemorrhage, and other non-traumatic intracranial hemorrhage; cerebral infarction, stroke, occlusion and stenosis of anterior and cerebral arteries that do not lead to cerebral infarction, 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; glaucoma and other neurological disorders; dementia, vascular dementia, Lewis body dementia, frontotemporal dementia, and HIV-related dementia; vertigo and nystagmus; tinnitus; neurological systemic lupus erythematosus; disruptive mood disorders; schizophrenia spectrum disorders; and sleep / wake disorders.

[0118] In the treatment methods according to the invention, an effective amount of the pharmaceutical agent according to the invention is administered to a patient suffering from or diagnosed with such a disease, disorder, or condition. "Effective amount" means an amount or dose sufficient to produce the desired therapeutic or preventative beneficial effect in a patient requiring such treatment for a specified disease, disorder, or condition. The effective amount or dose of the compound of the invention can be determined by conventional methods, such as modeling, dose escalation studies, or clinical trials, and by taking into account conventional factors, such as the manner or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and duration of the disease, disorder, or condition, the patient's previous and current treatments, the patient's health status and response to the drug, and the judgment of the attending physician. Examples of doses are dose ranges such as about 0.001 mg to about 200 mg compound / kg patient body weight / day, preferably about 0.05 mg / kg / day to 100 mg / kg / day, or about 1 mg / kg / day to 35 mg / kg / day, in the form of a single dose unit or separate dose units (e.g., twice daily, three times daily, four times daily). For a person weighing 70 kg, an exemplary range of appropriate dosage is about 0.05 g / day to about 7 g / day, or about 0.2 g / day to about 2.5 g / day.

[0119] Once the patient's disease, symptoms, or condition improve, the dosage can be adjusted for preventative or maintenance treatment. For example, the dosage or frequency of administration, or both, can be reduced to a level that maintains the desired therapeutic or preventative effect, depending on the symptoms. Of course, treatment can be discontinued if symptoms have lessened to an appropriate level. However, patients may require long-term intermittent treatment due to any recurrence of symptoms.

[0120] Furthermore, in the treatment of the aforementioned conditions, the active agents of the present invention can be used in combination with additional active ingredients. These additional active ingredients can be administered alone with the active agents of the compounds in Table 1, or included together with such agents in the pharmaceutical compositions according to the present invention. In one exemplary embodiment, the additional active ingredients are those known or found to be effective in treating GluN2B-mediated conditions, disorders, or diseases, such as another GluN2B modulator or a compound active against another target associated with that particular condition, disorder, or disease. The combination can be used to improve efficacy (e.g., by including compounds that enhance the potency or effectiveness of the active agent according to the present invention), reduce one or more side effects, or reduce the required dosage of the active agent according to the present invention.

[0121] The active agent of the present invention may be used alone or in combination with one or more other active ingredients to formulate the pharmaceutical composition of the present invention. The pharmaceutical composition of the present invention comprises: (a) an effective amount of at least one active agent according to the present invention; and (b) a pharmaceutically acceptable excipient.

[0122] "Pharmaceutically acceptable excipients" refer to substances that are non-toxic, biologically tolerable, or in other words, biologically suitable for administration to a patient, such as inert substances, which are added to a pharmacological composition or used as a medium, carrier, or diluent to facilitate the administration of a drug, and which are compatible with the drug. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0123] The delivery form of a pharmaceutical composition containing one or more dose units of an active agent can be prepared using suitable pharmaceutical excipients and compounding techniques known or available to those skilled in the art. The composition can be administered in the method of the present invention via a suitable route of delivery, such as oral, parenteral, rectal, topical, or ocular administration, or by inhalation.

[0124] The formulation may be in the form of tablets, capsules, sacs, sugar-coated pills, powders, granules, lozenges, reconstituted powders, liquid formulations, or suppositories. Preferably, the composition is formulated for intravenous infusion, topical application, or oral administration.

[0125] For oral administration, the compounds of the present invention may be provided in tablet or capsule form, or as a solution, emulsion, or suspension. To prepare oral compositions, the compounds may be formulated to produce, for example, a dose of about 0.05 mg / kg / day to about 100 mg / kg / day, or about 0.05 mg / kg / day to about 35 mg / kg / day, or about 0.1 mg / kg / day to about 10 mg / kg / day. For example, a total daily dose of about 5 mg to 5 g may be achieved by taking the medication once, twice, three times, or four times daily.

[0126] Oral tablets may comprise compounds according to the invention mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, colorants, and preservatives. Suitable inert fillers include sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, etc. Exemplary liquid oral excipients include ethanol, glycerol, water, etc. Starch, polyvinylpyrrolidone (PVP), sodium glycolate starch, microcrystalline cellulose, and alginate are suitable disintegrants. Binders may include starch and gelatin. Lubricants (when present) may be magnesium stearate, stearic acid, or talc. If desired, tablets may be coated with materials such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0127] Capsules for oral administration include hard gelatin capsules and soft gelatin capsules. To prepare hard gelatin capsules, the compounds of the present invention can be mixed with solid, semi-solid, or liquid diluents. Soft gelatin capsules can be prepared by mixing the compounds 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.

[0128] Orally administered liquids may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as dried products for reconstitution with water or other suitable media immediately 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 media, such as oils (e.g., almond oil or graded coconut oil), propylene glycol, ethanol, or water; preservatives (e.g., methylparaben or propylparaben or sorbic acid); wetting agents, such as lecithin; and (if desired) flavoring agents or coloring agents.

[0129] The active agents of this invention can also be administered via non-oral routes. For example, the compositions can be formulated as suppositories for rectal administration. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of this invention can be provided in the form of sterile aqueous solutions or suspensions buffered to an appropriate pH and isotonicity or in parenteral acceptable oils. Suitable aqueous media include Ringer's solution and isotonic sodium chloride. Such forms will be presented in unit dose form, such as ampoules or disposable injection devices, in multi-dose form, such as vials from which appropriate doses can be drawn, or in solid or pre-concentrated forms that can be used to prepare injectable formulations. Exemplary infusion doses can range from about 1 µg to 1000 µg compound / kg / min, infused with a drug carrier over a period of minutes to days.

[0130] For topical application, the compound can be mixed with a drug carrier, with a drug-to-solvent concentration ratio of about 0.1% to about 10%. Another method of applying the compound of the invention is transdermal delivery via a patch.

[0131] Alternatively, the compounds of the present invention can be administered by inhalation, intranasal route or oral route (e.g. in a spray also containing a suitable carrier) according to the methods of the present invention.

[0132] Exemplary compounds that can be used in the methods of the present invention will now be described with reference to exemplary synthetic schemes for their general preparation and specific examples described below. Those skilled in the art will recognize that, to obtain the various compounds described herein, the starting materials may be suitably selected such that, with or without protection as needed, the desired substituent will be carried throughout the reaction scheme to obtain the desired product. Alternatively, it may be necessary or desirable to substitute a suitable group for the ultimately desired substituent, which may undergo the entire reaction scheme and, where appropriate, be replaced by the desired substituent. Unless otherwise specified, variables are as defined above with respect to formula (I). The reaction may be carried out between the melting point and reflux temperature of the solvent, and preferably between 0°C and the reflux temperature of the solvent. The reaction may be heated using conventional heating or microwave heating. The reaction may also be carried out in a closed pressure vessel at a temperature above the normal reflux temperature of the solvent.

[0133] The abbreviations and acronyms used in this article include the following: Table 2 : the term acronym Water content aq Atmospheric pressure atm tert-butylcarbamoyl Boc Width br diatomite Celite ® ]]> Electrospray ionization ESI Normal phase silica gel chromatography FCC GluNR2B * GluN 2B , NMDA-R2B, NR2B, hNR3 gram g Hour h High-performance liquid chromatography HPLC hertz Hz Isopropanol PrOH, IPA Liquid chromatography and mass spectrometry LCMS Moore M mass to charge ratio m / z mg mg minute min milliliters mL microliter µL millimole mmol mass spectrometry MS normal N Nuclear magnetic resonance NMR one in a million ppm precipitates ppt polytetrafluoroethylene PTFE Retention time [R t ]]> room temperature rt saturated sat Supercritical fluid chromatography SFC temperature T Thin-layer chromatography TLC Solvent volume per gram of substrate (in milliliters) V or volume * (Collingridge, GL et al., Neuropharmacology (2009, 56, 2-5) Preparation Example Exemplary compounds that can be used in the methods of the present invention will now be described with reference to exemplary synthetic schemes for their general preparation and specific examples thereafter.

[0134] Option 1 According to scheme 1, 6-bromo-1H-pyrazolo[4,3-b]pyridine, which is commercially available or synthetically available, is halogenated under conditions known to those skilled in the art to provide a compound of formula (V), wherein R 1 Halogens. For example, 6-bromo-1H-pyrazolo[4,3-b]pyridine uses an electrophilic fluorine source such as... N 1-Fluorobenzenesulfonamide (NFSI)N -Fluoro-phthalimide (NFOBS) or 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanebis(tetrafluoroborate) (Selectflor ® ), preferably Selectflor ® Fluorination in a suitable solvent such as acetonitrile (ACN) at a temperature range of 0°C to 100°C yields a compound of formula (V), wherein R 1 It is F.

[0135] Option 2 According to Scheme 2, at a temperature ranging from 0°C to room temperature, in the presence of a base (such as triethylamine (TEA) or sodium bicarbonate), a 2-haloacetyl chloride of formula (VI) (where X is Cl or Br), such as 2-chloroacetyl chloride, 2-bromoacetyl chloride, etc., is reacted with a commercially available or synthetically obtained appropriately substituted azacyclic butane of formula (VII) (where R... a H, halogen or C 1-6 Alkyl, and n A suitable substituted heterocyclic alkylamine of formula (1 or 2) or formula (IX) (where ring A is as described in formula (IB)) or a suitable substituted amine of formula (XI) (where R is as described in formula (IX)). d C 3-6 Cycloalkyl or C substituted with two F members 3-6 Cycloalkyl, and R e The reaction of H or CH3 in a solvent such as acetonitrile (ACN) or dichloromethane (DCM) yields compounds of formula (VIII), (X) and (XII).

[0136] Option 3 According to scheme 3, the difluorination of bromoarylformaldehyde (II) is achieved using diethylaminosulfur trifluoride (DAST) or similar solvents in a suitable solvent such as DCM to obtain bromo(difluoromethyl)aryl (III). Bromo(difluoromethyl)aryl (III) is then boronized by methods known to those skilled in the art, for example, bromo(difluoromethyl)aryl (III) can be treated with a transition metal catalyst, 1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (Pd(dppf)Cl2), in a solvent such as dimethyl sulfoxide (DMSO) or 1,4-dioxane, and with a base such as KOAc and bis(pinacolyl)diboron to obtain the compound of formula (IV).

[0137] Alternatively, at a temperature of about -78°C, in a solvent such as ether or tetrahydrofuran (THF), with or without lithium chloride, a compound of formula (III) (e.g., 2-bromo-5-(difluoromethyl)thiophene) is borated by metal halide exchange of bromide with an organolithium or magnesium reagent, and then treated with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane to obtain, for example, a compound of formula (IV) (e.g., 2-(5-(difluoromethyl)thiophene-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane).

[0138] Option 4 According to Scheme 4, at a temperature range of 0°C to room temperature, using alkalis such as Cs₂CO₃ or NaH, a compound of formula (VIII), (X), or (XII) (where X is Cl or Br) is used to react the compound of formula (V) (where R is Cl or Br). 1 Alkylation of (H, CH3, or F) in a suitable solvent such as dimethylformamide (DMF) yields a compound of formula (XIII) (where R is H, CH3, or F). 2 As defined in claim 1). The compound of formula (XIII) reacts in a metal-mediated cross-coupling reaction to give the compound of formula (I), wherein Ar 1 As defined in claim 1. For example, at temperatures ranging from 60°C to 120°C, palladium catalysts such as PdCl2(dtbpf), Pd(PPh3)4, bis(triphenylphosphine)palladium(II) chloride (PdCl2(PPh3)2), bis(diphenylphosphine)ferrocene]palladium(II) dichloride (a complex with dichloromethane), (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]palladium(II) dichloride (Pd(dppf)Cl2), etc., in the presence of a base such as KF, K3PO4, aqueous solution of Na2CO3, Cs2CO3, etc., the compound of formula (XIII) (wherein H, CH3 or F) is reacted with a suitably substituted aryl or heteroaryl boronic acid, boronic acid ester, etc., in a suitable solvent such as 1,4-dioxane, DMF, acetonitrile (ACN), water or a mixture thereof, for a period of about 16 to 48 hours to give the compound of formula (I).

[0139] Option 5 According to scheme 5, the compound of formula (V) (where R) is made into a compound of formula (V) (where R) 1(H, CH3, or F) reacts with appropriately substituted aryl or heteroaryl boronic acids or boronic esters as described above in a metal-mediated cross-coupling reaction to give a compound of formula (XIV) (where Ar is H, CH3, or F). 1 (The group is as defined in formula (I)). Then, under the aforementioned conditions, the compound is alkylated with a compound of formula (VIII), (X), or (XII) to obtain the compound of formula (I).

[0140] Option 6 According to Scheme 6, at a temperature ranging from 0°C to room temperature, a compound of formula (V) or a compound of formula (XV) (where R) is... 1 It is H, CH3 or F, and Ar 1 As described in formula (I), the compound is alkylated in a suitable solvent such as DMF using an electrophilic reagent such as ethyl 2-bromoacetate or tert-butyl 2-bromoacetate, and a base such as NaH or Cs₂CO₃. Under the aforementioned conditions, the compound of formula (XIV) is coupled with a suitably substituted phenyl or thiophene borate ester in a metal-mediated cross-coupling reaction as described above to obtain the compound of formula (XVI).

[0141] At 0°C, in a suitable solvent such as DCM, the compound of formula (XVI) (where Ar) 1 (The phenyl group substituted with CH2OH) is fluorinated with fluorinating agents such as bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor). ® Fluorination for 1 to 4 hours yields a compound of formula (XVI), wherein Ar... 1 It is a phenyl group substituted with CH2F.

[0142] The ester of formula (XVI) is saponified under alkaline conditions such as NaOH, LiOH, KOH, etc., in a suitable solvent such as methanol (MeOH), ethanol (EtOH), THF, ACN, H2O, or mixtures thereof, to obtain the compound of formula (XVII). Alternatively, the acidic hydrolysis of the ester of formula (XVI) is carried out using an acidic solvent such as an aqueous solution of 6N HCl at a temperature ranging from room temperature (rt) to 80°C to obtain the compound of formula (XVII). It should be understood that, in some cases, in-situ ester hydrolysis may be performed without separating the discrete ester (XVI) to provide the compound of formula (XVII).

[0143] Option 7 According to scheme 7, the compound of formula (I) (where R) 1 For H, CH3 or F, Ar 1For appropriately substituted phenyl or thiophene groups, and R 2 As defined in claim 1, it is formed by conventional amide bond formation techniques such as coupling reactions well known to those skilled in the art (such as HATU(1-[bis(dimethylamino)methylene]-1) H -1,2,3-triazolo[4,5- b Prepared by converting pyridinium 3-oxide hexafluorophosphate, BOP (benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate), or acid to acyl chloride. For example, by a suitably substituted heterocyclic alkylamine of formula (IX) or a suitably substituted azacyclic butane of formula (XVIII) or an amine of formula (XI) (wherein R d As defined in claim 1 and R e The reaction of H or CH3 with an acid compound of formula (XVII) (wherein the acid is activated with a suitable activator such as a carbodiimide, such as N,N'-dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC, or EDCI)), optionally in the presence of a hydroxybenzotriazole (HOBt) and / or a catalyst such as 4-dimethylaminopyridine (DMAP); a halotriaminophosphonium salt, such as (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) or tripyrrolidinylphosphonium hexafluorophosphate (PyBroP). ® ); a suitable pyridinium salt such as 2-chloro-1-methylpyridinium chloride; or another suitable coupling agent (such as N,N,N′,N′ -Tetramethyl- O- (1 H 1-Benzotriazol-1-yl)urea hexafluorophosphate (HBTU), 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b Pyridinium 3-oxide hexafluorophosphate (HATU), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphazenecyclohexane-2,4,6-trioxide (T3P) ® The reaction is carried out in the presence of tertiary amines such as N-methylmorpholine, N-ethyldiisopropylamine (DIEA, DIPEA) or triethylamine (TEA), in a suitable solvent such as DCM, THF, DMF, etc., at a temperature in the range of about 0°C to room temperature to obtain the compound of formula (I).

[0144] Compounds of formula (I) can be converted into their corresponding salts using methods known to those skilled in the art. For example, the amines of formula (I) can be treated with trifluoroacetic acid, HCl, or citric acid in solvents such as Et₂O, CH₂Cl₂, THF, MeOH, chloroform, or isopropanol to provide the corresponding salt forms. Alternatively, trifluoroacetic acid or formate salts can be obtained by purification under reversed-phase HPLC conditions. Crystalline forms of pharmaceutically acceptable salts of compounds of formula (I) can be obtained by recrystallization using polar solvents (including mixtures of polar solvents and aqueous mixtures of polar solvents) or nonpolar solvents (including mixtures of nonpolar solvents).

[0145] If the compounds according to the invention have at least one chiral center, they may exist accordingly in enantiomeric form. If the compounds have two or more chiral centers, they may additionally exist in diastereomeric form. It should be understood that all such isomers and mixtures thereof are covered within the scope of the invention.

[0146] Compounds prepared according to the above schemes can be obtained as a single form, such as a single enantiomer, through form-specific synthesis or resolution. Alternatively, compounds prepared according to the above schemes can be obtained as mixtures of various forms, such as racemic mixtures (1:1) or non-racemic mixtures (not 1:1). In the case of obtaining racemic and non-racemic mixtures of enantiomers, conventional separation methods known to those skilled in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation, or enzymatic transformation, can be used to separate single enantiomers. In the case of obtaining mixtures of regioisomers or diastereomeric mixtures, if applicable, conventional methods such as chromatography or crystallization can be used to separate single isomers.

[0147] The following specific embodiments are provided to further illustrate the present invention and various preferred embodiments. Example

[0148] When obtaining the compounds and corresponding analytical data described in the examples below, unless otherwise specified, the following experimental and analytical protocols shall be followed.

[0149] Unless otherwise specified, the reaction mixtures were magnetically stirred at room temperature (rt) under a nitrogen atmosphere. Solutions intended for "drying" were typically dried with a drying agent such as Na₂SO₄ or MgSO₄. Mixtures, solutions, and extracts intended for "concentration" were typically concentrated under reduced pressure using a rotary evaporator. Reactions under microwave irradiation conditions were carried out in a Biotage Initiator or a CEM (Microwave Reactor) Discover instrument.

[0150] For reactions carried out under continuous flow conditions, unless otherwise specified, “flow through LTF-VS mixer” means using a Chemyx Fusion 100 Touch syringe pump (Little Things Factory GmbH (http: / / www.ltf-gmbh.com) connected to the LTF-VS mixer via a 1 / 16” PTFE tube.

[0151] Normal phase silica gel chromatography (FCC) was performed on silica gel (SiO2) using a pre-packed column.

[0152] Preparative reversed-phase high-performance liquid chromatography (RP HPLC) is performed on any of the following devices: Method A The instrument used was an Agilent HPLC system with an Xterra Prep RP18 column (5µm, 30mm×100mm or 50mm×150mm) or an XBridge C18 OBD column (5µM, 30mm×100mm or 50mm×150mm). The mobile phase consisted of 20mM NH4OH solution containing 5% ACN for 2 minutes, followed by a step-up to 5%-99% ACN over 15 minutes, and then a hold at 99% ACN for 5 minutes at a flow rate of 40mL / min or 80mL / min.

[0153] or Method B The Shimadzu LC-8A series HPLC system, featuring an Inertsil ODS-3 column (3µm, 30mm × 100mm, T = 45℃), was used. The mobile phase consisted of 5% ACN in H2O solution (both containing 0.05% TFA) for 1 minute, followed by a step-up to 5%-99% ACN over 6 minutes, and then a hold at 99% ACN for 3 minutes at a flow rate of 80 mL / min.

[0154] or Method C: The Shimadzu LC-8A series HPLC uses an XBridge C18 OBD column (5µm, 50mm × 100mm). The mobile phase consists of 5% ACN in H2O solution (both containing 0.05% TFA) held for 1 minute, then stepped up to 5%-99% ACN over 14 minutes, followed by holding at 99% ACN for 10 minutes at a flow rate of 80 mL / min.

[0155] or Method DThe assay was performed using a Gilson HPLC system with an XBridge C18 column (5µm, 100mm × 50mm), a mobile phase of 20mM NH4OH solution of 5%-99% ACN, for 10 minutes, followed by a 2-minute hold at 99% ACN, at a flow rate of 80 mL / min.

[0156] or Method E. The Wufeng LC100 is equipped with a manual Rheodyne 3725i sampler, which features a Gemini-NX C18 column (5µM, 30×100mm) and a mobile phase of 0-90% ACN:10mM (NH4)HCO3 (9:1) in 10mM aqueous (NH4)HCO3 containing 0.1% NH4OH at a flow rate of 30mL / min over 16 or 18 minutes.

[0157] Method F Gilson HPLC with a C18 Xbridge column (30 × 100 mm 5 µm), mobile phase gradient from 60% 0.1% NH4CO3H / NH4OH pH 9 aqueous solution (40% CH3CN) to 43% 0.1% NH4CO3H / NH4OH pH 9 aqueous solution (57% CH3CN), flow rate 80 mL / min.

[0158] Preparative supercritical fluid high-performance liquid chromatography (SFC) was performed on a Jasco preparative SFC system, an APS 1010 system from Berger Instruments, or an SFC-PICLAB-PREP200 (PIC SOLUTION, Avignon, France). Separations were performed at flow rates ranging from 40 mL / min to 60 mL / min at 100 to 150 bar. The column was heated to 35°C to 40°C.

[0159] Unless otherwise specified, mass spectrometry (MS) was performed on an Agilent 1100 series MSD using electrospray ionization (ESI) in positive ion mode. Calculated masses (calcd.) correspond to exact masses.

[0160] Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker DRX spectrometer. Multiplicity is defined as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad peak. It should 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 for NMR spectroscopy and the concentration of the compound in solution.

[0161] Use ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChemV1.4.0.4 (Open Eye) to generate chemical names.

[0162] Compounds named R* or S* are enantiomeric pure compounds with undetermined absolute configuration. Example

[0163] Intermediate 1: 2-chloro-1-(3-fluorozacricyclobutan-1-yl)ethyl ketone .

[0164] Method A. Under argon atmosphere, a mixture of chloroacetyl chloride (1.57 mL, 19.7 mmol, 1.42 g / mL) and sodium bicarbonate (NaHCO3) (4.52 g, 53.8 mmol) in dichloromethane (DCM) (40 mL) was added fractionally to 3-fluorozahexacyclic butane hydrochloride (2.0 g, 17.9 mmol), and the reaction mixture was 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): C5H7ClFNO calculated mass 151.0; m / z determined value 152.1 [M+H] + .

[0165] Method B. Potassium carbonate (K₂CO₃) (46 g, 330 mmol) and 3-fluorozacriane (16.7 g, 150 mmol) were stirred in 100 mL of distilled water until all solids were completely dissolved. 100 mL of DCM was added to the solution, and the two-phase reaction was cooled to 0 °C and stirred vigorously 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 hours and diluted with water until all solids were dissolved. The layers were separated, and the aqueous layer was extracted four times with DCM. The combined organic compounds were concentrated to give the title compound as a pale yellow liquid of sufficient purity for direct use in subsequent steps (15.9 g, 105 mmol, 70%). 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).

[0166] Intermediate 2: 2-chloro- N - (3,3-difluorocyclobutyl)acetamide .

[0167] The title compound was prepared by using 3,3-difluorocyclobutane instead of 3-fluorozahexacyclobutane, similar to method A for intermediate 1. MS (ESI): C6H8ClF2NO calculated mass 183.0; m / z measured value 182.1 [MH] - .

[0168] Intermediate 3: 2-chloro-1-(3,3-difluoropyrrolidone-1-yl)ethyl-1-one .

[0169] The title compound was prepared by using 3,3-difluoropyrrolidine instead of 3-fluorozahexacyclic butane, similar to method A for intermediate 1. MS (ESI): C6H8ClF2NO calculated mass 183.0; m / z measured value 184.1 [M+H] + .

[0170] Intermediate 4: (racemic) 2-chloro-1-(3-hydroxypyrrolidone-1-yl)ethyl-1-one .

[0171] The title compound was prepared by using 3-hydroxypyrrolidine instead of 3-fluorozahexacyclic butane, similar to method A for intermediate 1. MS (ESI): C6H 10 The calculated mass of ClNO2 is 163.0; the measured m / z value is 164.1 [M+H]. + .

[0172] Intermediate 5: (racemic) 2-chloro-1-(3-fluoropyrrolidone-1-yl)ethyl-1-one .

[0173] The title compound was prepared using a method similar to that of intermediate 1 (Method A), with 3-fluoropyrrolidine used instead of 3-fluoroazacyclobutane. MS (ESI): C6H9ClFNO calculated mass 165.0; m / z measured value 166.1 [M+H] + .

[0174] Intermediate 6: 2-chloro-1-(3-methylazacyclobutan-1-yl)ethyl-1-one .

[0175] K₂CO₃ (1.93 g, 14.0 mmol) was added to a solution of 3-methylazacyclobutane hydrochloride (500 mg, 4.65 mmol) in DCM (7.75 mL) at 0 °C, and the reaction mixture was stirred for 10 min. Chloroacetyl chloride (407 µL, 5.11 mmol, 1.42 g / mL) was added dropwise to the reaction mixture 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% to 100% DCM / MeOH) gave the title compound (580 mg, 3.93 mmol, 85%) as a yellow oil. MS (ESI): C₆H₂O 10 The calculated mass of ClNO is 147.1; the measured m / z value is 148.1 [M+H] + .

[0176] Intermediate 7: 2-chloro- N -cyclobutylacetamide .

[0177] Triethylamine (Et3N) (2.16 mL, 15.5 mmol, 0.726 g / mL) was added dropwise to a freshly distilled tetrahydrofuran (THF) (60 mL) solution of cyclobutylamine (1.0 g, 14.1 mmol). 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 mixture was stirred for 1 hour. The reaction mixture was brought to room temperature and stirred for 17 hours. The reaction mixture was concentrated, and the residue was dissolved 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 NaHCO3 (1 × 35 mL), and saturated ammonium chloride (NH4Cl) (1 × 35 mL), dried over sodium sulfate (Na2SO4), filtered, and concentrated. Purification (FCC, SiO2, 10% to 100% n-heptane / EtOAc) yielded a residue, which was ground with n-heptane (10 mL) to give the title compound (1.37 g, 9.28 mmol, 66%) as a white crystalline solid. MS (ESI): C6H 10 The calculated mass of ClNO is 147.1; the measured m / z value is 148.1 [M+H] + .

[0178] Intermediate 8: 2-(5-(difluoromethyl)thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxanepentaneboron alkyl .

[0179] Step A. 2-Bromo-5-(difluoromethyl)thiophene5-Bromothiophene-2-carboxaldehyde (2.00 g, 10.5 mmol) was added dropwise to dimethylaminosulfur trifluoride (5.6 mL, 42.4 mmol, 1.22 g / mL) under argon atmosphere. The reaction mixture was then stirred at room temperature for 2 hours. The reaction was quenched by adding 2 M sodium hydroxide (NaOH) (10 mL) dropwise at 0 °C. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic matter was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification (FCC, SiO₂, n-heptane) gave the title compound (1.07 g, 5.03 mmol, 48%) as a colorless liquid. No mass ions were found in MS.

[0180] Step B. 2-(5-(difluoromethyl)thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane At -78°C and under argon atmosphere, n-butyllithium was added dropwise to a 17 mL THF solution of 2-bromo-5-(difluoromethyl)thiophene (930 mg, 4.37 mmol). n -BuLi) (1.6M hexane solution, 3 mL, 4.8 mmol), and the reaction mixture was stirred at -78 °C for 1 hour. A solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxane-pentaborane (980 µL, 4.8 mmol, 0.912 g / mL) in THF (2 mL) was added to the reaction mixture, and the reaction was stirred at -78 °C for 1 hour. The reaction mixture was allowed to reach room temperature and then stirred for 16 hours. The reactants were diluted with saturated NH4Cl aqueous solution (30 mL) and EtOAc (40 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (1 × 50 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated to give the title compound (1.00 g) as a brown oil, which was ready for use without further purification. The calculated mass of boric acid (ESI) C5H5BF2O2S is 178.0; the measured m / z value is 177.1 [MH]. - .

[0181] Intermediate 9: 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine .

[0182] Add to a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (2.5 g, 12.6 mmol) in acetonitrile (62.5 mL) N -fluorine- N'1-(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 MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by basic reversed-phase preparative HPLC (Method E) to give the title compound (641 mg, 2.97 mmol, 23%) as a brown powder. MS (ESI): C6H3BrFN3 calculated value 214.9; m / z determined value 216.0 [M+H] + .

[0183] Intermediate 10: 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)- N , N -Dimethylacetamide .

[0184] Method A. At 0 °C, NaH (60% in mineral oil, 444 mg, 11.1 mmol) was added to an anhydrous DMF (40 mL) solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (2.00 g, 10.1 mmol). The reaction mixture was stirred at 0 °C for 0.5 h. At 0 °C, 2-chloro- N , N -Dimethylacetamide (1.14 mL, 11.1 mmol, 1.18 g / mL). The reaction mixture was heated to room temperature and stirred for 18 hours. 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, SiO2, 25% to 100% hexane / EtOAc) yielded a solid, which was ground with Et2O (4 mL) to give the title compound (1.83 g, 6.47 mmol, 64%) as a grayish-white powder. MS (ESI): C 10 H 11 The calculated mass of BrN4O is 282.0; the measured m / z value is 283.0 [M+H]. + Method B. 6-bromo-1H-pyrazole[4,3- b A solution of pyridine (15.0 g, 75.7 mmol) in DMF (250 mL) was prepared with 2-chloro- N , NThe mixture was treated with dimethylacetamide (8.6 mL, 83 mmol) and K₂CO₃ (12.6 g, 90.9 mmol), and the reaction mixture was stirred overnight at room temperature. DMF was removed under reduced pressure to approximately 50 mL total volume, 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 The calculated mass of BrN4O is 282.0; the measured m / z value is 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).

[0185] Intermediate 11: 2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)- N , N -Dimethylacetamide .

[0186] The title compound was prepared using 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (intermediate 9) in a manner similar to method A, which is similar to that of intermediate 10. MS (ESI): C 10 H 10 The calculated mass of BrFN4O is 300.0; the measured m / z value is 301.0 [M+H]. + .

[0187] Intermediate 12: 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluorozacricyclobutan-1-yl) Ethyl-1-one .

[0188] 6-bromo-1H-pyrazole[4,3- bA solution of pyridine (10.0 g, 50.5 mmol) in DMF (100 mL) was treated with 2-chloro-1-(3-fluorozazepicyclobutan-1-yl)ethyl-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 hours. The reaction mixture was partitioned between DCM and water, and the aqueous layer was extracted with DCM (twice). The combined organic compounds were concentrated. Residual DMF was removed with heptane under azeotropic conditions. Purification (FCC, SiO₂, 0 to 10% DCM / MeOH) was performed to give 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 The calculated mass of BrFN4O is 312.0; the measured m / z value is 313.0 [M+H]. + . 1 H NMR (400MHz, DMSO-) d 6) 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).

[0189] Intermediate 13: 1-(azacyclobutane-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl-1- ketone .

[0190] In a manner similar to intermediate 10, method A, 1-(azacyclobutan-1-yl)-2-chloroethyl-1-one is used instead of 2-chloro- N , N The title compound was prepared using dimethylacetamide. MS (ESI): C 11 H 11 The calculated mass of BrN4O is 294.0; the measured m / z value is 295.0 [M+H]. + .

[0191] Intermediate 14: 1-(azacyclobutan-1-yl)-2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl) Ethyl-1-one .

[0192] In a manner similar to intermediate 10, method A, 1-(azacyclobutan-1-yl)-2-chloroethyl-1-one is used instead of 2-chloro- N , N The title compound was prepared by using dimethylacetamide and replacing 6-bromo-1H-pyrazolo[4,3-b]pyridine (intermediate 9) with 6-bromo-1H-pyrazolo[4,3-b]pyridine. MS (ESI): C 11 H 10 The calculated mass of BrFN4O is 312.0; the measured m / z value is 313.0 [M+H]. + .

[0193] Intermediate 15: 2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluorozahexacyclobutane-1-yl) 1-ethyl-1-one .

[0194] The title compound was prepared by using 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (intermediate 9) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine, similar to intermediate 12. MS (ESI): C 11 The calculated mass of H9BrF2N4O is 329.9; the measured m / z value is 331.0 [M+H]. + .

[0195] Intermediate 16: 6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine .

[0196] 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-dioxacyclopentaborane (2.31 g, 8.49 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (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 hours under microwave irradiation. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification (FCC, SiO2, 10% to 50% n-heptane / EtOAc) yielded a solid, which was ground with Et2O (4 mL) to give the title compound (1.41 g, 5.36 mmol, 76%) as a grayish-white powder. MS (ESI): C 13 The calculated mass of H8F3N3 is 263.1; the measured m / z value is 264.2 [M+H].+ . 1 H NMR (300MHz, DMSO- d 6) δ 13.48 (br s, 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).

[0197] Intermediate 17: 6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine .

[0198] The title compound was prepared in a manner similar to intermediate 16, using 2-(3-(difluoromethoxy)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane instead of 2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane. MS (ESI): C 13 The calculated mass of H8F3N3O is 279.0; the measured m / z value is 280.2 [M+H]. + .

[0199] Intermediate 18: 6-(4-chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine .

[0200] The title compound was prepared in a manner similar to intermediate 16, using 2-(3-(difluoromethoxy)-4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane instead of 2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane. MS (ESI): C 13 The calculated mass of H8ClF2N3O is 295.0; the measured m / z value is 296.0 [M+H] + .

[0201] Intermediate 19: 6-(3-(1,1-difluoroethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine .

[0202] The title compound was prepared in a manner similar to intermediate 16, using 2-(3-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane instead of 2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane. MS (ESI): C 14 H 10 The calculated mass of F3N3 is 277.1; the measured m / z value is 278.1 [M+H]. + .

[0203] Intermediate 20: 6-(3-(1,1-difluoroethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine .

[0204] The title compound was prepared in a manner similar to intermediate 16, using 2-(3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane instead of 2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane. MS (ESI): C 14 H 11 The calculated mass of F₂N₃ is 259.1; the measured m / z value is 260.1 [M+H]. + .

[0205] Intermediate 21: 6-(3-(difluoromethyl)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine .

[0206] The title compound was prepared by using 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (intermediate 9) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine, similar to intermediate 16. MS (ESI): C 13 The calculated mass of H7F4N3 is 281.1; the measured m / z value is 282.1 [M+H]. + .

[0207] Intermediate 22: 6-(4-chloro-3-(difluoromethoxy)phenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine .

[0208] The title compound was prepared in a manner similar 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-dioxacyclopentaborane instead of 2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane. MS (ESI): C 13 The calculated mass of H7ClF3N3O is 313.0; the measured m / z value is 314.1 [M+H]. + .

[0209] Intermediate 23: 6-(3-(difluoromethoxy)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine .

[0210] The title compound was prepared in a manner similar 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-dioxacyclopentaborane instead of 2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane. MS (ESI): C 13 The calculated mass of H7F4N3O is 297.1; the measured m / z value is 298.0 [M+H]. + .

[0211] Intermediate 24: 6-(3-(1,1-difluoroethyl)phenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine .

[0212] The title compound was prepared in a manner similar 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-dioxacyclopentaborane instead of 2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane. MS (ESI): C 14 H 10 The calculated mass of F3N3 is 277.1; the measured m / z value is 278.1 [M+H]. + .

[0213] Intermediate 25: 6-(4-fluoro-3-methylphenyl)-1H-pyrazolo[4,3-b]pyridine .

[0214] The title compound was prepared by replacing 2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane with 2-(4-fluoro-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane, in a manner similar to intermediate 16. MS (ESI): C 13 H 10 The calculated mass of FN3 is 227.1; the measured m / z value is 228.1 [M+H]. + .

[0215] Intermediate 26: 6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3- b ]Pyridine .

[0216] The title compound was prepared by using 6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine, similar to intermediate 16. MS (ESI): C 14 H 10 The calculated mass of F3N3 is 277.1; the measured m / z value is 278.1 [M+H]. + .

[0217] Intermediate 27: 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid .

[0218] Step A. Ethyl 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo(4,3-b)pyridin-1-yl] At 0 °C, Cs₂CO₃ (2.72 g, 8.35 mmol) was added to a DMF (30 mL) solution of 6-[3-(difluoromethyl)-4-fluoro-phenyl]-1H-pyrazolo(4,3-b)pyridine (intermediate 16, 2.00 g, 7.6 mmol). 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 heated to room temperature and stirred for 1 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 × 75 mL). The organic layers were combined and concentrated under reduced pressure. Purification (FCC, SiO₂, 0% to 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 The calculated mass of F3N3O2 is 349.1; the measured m / z value is 350.1 [M+H]. + .

[0219] Step B. 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetic acidTo a solution of ethyl 2-[6-[3-(difluoromethyl)-4-fluorophenyl]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 hour, concentrated to about 9 mL, and diluted with water (75 mL). The mixture was acidified to pH 4 with 1 M HCl. The precipitate was collected and washed with water (2 × 10 mL) and Et₂O (3 × 10 mL) to give the title compound (1.74 g, 5.416 mmol, 118%) as a white powder, which was ready for use without further purification. MS (ESI): C 15 H 10 The calculated mass of F3N3O2 is 321.1; the measured m / z value is 322.1 [M+H]. + .

[0220] Intermediate 28: 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl) Acetic acid .

[0221] The title compound was prepared in a manner similar 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 The calculated mass of H9F4N3O2 is 339.1; the measured m / z value is 340.1 [M+H]. + .

[0222] Intermediate 29: 2-(6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl acid .

[0223] The title compound was prepared in a manner similar 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 The calculated mass of F3N3O3 is 337.1; the measured m / z value is 338.1 [M+H] + .

[0224] Intermediate 30: 6-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine 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 dissolved in dioxane (15 mL) and water (5 mL). A nitrogen stream was bubbled through the reaction mixture for 10 min, followed by the addition of tetrakis(triphenylphosphine)palladium (247 mg, 0.21 mmol), and the reaction mixture was stirred at 90 °C for 24 h. The reaction mixture was then cooled to room temperature, diluted with water and DCM, and the aqueous layer was extracted with DCM (twice). The combined organic layers were dried (MgSO4), concentrated, and adsorbed onto silica gel. Purification (FCC, SiO2, 0–100% hexane / EtOAc, then 3–8% MeOH / DCM) yielded the title compound (530 mg, 58%). MS (ESI): C 12 The calculated mass of H8FN3 is 213.1; the measured m / z value is 214.1 [M+H]. + .

[0225] Intermediate 31: 2-(6-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid .

[0226] Step A. Ethyl 2-(6-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl) 6-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine (intermediate 30, 470 mg, 2.20 mmol) was dissolved in DMF (7 mL) and heated to 50 °C. Sodium hydride (60% dispersion in mineral oil, 106 mg, 2.65 mmol) was added to the solution, and the reaction mixture was stirred at 50 °C for 15 min. The mixture was cooled 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 (twice) with EtOAc. The combined organic layers were dried (MgSO4) and concentrated. Purification (FCC, SiO2, 0% to 100% hexane / EtOAc) yielded 422 mg (1.41 mmol, 64%). MS (ESI): C 16 H 14 The calculated mass of FN3O2 is 299.1; the measured m / z value is 300.1 [M+H]. + .

[0227] Step B. 2-(6-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acidEthyl 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 overnight at 50 °C. The pH of the mixture was adjusted to pH 1 with aqueous HCl, and then extracted with DCM (4 times). The combined organic layers (MgSO4) were dried and concentrated to give the title compound (400 mg, 1.475 mmol, 110%). The title compound was then used in the crude form for the next step. MS (ESI): C 14 H 10 The calculated mass of FN3O2 is 271.1; the measured m / z value is 272.1 [M+H]. + .

[0228] Intermediate 32: 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3] -b ]Pyridine-1- acetic acid .

[0229] Step A. 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl) Ethyl acetate To 6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3] -b Cs₂CO₃ (1.06 g, 3.25 mmol) was added to a stirred solution of pyridine (intermediate 26, 300 mg, 1.08 mmol) in DMF (6 mL), followed by ethyl bromoacetate (240 mg, 1.41 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and Et₂O, and the aqueous layer was extracted with Et₂O (twice). The combined organic matter was washed with water and brine, dried over MgSO₄, and concentrated. Purification (FCC, SiO₂, 0% to 100% hexane / EtOAc) gave the title compound (313 mg, 0.861 mmol, 80%). MS (ESI): C 18 H 16 The calculated mass of F3N3O2 is 363.1; the measured m / z value is 364.1 [M+H]. + .

[0230] Step B. 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3] -b ]pyridin-1-yl) Acetic acid To 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3- bA solution of 15 mL of pyridin-1-yl)ethyl acetate (313 mg, 0.861 mmol) in THF was added to a 5 mL solution of 4 N lithium hydroxide. The biphase mixture was stirred vigorously overnight. The reaction mixture was partitioned between water and Et₂O, and the layers were separated. The organic layer was extracted with water (twice). 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 give the title compound (293 mg, 100%) as a white solid. The purity of this compound was sufficient to proceed to subsequent steps without further purification. MS (ESI): C 16 H 12 The calculated mass of F3N3O2 is 335.1; the measured m / z value is 336.1 [M+H] + .

[0231] Intermediate 33: 3-ethynylazine-butane•HCl salt .

[0232] Step A. 3-Ethynylazyrobutane-1-carboxylic acid tert-butyl ester 3-Formylazacyclobutane-1-carboxylic acid tert-butyl ester (500 mg, 2.70 mmol), dimethyl (1-diaza-2-oxopropyl)phosphonate (10% wt, 9.2 mL, 4.05 mmol), and potassium carbonate (1120 mg, 8.10 mmol) were dissolved in methanol (10 mL). The reaction mixture was stirred at room temperature for 3 hours, concentrated, and diluted with diethyl ether and water. The organic layer was separated, washed with water, then washed with a saturated aqueous sodium carbonate solution, dried (MgSO4), and concentrated. Purification (FCC, SiO2, 0%–25% ethyl acetate / hexane gradient) gave the title compound (356 mg, 1.96 mmol, 73%). 1 H 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).

[0233] Step B. 3-Ethynylazyrobutane•HCl salt 3-ethynylazetane-1-carboxylic acid tert-butyl ester (50 mg, 0.28 mmol) was dissolved in a dioxane solution (1 mL) of 4N HCl, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the hydrochloride salt of the title compound was used directly in the next step without further purification.

[0234] Intermediate 34: ( Z )-3-(prop-1-en-1-yl)azacyclobutane•HCl salt .

[0235] Step A. (Z)-3-(prop-1-en-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester Ethyl(triphenyl)phosphonium bromide (1.21 g, 3.24 mmol) was suspended in anhydrous THF (15 mL). The suspension was cooled to 0 °C. The solution was then stirred... n BuLi (2.5 M hexane solution, 1.3 mL, 3.24 mmol) was added dropwise to the reaction mixture, and the reaction mixture was stirred at 0 °C for 1 hour. 3-Formylazetane-1-carboxylic acid tert-butyl ester (500 mg, 2.70 mmol) was slowly added to the reaction mixture at 0 °C, and the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated, partitioned between DCM and water, the aqueous layer was extracted with DCM (twice), and the combined organic matter was concentrated. The crude material was purified on silica gel (FCC, SiO2, 0%–50% ethyl acetate / hexane gradient) to give the title compound as a 7:1 mixture of Z / E isomers (318 mg, 1.61 mmol, 60%). 1 H 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).

[0236] Step B. Z 3-(prop-1-en-1-yl)azacyclobutane HCl salt .Will( Z 50 mg (0.28 mmol) of tert-butyl 3-(prop-1-en-1-yl)azacyclobutane-1-carboxylic acid was dissolved in a dioxane solution (1 mL) of 4 N HCl, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the hydrochloride salt of the title compound was used directly in the next step.

[0237] Intermediate 35: 3-(2,2-difluorovinyl)azacyclobutane HCl salt .

[0238] Step A. 3-(2,2-difluorovinyl)azacyclobutane-1-carboxylic acid tert-butyl ester3-Formylazetane-1-carboxylic acid tert-butyl ester (1000 mg, 5.40 mmol) and triphenylphosphine (2.8 g, 10.8 mmol) were dissolved in anhydrous DMF (10 mL) and stirred and heated to 100 °C. Sodium difluorochloroacetate (1.7 g, 10.8 mmol) was added dropwise over 30 minutes, and the reaction mixture was stirred at 100 °C for another 15 minutes after the addition was complete. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove DMF, diluted with DCM, and briefly shaken with a 30% aqueous solution of H2O2. The resulting biphasic mixture was further diluted with DCM and water. The aqueous layer was extracted with DCM (twice), and the combined organic matter was concentrated. Purification (FCC, SiO2, 0%–50% ethyl acetate / hexane gradient) gave the title compound (786 mg, 3.58 mmol, 66%). 1 H 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).

[0239] Step B. HCl salt of 3-(2,2-difluorovinyl)azacyclobutane 75 mg (0.34 mmol) of tert-butyl 3-(2,2-difluorovinyl)azacyclobutane-1-carboxylic acid was dissolved in 1 mL of dioxane in 4 N HCl, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the hydrochloride salt of the title compound was used directly in the next step.

[0240] Intermediate 36: ( Z 3-(2-Fluorovinyl)azacyclobutane HCl salt .

[0241] Step A. (Z)-3-(2-fluorovinyl)azacyclobutane-1-carboxylic acid tert-butyl ester 3-(2,2-difluorovinyl)azacyclobutane-1-carboxylic acid tert-butyl ester (500 mg, 2.28 mmol), bis(neopentylethylene glycol)diboron (1.6 g, 6.8 mmol), and water (120 µL, 6.8 mmol) were dissolved in dimethylacetamide (10 mL), and the solution was degassed by bubbling with N2. Thiophene-2-carboxylic acid copper (43 mg, 0.23 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthrene (Xantphos) were added. ®(135 mg, 0.23 mmol) and lithium tert-butoxide (565 mg, 6.8 mmol) (which reacts exothermically upon addition of alkali). The reaction mixture was stirred overnight at 40 °C and then partitioned between water and a 3:1 mixture of ethyl acetate / hexane. The organic layer was extracted with water (twice). The organic layer was concentrated. Purification (FCC, SiO2, 0%–50% ethyl acetate / hexane gradient) gave the title compound (319 mg, 1.59 mmol, 70%), obtained by reacting approximately 20 mol% of the starting material with 7 mol% of the ethyl acetate / hexane. E Isomer contamination. Proceed to the next step with the title compound as is. 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).

[0242] Step B. (Z)-3-(2-fluorovinyl)azacyclobutane HCl salt (Z)-3-(2-fluorovinyl)azacyclobutane-1-carboxylic acid tert-butyl ester (319 mg, 1.59 mmol) was dissolved in a dioxane solution (5 mL) of 4N HCl, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the hydrochloride salt of the title compound was used directly without further purification.

[0243] Intermediate 37: 6-(5-chloro-2-thienyl)-1 H -pyrazolo[4,3- b ]Pyridine .

[0244] To 6-bromo- 1 H-pyrazolo[4,3- bPyridine (500 mg, 2.52 mmol) was added to a solution of degassed 1,4-dioxane (39.4 mL) and water (9.55 mL) with 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 at 80 °C for 1 hour under argon. Further addition of 5-chlorothiophene-2-boronic acid (123 mg, 0.757 mmol) and tetrakis(triphenylphosphine)palladium(0) (87 mg, 0.075 mmol) was introduced, and the reaction mixture was stirred at 80 °C for 2 hours under argon. 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 (3 × 40 mL). The combined organic matter was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Purification (FCC, SiO2, 25% to 100% n-heptane / EtOAc) yielded the title compound (419 mg, 1.78 mmol, 70%) as a yellow powder after grinding with diethyl ether (7 mL). MS (ESI): C 10 The calculated mass of H6ClN3S is 235.0; the measured m / z value is 236.0 [M+H]. + . 1 H NMR (300MHz, DMSO- d 6) 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).

[0245] Intermediate 38: 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine .

[0246] 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-tetra(triphenylphosphine) (1.5 g, 1.3 mmol) in an aqueous sodium carbonate solution (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 hours, EtOAc was added, and the mixture was washed twice with H2O. The organic layer was dried (Na2SO4) and concentrated under vacuum. The residue was purified (FCC, SiO2, 0%–50% heptane solution of EtOAc) to give a yellow solid. The solid was ground with Et2O and collected by filtration to give the title compound (2.1 g, 8.0 mmol, 31.6%). MS (ESI): C 13 The calculated mass of H8F3N3 is 263.1; the measured m / z value is 264.1 [M+H]. + .

[0247] Intermediate 39: 2-(6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid .

[0248] Sodium hydride (60% dispersion in mineral oil, 387.5 mg, 9.7 mmol) was added to a stirred DMF (20 mL) solution of 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine (intermediate 38,850 mg, 3.2 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. Then ethyl bromoacetate (0.54 mL, 4.8 mmol) was added, and the reaction mixture was heated to room temperature. After 16 hours, an aqueous solution of potassium hydroxide (1 M, 16.1 mL, 16.1 mmol) was added to the reaction mixture, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under vacuum, 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 ground from Et2O to give the title product (630 mg, 2.0 mmol, 60.7%). MS (ESI): C 15 H 10 The calculated mass of F3N3O2 is 321.1; the measured m / z value is 322.2 [M+H]. + .

[0249] Intermediate 40: ethyl 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl) .

[0250] 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 and under a nitrogen atmosphere. After 10 minutes, ethyl bromoacetate (0.5 mL, 4.5 mmol) was added to the reaction mixture. After 16 hours, water (80 mL) was added, and precipitation occurred slowly. The solid was collected by filtration and purified (FCC, SiO2, 0%–90% hexane solution of EtOAc) to give the title compound (917 mg, 3.2 mmol, 100%). MS (ESI): C 10 H 10 The calculated mass of BrN3O2 is 283.0; the measured m / z value is 284.0 [M+H] + .

[0251] Intermediate 41: 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid .

[0252] At room temperature, lithium hydroxide (4 M aqueous solution, 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). Complete conversion was observed after 16 hours, and the precipitate was collected by filtration, washed with THF, and dried under vacuum to give the title compound (1.16 g, 4.5 mmol, 83.6%). MS (ESI): C8H6BrN3O2, calculated mass 255.0; m / z determined 256.0 [M+H] + . 1 H NMR (500MHz, DMSO- d 6) δ 8.50 (d, J = 2.0Hz, 1H), 8.26 – 8.24 (m, 1H), 8.17 – 8.15 (m, 1H), 4.66 (s, 2H).

[0253] Intermediate 42: 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3,3-difluoroazacyclobutane-1-yl) 1-ethyl-1-one .

[0254] 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (intermediate 41, 300 mg, 1.2 mmol), 3,3-difluorozacriane hydrochloride (182 mg, 1.4 mmol), and T3P were added. ®The mixture of (50% DMF solution, 2.1 mL, 3.5 mmol) and DIPEA (0.4 mL, 2.5 mmol) in DCM (11.7 mL) was stirred at room temperature. After 16 hours, complete conversion was observed, and water (20 mL) was added. The mixture was extracted with EtOAc (3 × 35 mL). The combined organic matter was dried (MgSO4), filtered, and concentrated under vacuum to give the title compound (287 mg, 0.9 mmol, 74.0%). MS (ESI): C 11 The calculated mass of H9BrF2N4O is 330.0; the measured m / z value is 331.0 [M+H] + .

[0255] Intermediate 43: 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(pyrrolidone-1-yl)ethyl-1-one .

[0256] The title compound was prepared by replacing 3,3-difluoroazacyclobutane hydrochloride with pyrrolidine in a manner similar to intermediate 42. MS (ESI): C 12 H 13 The calculated mass of BrN4O is 308.0; the measured m / z value is 309.0 [M+H] + .

[0257] Intermediate 44: ( S )-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoropyrrolidine-1-yl) Ethyl-1-one .

[0258] Use it in a manner similar to intermediate 42 ( S The title compound was prepared by replacing 3,3-difluorozahexacyclic butane hydrochloride with 3-fluoropyrrolidine hydrochloride. MS (ESI): C 12 H 12 The calculated mass of BrFN4O is 326.0; the measured m / z value is 327.0 [M+H]. + .

[0259] Intermediate 45: ( R )-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoropyrrolidine-1-yl) Ethyl-1-one .

[0260] Use it in a manner similar to intermediate 42 ( R The title compound was prepared by replacing 3,3-difluorozahexacyclic butane hydrochloride with 3-fluoropyrrolidine hydrochloride. MS (ESI): C 12 H 12 The calculated mass of BrFN4O is 326.0; the measured m / z value is 327.0 [M+H]. + .

[0261] Intermediate 46: ethyl 2-(6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl) .

[0262] The title compound was prepared by using 6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine, similar to intermediate 40. MS (ESI): C 11 H 12 The calculated mass of BrN3O2 is 297.0; the measured m / z value is 298.1 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0263] Intermediate 47: 2-(6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid .

[0264] The title compound was prepared in a manner similar 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): C9H8BrN3O2, calculated mass 269.0; m / z measured 270.0 [M+H] + .

[0265] Intermediate 48: 1-(azacyclobutane-1-yl)-2-(6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine-1- 1-ethyl-1-one .

[0266] The title compound was prepared in a manner similar 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 The calculated mass of BrN4O is 308.0; the measured m / z value is 309.1 [M+H] + .1 H NMR (500MHz, DMSO-) d 6) 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).

[0267] Intermediate 49: 3-Methyl-6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine .

[0268] 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]palladium(II) dichloride (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 hours, the reaction mixture was concentrated under vacuum. Purification (FCC, SiO2, 0%–90% EtOAc in hexane solution) gave the title compound (229 mg, 0.8 mmol, 87.6%). MS (ESI): C 14 H 10 The calculated mass of F3N3 is 277.1; the measured m / z value is 278.1 [M+H]. + . 1 H NMR (400MHz, DMSO- d 6) 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).

[0269] Intermediate 50: 2-(3-methyl-6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl Ethyl acetate .

[0270] The title compound was prepared in a manner similar 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 The calculated mass of F3N3O2 is 363.1; the measured m / z value is 364.1 [M+H]. + . 1 H NMR (400MHz, DMSO- d 6)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).

[0271] Intermediate 51: 2-(3-methyl-6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl acid .

[0272] The title compound was prepared in a manner similar 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 The calculated mass of F3N3O2 is 335.1; the measured m / z value is 336.1 [M+H]. + .

[0273] Intermediate 52: 2-(6-(4-fluoro-3-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid .

[0274] 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]palladium(II) dichloride (a complex with dichloromethane) (9.9 mg, 0.014 mmol), sodium carbonate (86 mg, 0.82 mmol), 1,4-dioxane (1.4 mL), and water (0.8 mL) was heated at 110 °C for 16 hours. The reaction mixture was diluted with water and washed with ethyl acetate (3 times). The aqueous layer was acidified with 1 N HCl and extracted with ethyl acetate (3 times). The combined organic matter was dried (MgSO4) and concentrated to give the title compound (71 mg, 0.25 mmol, 92%), which was of sufficient purity for subsequent transformations. MS (ESI): C 15 H 12 The calculated mass of FN3O2 is 285.1; the measured m / z value is 286.1 [M+H] + .

[0275] Intermediate 53: 2-(6-(4-fluoro-2-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid .

[0276] The title compound was prepared by using 4-fluoro-2-methylboronic acid instead of 4-fluoro-3-methylboronic acid, similar to intermediate 52. MS (ESI): C 15 H 12 The calculated mass of FN3O2 is 285.1; the measured m / z value is 286.1 [M+H] + .

[0277] Intermediate 54: ethyl acetate of 2-(6-(3-(hydroxymethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl) .

[0278] 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]palladium(II) dichloride (a complex with dichloromethane) (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 organic matter was dried (MgSO4), filtered, and concentrated under vacuum. Purification (FCC, SiO2, 0%–90% hexane solution of EtOAc) gave the title compound (325 mg, 1.0 mmol, 20%). MS (ESI): C 17 H 17 The calculated mass of N3O3 is 311.1; the measured m / z value is 312.2 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0279] Intermediate 55: ethyl acetate of 2-(6-(3-(fluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl) .

[0280] Under a nitrogen atmosphere at 0°C, bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) was... ®(0.2 mL, 1.2 mmol) was added to a mixture of 2-(6-(3-(hydroxymethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl acetate (intermediate 54, 300 mg, 1.0 mmol) in DCM (6.6 mL). After 3 hours, the reaction mixture was slowly poured into a mixture of saturated NaHCO3 aqueous solution (20 mL) and DCM (20 mL) at 0 °C. The mixture was extracted with DCM (3 × 30 mL). The combined organic matter was dried (MgSO4), filtered, and concentrated under vacuum to give the title compound. MS (ESI): C 17 H 16 The calculated mass of FN3O2 is 313.1; the measured m / z value is 314.2 [M+H]. + .

[0281] Intermediate 56: 2-(6-(3-(fluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid .

[0282] The title compound was prepared in a manner similar 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 The calculated mass of FN3O2 is 285.1; the measured m / z value is 286.1 [M+H] + .

[0283] Intermediate 57: ethyl acetate of 2-(6-(3,4-difluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl) .

[0284] The title compound was prepared by using 3,4-difluorophenylboronic acid instead of (3-(hydroxymethyl)phenyl)boronic acid, similar to intermediate 54. MS (ESI): C 16 H 13 The calculated mass of F₂N₃O₂ is 317.1; the measured m / z value is 318.1 [M+H]. + .

[0285] Intermediate 58: 2-(6-(3,4-difluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid .

[0286] The title compound was prepared in a manner similar 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 The calculated mass of H9FN3O2 is 289.1; the measured m / z value is 290.1 ​​[M+H]. + .

[0287] Intermediate 59: 2-Bromo-N-cyclopropylacetamide .

[0288] At -78 °C, 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). The frozen reaction mixture was slowly warmed to room temperature. After 2 hours, water (30 mL) was added, and the mixture was extracted with DCM (3 × 40 mL). The combined organics were concentrated under vacuum to give a mixture of the title compounds contaminated with chlorine derivatives. MS (ESI): C5H8BrNO calculated mass 177.0; m / z determined 178.0 [M+H] + .

[0289] Intermediate 60: 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine .

[0290] 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-tetra(triphenylphosphine) (1.5 g, 1.3 mmol) in an aqueous sodium carbonate solution (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 hours, EtOAc was added, and the mixture was washed twice with H2O. The organic layer was dried (Na2SO4) and concentrated under vacuum. The residue was purified (FCC, SiO2, 0%–50% heptane solution of EtOAc) to give a yellow solid. The solid was ground with Et2O and collected by filtration to give the title compound (2.1 g, 8.0 mmol, 31.6%). MS (ESI): C 13 The calculated mass of H8F3N3 is 263.1; the measured m / z value is 264.1 [M+H]. + .

[0291] Intermediate 61: 2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxanepentaneboron alkyl .

[0292] A solution of 4-bromo-2-(difluoromethyl)-1-fluorobenzene (20 g, 88.9 mmol), bis(pinacolyl)diboron (24.8 g, 97.8 mmol), potassium acetate (26.2 g, 267 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (3.12 g, 4.44 mmol) in 1,4-dioxane (400 mL) was purged with N2, and the reaction mixture was stirred overnight at 90 °C. Upon completion, the reaction mixture was cooled to room temperature and analyzed by Celite. ® Filter and rinse with EtOAc. Wash the filtrate with water and brine. Dry the combined organic matter with Na2SO4, filter and concentrate to give a clear oil (22.1 g, 81.0 mmol, 91%), which solidifies upon standing. 1 H NMR (400MHz, 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 = 54.9Hz, 1H), 1.35 (s, 12H). MS (ESI): C 13 H 16 The calculated mass of BF3O2 is 272.1; the measured m / z value is 273.0 [M+H]. + .

[0293] Intermediate 62: 2-(3-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane Pentylborane .

[0294] Step A: 4-Bromo-2-(1,1-Difluoroethyl)-1-fluorobenzene In a round-bottom flask, a mixture of 1-(5-bromo-2-fluorophenyl)-1-ethylone (2.5 g, 11.5 mmol, 1 equivalent) and DAST (1.9 mL, 14.4 mmol, 1.25 equivalent) was heated at 60 °C for 16 hours. Then, a saturated aqueous solution of NaHCO3 was slowly added at 0 °C and extracted with DCM. The organic layers were combined, dried over MgSO4, filtered, and partially concentrated (the product was volatile). Purification (FCC, SiO2, 100% DCM) gave 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).

[0295] Step B: 2-(3-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxanepentaneboron Alkane. In a round-bottom flask, bis(pinacol)diboron (2.87 g, 11.3 mmol), potassium acetate (2.22 g, 22.6 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]-palladium(II) dichloride (615 mg, 0.75 mmol) were added to an anhydrous 1,4-dioxane (40 mL) solution of 4-bromo-2-(1,1-difluoroethyl)-1-fluorobenzene (3 g, 7.5 mmol). The mixture was purged with nitrogen and stirred at 90 °C for 16 hours. Then, a saturated aqueous solution of NaHCO3 was added and the mixture was extracted with EtOAc. The combined organic matter was dried over MgSO4, filtered, and concentrated to give a brown oil (2.15 g, 7.53 mmol), which was used for the next step without further purification. MS (ESI): C 14 H 18 The calculated mass of BF3O2 is 286.1; the measured m / z value is 287.1 [M+H]. + .

[0296] Intermediate 63: 2-(3-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane .

[0297] The title compound was prepared by using 1-bromo-3-(difluoromethyl)benzene instead of 4-bromo-2-(difluoromethyl)-1-fluorobenzene, similar to intermediate 61. No mass was observed.

[0298] Intermediate 64: 2-(3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxanepentaneboron alkyl .

[0299] The title compound was prepared by replacing 4-bromo-2-(difluoromethyl)-1-fluorobenzene with 1-bromo-3-(1,1-difluoroethyl)benzene, in a manner similar to intermediate 61. No mass was observed.

[0300] Intermediate 65: 2-(3-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxanepentaneboron alkyl .

[0301] The title compound was prepared by replacing 4-bromo-2-(difluoromethyl)-1-fluorobenzene with 1-bromo-3-(1,1-difluoroethyl)benzene, in a manner similar to intermediate 61. MS (ESI): C 13 H 16 The calculated mass value of BF3O2 is 272.1; the measured m / z value is 273.2 [M+H]+.

[0302] Intermediate 66: 2-(3-(difluoromethoxy)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane-pentane Borane .

[0303] The title compound was prepared by replacing 4-bromo-2-(difluoromethoxy)-1-fluorobenzene with 4-bromo-2-(difluoromethyl)-1-fluorobenzene, similar to intermediate 61. MS (ESI): C 13 H 16 The calculated mass value of BF3O3 is 288.1; the measured m / z value is 289.0 [M+H]+.

[0304] Intermediate 67: 2-(4-chloro-3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane-pentane Borane .

[0305] The title compound was prepared by using 4-bromo-1-chloro-2-(difluoromethoxy)benzene instead of 4-bromo-2-(difluoromethyl)-1-fluorobenzene in a manner similar to intermediate 61. 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).

[0306] Intermediate 68: 2-(4-chloro-3-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxanepentaneboron alkyl .

[0307] The title compound was prepared in step A by replacing 1-(5-bromo-2-chlorobenzaldehyde with 1-(5-bromo-2-fluorophenyl)-1-ethylone, similar to intermediate 62. MS (ESI): C 13 H 16 The calculated mass of BClF₂O₂ is 288.1; the measured m / z value is 289.1 [M+H]. + .

[0308] Intermediate 69: 2-(4-chloro-3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane Pentylborane .

[0309] The title compound was prepared in step A by using 1-(5-bromo-2-chlorophenyl)ethyl-1-one instead of 1-(5-bromo-2-fluorophenyl)-1-ethylone, similar to intermediate 62. 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).

[0310] Intermediate 70: 1-(2-(6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetyl) Azacyclobutane-3-yl-4-methylbenzenesulfonate .

[0311] To a DCM (2 mL) solution of 1-(3-hydroxyazacyclobutan-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetone trifluoroacetate (Example 113, 32 mg, 0.085 mmol), 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) were added. The resulting mixture was stirred at room temperature for 15 hours. The mixture was then diluted with EtOAc (20 mL) and washed with brine (20 mL), followed by washing with water (2 × 20 mL), and dried over Na2SO4 and concentrated. The residue was purified by FCC (hexane / EtOAc, 0% to 100%) to give the title compound (36 mg, 0.067 mmol). MS (ESI): C 25 H 21 The calculated mass of F3N4O4S is 530.1; the measured m / z value is 531.2 [M+H]. + . 1 1H 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). Example

[0312] Example 1: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3- b ]pyridin-1-yl]-1-[3-hydroxy [3-(trifluoromethyl)azacyclobutane-1-yl]ethyl ketone .

[0313] By using 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3- b The mother liquor for preparing the active ester was prepared by dissolving 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 anhydrous ACN (6 mL). A 1 mL aliquot (30 mg carboxylic acid, 0.93 mmol) was added to a vial containing 3-(trifluoromethyl)azacyclobutane-3-ol (15.8 mg, 0.112 mmol). The reaction mixture was stirred overnight and purified by reversed-phase HPLC (Method D) to give the title compound (3.4 mg, 8%). MS (ESI): C 19 H 14 The calculated mass of F6N4O2 is 444.1; the measured m / z value is 445.0 [M+H]. + . 1 H NMR (400MHz, CDCl3) δ8.81 (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).

[0314] Example 2: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-(3-imide Methylazon-1-yl)ethyl ketone .

[0315] 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3- b Pyridin-1-yl)acetic acid (intermediate 27, 50 mg, 0.156 mmol), 3-methyleneazacyclobutane hydrochloride (33 mg, 0.31 mmol), (benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate (PyBOP) ® A solution of anhydrous DCM (2 mL) containing 97 mg (0.19 mmol) and DIPEA (110 µL, 0.62 mmol) was stirred at room temperature for 30 minutes. The reaction mixture was injected directly onto a silica gel column and purified by chromatography (FCC, SiO2, 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 The calculated mass of F3N4O is 372.1; the measured m / z value is 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).

[0316] Example 3: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-[3-(methyl] [1-yl]amino(azine)butane-1-yl]ethyl ketone .

[0317] Step A. (1-(2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl Acyl)azacyclobutane-3-yl)(methyl)carbamate tert-butyl The title compound was prepared in a manner similar to Example 1, using tert-butyl aziridine-3-yl(methyl)carbamate instead of 3-(trifluoromethyl)aziridine-3-ol. MS(ESI): C 24 H 26 The calculated mass of F3N5O3 is 489.2; the measured m / z value is 490.0 [M+H]. + .

[0318] Step B. 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-[3-(methyl] [1-yl]amino(azine)butane-1-yl]ethyl ketone (1-(2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetyl)azacyclobutane-3-yl)(methyl)carbamate tert-butyl ester (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 hour, concentrated, and partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with DCM (twice), and the combined organic matter was concentrated and purified on silica gel (nonpolar phase DCM, polar phase 10% NH4OH / MeOH, 0%–10% gradient) to give the title compound (45 mg, 0.116 mmol, 37% yield). MS (ESI): C 19 H 18 The calculated mass of F3N5O is 389.1; the measured m / z value is 390.0 [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 = 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).

[0319] Example 4: N -[1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]ethyl [Acyl]azacyclobutane-3-yl]- N -Methylacetamide .

[0320] To 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b Acetyl chloride (10 µL, 0.14 mmol) was added to an anhydrous DCM solution of pyridin-1-yl]-1-[3-(methylamino)azacyclobutan-1-yl]acetone (Example 3, 36.5 mg, 0.094 mmol) and triethylamine (40 µL, 0.28 mmol) in 1 mL. The reaction mixture was stirred at room temperature for 15 min, then injected 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 The calculated mass of F3N5O2 is 431.2; the measured m / z value is 432.1 [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 = 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).

[0321] Example 5: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoro (Zyrocyclobutane-1-yl)ethyl ketone .

[0322] Method A.To a mixture of 6-[3-(difluoromethyl)-4-fluorophenyl]-1H-pyrazolo[4,3-b]pyridine (intermediate 16, 1.10 g, 4.18 mmol) and Cs₂CO₃ (2.05 g, 6.29 mmol) in anhydrous DMF (22 mL), 2-chloro-1-(3-fluoroazacyclobutan-1-yl)acetone (intermediate 1, 697 mg, 4.60 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by gradient silica column chromatography, eluting with n-heptane:EtOAc (100:0 → 0:100). The product was recrystallized from ethanol (20 mL) and ground 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 The calculated mass of F4N4O is 378.1; the measured m / z value is 379.1 [M+H]. + .

[0323] Method B. 2-(6-bromo-1H-pyrazolo[4,3] -b A solution of pyridin-1-yl)-1-(3-fluorozacyclobutan-1-yl)ethyl-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-dioxacyclopentaborane (8.7 g, 32 mmol), cesium carbonate (26 g, 80 mmol), and palladium(II) methanesulfonate (RuPhos Pd G3) (1.1 g, 1.3 mmol, 5 mol%) of (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate (RuPhos Pd G3) (1.1 g, 1.3 mmol, 5 mol%), and the reaction mixture was refluxed and stirred for 16 hours. The mixture was cooled to room temperature, concentrated to remove dioxane, partitioned between DCM and water, and the aqueous layer was extracted using DCM (twice). The combined organic matter was washed with 4N LiOH, dried (MgSO4), filtered, and stirred overnight with SiliaMetSH thiol scavenger. (By Celite) ® Filter, purify on silica gel (0%–10% MeOH / DCM gradient), recrystallize from hot ethanol, and then recrystallize from hot ethyl acetate. 4.78 g (12.6 mmol, 47% yield) of the title compound was isolated. MS (ESI): C 18 H 14The calculated mass of F4N4O is 378.1; the measured m / z value is 379.1 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) δ 8.88 (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, 1H), 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).

[0324] Example 6: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl] N , N -II α-acetamide .

[0325] Method A. At 0 °C and under argon atmosphere, 6-[3-(difluoromethyl)-4-fluoro-phenyl]-1-difluoromethyl sodium hydroxide (60% in mineral oil, 164 mg, 4.10 mmol) was added to an anhydrous DMF (8.9 mL) suspension. H -pyrazolo[4,3- b An anhydrous DMF solution (8.9 mL) of pyridine (intermediate 16, 900 mg, 3.42 mmol) was added. The reaction mixture was stirred at 0 °C for 0.5 h. 2-chloro- N , N -Dimethylacetamide (387 µL, 3.76 mmol, 1.18 g / mL). The reaction mixture was heated to room temperature and stirred for 3 hours. The reaction mixture was 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 organic matter was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification (FCC, SiO₂, 1% to 20% EtOAc / EtOH) yielded a solid, which was recrystallized from ethanol (8 mL) to give the title compound (708 mg, 2.03 mmol, 59%) as a white powder. MS (ESI): C17 H 15 The calculated mass of F3N4O is 348.1; the measured m / z value is 349.2 [M+H]. + .

[0326] Method B. To 2-(6) - Bromo-1H-pyrazolo[4,3- b ]pyridin-1-yl)- N , N To a solution of dioxane (400 mL) of dimethylacetamide (intermediate 10, 14.0 g, 49.5 mmol), 2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (16.2 g, 59.4 mmol), cesium carbonate (48.4 g, 149 mmol), and RuPhos Pd G3 (2.35 g, 2.81 mmol) were added. The reaction mixture was refluxed and stirred for 4 hours, cooled to room temperature, concentrated to approximately 25 mL of dioxane, and diluted with water (300 mL). The resulting precipitate was collected by filtration and then adsorbed onto Celite. ® The product was purified by silica gel chromatography (FCC; 0%–10% MeOH / DCM). The product obtained in this manner was recrystallized from hot ethyl acetate, followed by a second recrystallization from hot ethanol. The crystals were redissolved in hot ethyl acetate and reconcentrated; this process was repeated three times until all remaining trace amounts 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 The calculated mass of F3N4O is 348.1; the measured m / z value is 349.2 [M+H]. + . 1 H NMR (500MHz, DMSO-) d 6) 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).

[0327] Example 7: 2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]- N , N -dimethyl-ethyl amide .

[0328] 2-(6-bromopyrazolo[4,3-b]pyridin-1-yl)- N , N Dimethylacetamide (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]palladium(II) dichloride (196 mg, 0.268 mmol) in a capped vial rinsed with argon in water (1.72 mL) and acetonitrile (11.2 mL) were stirred at 120 °C under microwave irradiation 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 thus obtained from FCC was then recrystallized from ethanol (20 mL) to give the title compound (380 mg, 1.22 mmol, 59%) as a grayish-white crystalline solid. MS (ESI): C 17 H 17 The calculated mass of FN4O is 312.1; the measured m / z value is 313.2 [M+H]. + . 1 H NMR (300MHz, DMSO- d 6) 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).

[0329] Example 8: N , N -Dimethyl-2-[6-[6-(trifluoromethyl)-2-pyridyl]pyrazolo[4,3-b]pyridine-1- Acetamide .

[0330] To 2-(6-bromopyrazolo[4,3- b ]pyridin-1-yl)- N , NTo a degassed 1,4-dioxane (550 µL) solution of dimethylacetamide (intermediate 10, 50 mg, 0.177 mmol), 2-(tributyltinyl)-6-(trifluoromethyl)pyridine (85 mg, 0.195 mmol) and bis(triphenylphosphine)palladium(II) chloride (13.0 mg, 0.0185 mmol) were added. The reaction mixture was stirred at 100 °C for 17 h. The reaction mixture was evaporated. Purification (FCC, SiO2, 10% to 100% hexane / EtOAc) gave the title compound (35 mg, 0.100 mmol, 56%) as a white powder after grinding with diethyl ether (4 mL). MS (ESI): C 16 H 14 The calculated mass of F3N5O is 349.1; the measured m / z value is 350.2 [M+H]. + . 1 H NMR (300MHz, DMSO- d 6) 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), 8.28(t, J = 7.9Hz, 1H), 7.96 (d, J = 7.7Hz, 1H), 5.59 (s, 2H), 3.15 (s, 3H), 2.86 (s, 3H).

[0331] Example 9: 2-[6-(4-chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoro (Zyrocyclobutane-1-yl)ethyl ketone .

[0332] To 2-(6-bromopyrazolo[4,3- bA solution of pyridin-1-yl)-1-(3-fluorozacricyclobutan-1-yl)acetone (intermediate 12, 400 mg, 1.28 mmol) in degassed 1,4-dioxane (24.7 mL) and water (7.38 mL) was supplemented with 2-[4-chloro-3-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (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 at 80 °C for 2 hours under argon atmosphere. Add 2-[4-chloro-3-(difluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxane (117 mg, 0.384 mmol), potassium fluoride (223 mg, 3.84 mmol), and tetra(triphenylphosphine)palladium(0) (104 mg, 0.090 mmol), and stir the reaction mixture at 80 °C for 15 hours. Dilute the mixture with water (32 mL) and DCM (50 mL), and separate the layers. Extract the aqueous layer with DCM (2 × 40 mL), and dry the combined organic matter to Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by gradient silica column chromatography, eluting with n-heptane:ethyl acetate:methanol (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%) as a white powder. MS (ESI): C 18 H 14 The calculated mass of ClF3N4O2 is 410.1; the measured m / z value is 411.1 [M+H]. + . 1 H NMR (300MHz, DMSO- d 6) 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).

[0333] Example 10: 2-[6-[4-chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]- N , N -two Methylacetamide .

[0334] Under argon atmosphere, 2-(6-bromopyrazolo[4,3-) b ]pyridin-1-yl)- N , N A mixture of dimethylacetamide (intermediate 10, 46 mg, 0.162 mmol), 2-[4-chloro-3-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxane (59 mg, 0.194 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (12 mg, 0.0164 mmol), and K₂CO₃ (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% to 5% EtOAc / EtOH) gave the title compound (32 mg, 0.084 mmol, 52%) as a grayish-white powder. MS (ESI): C 17 H 15 The calculated mass of ClF₂N₄O₂ is 380.1; the measured m / z value is 381.1 [M+H]. + . 1 H NMR (300MHz, DMSO- d 6) 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).

[0335] Example 11: N , N -Dimethyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethyl amide .

[0336] 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)- N , NA mixture of 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 PdCl2 (dppf) (18 mg, 0.07 mmol) was suspended in dioxane / water (1:1). The resulting reaction mixture was heated to 90 °C and stirred for 3 hours, then cooled to room temperature, diluted with water, and extracted with ethyl acetate (3 times). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. Purification (Method A) yielded the title compound (95 mg, 77%). MS (ESI): C 17 H 15 The calculated mass of F3N4O is 348.1; the measured m / z value is 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).

[0337] Example 12: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-morpholine methyl ethyl ketone .

[0338] Cs₂CO₃ (114.7 mg, 0.352 mmol) was added to 6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine (intermediate 16, 31.2 mg, 0.117 mmol) stirred in DMF (1 mL) at room temperature, followed by the addition of 4-(2-chloroacetyl)morpholine (34.1 mg, 0.208 mmol). The reaction mixture was stirred overnight at room temperature, then filtered through a 0.45 µM syringe filter and purified by preparative HPLC (Method D). Repurification (FCC, SiO₂, DCM solution of 0% to 5% MeOH) yielded the title compound. MS (ESI): C 19 H17 The calculated mass of F3N4O2 is 390.1; the measured m / z value is 391.0 [M+H]. + . 1 H NMR (400MHz, CDCl3) δ 8.79 (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).

[0339] Example 13: 1-morpholino-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetone .

[0340] At room temperature, DIPEA (0.11 mL, 0.6 mmol) was added 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). After 16 hours, EtOAc was added, and the mixture was washed twice with brine. The residue was purified (FCC, SiO2, DCM solution of 0%–10% MeOH) to give a yellow solid. Purification was performed according to method F (stationary phase: C18 XBridge 30×100mm 5µm), with a mobile phase gradient of 60% 0.1% NH4CO3H / NH4OH pH 9 aqueous solution (40% CH3CN) to 43% 0.1% NH4CO3H / NH4OH pH 9 aqueous solution (57% CH3CN), yielding the title compound (55 mg, 45%). MS (ESI): C 19 H 17 The calculated mass of F3N4O2 is 390.1; the measured m / z value is 391.1 [M+H] + . 1 HNMR (400MHz, CDCl3) δ 8.84 (d, J =1.85Hz, 1 H), 8.32 (d, J=0.92Hz, 1 H), 7.98(dd, J =1.85, 1.16Hz, 1 H), 7.89 (s, 1 H), 7.84 (d, J =7.63Hz, 1 H), 7.73 – 7.68 (m, 1 H), 7.67 – 7.60 (m, 1 H), 5.31 (s, 2 H), 3.74 – 3.58 (m, 8 H).

[0341] Example 14: N -Cyclopropyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl amine .

[0342] 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 this point, 2-bromo- N - Cyclopropylacetamide (intermediate 59, 230 mg, 1.29 mmol). 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 organic matter was dried (MgSO4) and concentrated. Purification (FCC, SiO2, 0% to 90% EtOAc / hexane) gave 44.2 mg (0.123 mmol, 19% yield) of the title compound. MS (ESI): C 18 H 15 The calculated mass of F3N4O is 360.1; the measured m / z value is 361.1 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0343] Example 15: N -(1-Methylazacyclobutane-3-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-] b]Pyridin-1-yl]acetamide ; 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-methylazacyclobutane-3-amine (25.4 mg, 0.3 mmol), HATU (102.6 mg, 0.3 mmol), and DIPEA (0.13 mL, 0.7 mmol) in DMF (1.5 mL) was stirred at room temperature. After completion, the reaction mixture was purified by reversed-phase HPLC (Method C) to give the desired product with trace impurities. The material was loaded onto a trap 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 MeOH solution of approximately 5% NH3 to give the title compound (28.3 mg, 0.07 mmol, 29.6%). MS (ESI): C 19 H 18 The calculated mass of F3N5O is 389.2; the measured m / z value is 390.2 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) δδ8.94 (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).

[0344] Example 16: 1-(3-fluorozacricyclobutane-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b] [Pyridin-1-yl]acetone trifluoroacetate .

[0345] 2-(6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetic acid (intermediate 39, 78.8 mg, 0.2 mmol), 3-fluorozacriane hydrochloride (32.8 mg, 0.3 mmol), and T3P were added. ®A mixture of (50% DMF solution, 0.44 mL, 0.7 mmol) and DIPEA (0.13 mL, 0.7 mmol) in DMF (2.0 mL) was stirred at room temperature. After completion, the reaction mixture was purified by reversed-phase HPLC (Method C) to give the title compound (29.4 mg, 0.06 mmol, 24.3%). MS (ESI): C 18 H 14 The calculated mass of F4N4O is 378.1; the measured m / z value is 379.2 [M+H]. + . 1 H NMR (400MHz, DMSO- d 6)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).

[0346] Example 17: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-(2,4-difluorophenyl)pyrazolo[4,3-b] [pyridin-1-yl] acetone .

[0347] A mixture of 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3,3-difluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 42, 116 mg, 0.4 mmol), (2,4-difluorophenyl)boronic acid (111 mg, 0.7 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (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 hours, the reaction mixture was concentrated under vacuum. The crude product was purified (FCC, SiO2, 0%–90% EtOAc in hexane solution) to give the title compound (29.7 mg, 0.08 mmol, 23.1%). MS (ESI): C 17 H 12 The calculated mass of F4N4O is 364.1; the measured m / z value is 365.1 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6)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).

[0348] Example 18: 1-(azacyclobutane-1-yl)-2-[6-(5-chloro-2-thienyl)-3-fluoro-pyrazolo[4,3-b] [pyridin-1-yl] acetone .

[0349] The title compound was prepared in a manner similar to Example 9, using 1-(azacyclobutan-1-yl)-2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl-1-one (intermediate 14) instead of intermediate 12 and using 5-chlorothiophene-2-boronic acid instead of 2-[4-chloro-3-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane. MS (ESI): C 15 H 12 The calculated mass of ClFN4OS is 350.1; the measured m / z value is 351.1 [M+H]. + . 1 H NMR (300MHz, DMSO-) d 6) 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 = 4.0Hz, 1H), 5.12 (s, 2H), 4.31 – 4.15 (m, 2H), 4.00 –3.79 (m, 2H), 2.38 – 2.18 (m, 2H).

[0350] Example 19: 1-(azacyclobutane-1-yl)-2-[6-[5-(difluoromethyl)-2-thienyl]-3-fluoro-pyrazol [4,3-b]pyridin-1-yl]acetone .

[0351] The title compound was prepared in a manner similar to that of Example 9, using 1-(azacyclobutan-1-yl)-2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl-1-one (intermediate 14) instead of intermediate 12 and using 2-(5-(difluoromethyl)thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (intermediate 8) instead of 2-[4-chloro-3-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane. MS (ESI): C 16 H 13 The calculated mass of F3N4OS is 366.1; the measured m / z value is 367.1 [M+H]. + . 1 H NMR (300MHz, DMSO- d 6) 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).

[0352] Example 20: 1-(azacyclobutane-1-yl)-2-[3-fluoro-6-[5-(trifluoromethyl)-2-thienyl]pyrazol [4,3-b]pyridin-1-yl]acetone .

[0353] The title compound was prepared in a manner similar to Example 9, using 1-(azacyclobutan-1-yl)-2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl) ethyl-1-one (intermediate 14) instead of intermediate 12 and using 4,4,5,5-tetramethyl-2-(5-(trifluoromethyl)thiophen-2-yl)-1,3,2-dioxacyclopentaborane instead of 4-fluoro-3-methylboronic acid. MS(ESI): C 16 H 12 The calculated mass of F4N4OS is 384.1; the measured m / z value is 385.1 [M+H]. + . 1 H NMR (500MHz, DMSO-) d 6) δ 9.01 (d, J= 2.0Hz, 1H), 8.56 – 8.52 (m, 1H), 7.90 – 7.85 (m, 2H), 5.15 (s, 2H), 4.27 – 4.21 (m, 2H), 3.94 – 3.88(m, 2H), 2.33 – 2.25 (m, 2H).

[0354] Example 21: 1-(azacyclobutane-1-yl)-2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethyl ketone .

[0355] In a manner similar to Example 13, 2-(6-(4-fluorophenyl)-1H-pyrazolo[4,3] -b The title compound was prepared by replacing intermediate 16 with pyridin-1-yl)acetic acid (intermediate 31) and using aziridine instead of 3-(trifluoromethyl)aziridine-3-ol. MS (ESI): C 17 H 15 The calculated mass of FN4O is 310.1; the measured m / z value is 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).

[0356] Example 22: 1-(azacyclobutane-1-yl)-2-[6-(3-chlorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethyl ketone .

[0357] The title compound was prepared in a manner similar to that of Example 17, using 1-(azacyclobutan-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl-1-one (intermediate 13) instead of intermediate 42, using (3-chlorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and using [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. The reaction mixture was heated to 90°C. MS (ESI): C 17 H 15The calculated mass of ClN4O is 326.1; the measured m / z value is 327.2 [M+H]. + . 1 H NMR (500MHz, DMSO-) d 6) 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 – 7.56 (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).

[0358] Example 23: 1-(azacyclobutane-1-yl)-2-[6-[3-(fluoromethyl)phenyl]pyrazolo[4,3-b]pyridine- 1-yl]ethyl ketone .

[0359] The title compound was prepared in a manner similar to Example 16, using aziridine instead of 3-fluoroaziridine 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 The calculated mass of FN4O is 324.1; the measured m / z value is 325.2 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0360] Example 24: 1-(azacyclobutane-1-yl)-2-[6-[3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyrazol [Pyridin-1-yl]acetone .

[0361] The title compound was prepared in a manner similar to that of Example 17, using 1-(azacyclobutan-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl-1-one (intermediate 13) instead of intermediate 42, using (3-(difluoromethyl)phenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and using [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. The reaction mixture was heated to 90°C. MS (ESI): C 18 H 16 The calculated mass of F₂N₄O is 342.1; the measured m / z value is 343.1 [M+H]. + . 1 H NMR (600MHz, DMSO-) d 6) 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).

[0362] Example 25: 1-(azacyclobutane-1-yl)-2-[6-[3-(1,1-difluoroethyl)phenyl]pyrazolo[4,3-b] [pyridin-1-yl] acetone .

[0363] Similar to Example 6 and Method A, 6-[3-(1,1-difluoroethyl)phenyl]pyrazolo[4,3-b]pyridine (intermediate 20) was used instead of intermediate 16 and 1-(azacyclobutane-1-yl)-2-chloroethyl-1-one was used instead of 2-chloro- N , N The title compound was prepared using dimethylacetamide. MS (ESI): C 19 H 18 The calculated mass of F₂N₄O is 356.1; the measured m / z value is 357.2 [M+H]. + .1 H NMR (300MHz, DMSO- d 6) 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).

[0364] Example 26: 1-(azacyclobutane-1-yl)-2-[6-[3-(1,1-difluoroethyl)phenyl]-3-fluoro-pyrazol [4,3-b]pyridin-1-yl]acetone .

[0365] The title compound was prepared in a manner similar to Example 5 and Method A, using 6-(3-(1,1-difluoroethyl)phenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine (intermediate 24) instead of intermediate 16 and 1-(azacyclobutan-1-yl)-2-chloroethyl-1-one instead of intermediate 1. MS (ESI): C 19 H 17 The calculated mass of F3N4O is 374.1; the measured m / z value is 375.1 [M+H]. + . 1 H NMR (300MHz, DMSO- d 6) 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).

[0366] Example 27: 1-(azacyclobutane-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyrazol [Pyridin-1-yl]acetone .

[0367] The title compound was prepared in a manner similar to that of Example 16, using aziridine instead of 3-fluoroaziridine hydrochloride and DCM instead of DMF. MS (ESI): C18 H 15 The calculated mass of F3N4O is 360.1; the measured m / z value is 361.2 [M+H]. + . 1 H NMR (400MHz, DMSO- d 6) 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).

[0368] Example 28: 1-(azacyclobutane-1-yl)-2-[3-methyl-6-[3-(trifluoromethyl)phenyl]pyrazolo[4, 3-b]pyridin-1-yl]acetone .

[0369] The title compound was prepared in a manner similar to that of Example 17, using 1-(azacyclobutan-1-yl)-2-(6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl-1-one (intermediate 48) instead of intermediate 42, using (3-(trifluoromethyl)phenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and using [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (II). The reaction mixture was heated to 90°C. MS (ESI): C 19 H 17 The calculated mass of F3N4O is 374.1; the measured m / z value is 375.2 [M+H]. + . 1 HNMR (500MHz, DMSO- d 6) 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), 5.17 (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).

[0370] Example 29: 1-(azacyclobutane-1-yl)-2-[6-(3,4-dichlorophenyl)pyrazolo[4,3-b]pyridine-1- [Base] Ethyl ketone .

[0371] The title compound was prepared in a manner similar to that of Example 17, using 1-(azacyclobutan-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl-1-one (intermediate 13) instead of intermediate 42, using (3,4-dichlorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and using [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (II). The reaction mixture was heated to 90°C. MS (ESI): C 17 H 14 The calculated mass of Cl2N4O is 360.1; the measured m / z value is 361.1 [M+H] + . 1 H NMR (500MHz, DMSO-) d 6) 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).

[0372] Example 30: 1-(azacyclobutane-1-yl)-2-[6-(2,3-dichlorophenyl)pyrazolo[4,3-b]pyridine-1- [Base] Ethyl ketone .

[0373] The title compound was prepared in a manner similar to that of Example 17, using 1-(azacyclobutan-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl-1-one (intermediate 13) instead of intermediate 42, using (2,3-dichlorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and using [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (II). The reaction mixture was heated to 90°C. MS (ESI): C 17 H 14 The calculated mass of Cl2N4O is 360.1; the measured m / z value is 361.1 [M+H] + . 1 H NMR (500MHz, DMSO-) d 6) 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).

[0374] Example 31: 1-(azacyclobutane-1-yl)-2-[6-(3-chloro-2-fluoro-phenyl)pyrazolo[4,3-b]pyridine- 1-yl]ethyl ketone .

[0375] The title compound was prepared in a manner similar to that of Example 17, using 1-(azacyclobutan-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl-1-one (intermediate 13) instead of intermediate 42, using (3-chloro-2-fluorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and using [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (II). The reaction mixture was heated to 90°C. MS (ESI): C 17 H 14 The calculated mass of ClFN4O is 344.1; the measured m / z value is 345.1 [M+H] + . 1 H NMR (500MHz, DMSO-) d 6) 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).

[0376] Example 32: 1-(azacyclobutane-1-yl)-2-[6-(3,4-difluorophenyl)pyrazolo[4,3-b]pyridine-1- [Base] Ethyl ketone .

[0377] The title compound was prepared in a manner similar to that of Example 17, using 1-(azacyclobutan-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl-1-one (intermediate 13) instead of intermediate 42, using (3,4-difluorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and using [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. The reaction mixture was heated to 90°C. MS (ESI): C 17 H 14 The calculated mass of F₂N₄O is 328.1; the measured m / z value is 329.1 [M+H]. + . 1 H NMR (600MHz, DMSO-) d 6) 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 – 7.68 (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).

[0378] Example 33: 1-(azacyclobutane-1-yl)-2-[6-[2-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3- b]pyridin-1-yl]acetone .

[0379] The title compound was prepared in a manner similar to that of Example 17, using 1-(azacyclobutan-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl-1-one (intermediate 13) instead of intermediate 42, using (2-fluoro-3-(trifluoromethyl)phenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and using [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (II). The reaction mixture was heated to 90°C. MS (ESI): C 18 H 14 The calculated mass of F4N4O is 378.1; the measured m / z value is 379.1 [M+H]. + . 1 HNMR (500MHz, DMSO- d 6) 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).

[0380] Example 34: 1-(azacyclobutane-1-yl)-2-[6-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]pyrazol [4,3-b]pyridin-1-yl]acetone .

[0381] Similar to Example 6 and Method A, 6-(3-(1,1-difluoroethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine (intermediate 19) was used instead of intermediate 16 and 1-(azacyclobutan-1-yl)-2-chloroethyl-1-one was used instead of 2-chloro- N , N The title compound was prepared using dimethylacetamide. MS (ESI): C 19 H 17 The calculated mass of F3N4O is 374.1; the measured m / z value is 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 (dd, 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).

[0382] Example 35: 1-(azacyclobutane-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3- b]pyridin-1-yl]acetone .

[0383] The title compound was prepared in a manner similar to Example 5, Method A, using 1-(azacyclobutan-1-yl)-2-chloroethyl-1-one instead of 2-chloro-1-(3-fluoroazacyclobutan-1-yl)ethylone. MS (ESI): C 18 H 15 The calculated mass of F3N4O is 360.1; the measured m / z value is 361.2 [M+H]. + . 1 H NMR (300MHz, DMSO- d 6) 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).

[0384] Example 36: 1-(azacyclobutane-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazole [4,3-b]pyridin-1-yl]acetone .

[0385] Similar to Example 6 and Method A, 6-[3-(difluoromethyl)-4-fluorophenyl]-3-fluoro-pyrazolo[4,3-b]pyridine (intermediate 21) was used instead of intermediate 16 and 1-(azacyclobutan-1-yl)-2-chloroethyl-1-one was used instead of 2-chloro- N , N The title compound was prepared using dimethylacetamide. MS (ESI): C 18 H 14 The calculated mass of F4N4O is 378.1; the measured m / z value is 379.1 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0386] Example 37: 1-(azacyclobutane-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-methyl-pyridine Azo[4,3] -b ]pyridin-1-yl] acetone .

[0387] Similar to Example 1, 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3] -b The title compound was prepared by replacing intermediate 27 with pyridin-1-yl)acetic acid (intermediate 32) and using aziridine instead of 3-(trifluoromethyl)aziridine-3-ol. MS (ESI): C 19 H 17 The calculated mass of F3N4O is 374.1; the measured m / z value is 375.1 [M+H]. + . 1 H 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).

[0388] Example 38: 1-(azacyclobutane-1-yl)-2-[6-(4-chloro-3-methylphenyl)pyrazolo[4,3-b]pyridine- 1-yl]ethyl ketone .

[0389] The title compound was prepared in a manner similar to that of Example 17, using 1-(azacyclobutan-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl-1-one (intermediate 13) instead of intermediate 42, using (4-chloro-3-methylphenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and using [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. The reaction mixture was heated to 90°C. MS (ESI): C 18 H 17 The calculated mass of ClN4O is 340.1; the measured m / z value is 341.2 [M+H]. + . 1 H NMR (500MHz, DMSO-) d 6) 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).

[0390] Example 39: 1-(azacyclobutane-1-yl)-2-[6-(4-chloro-3-methylphenyl)-3-methylpyrazolo[4, 3-b]pyridin-1-yl]acetone .

[0391] The title compound was prepared in a manner similar to that of Example 17, using 1-(azacyclobutan-1-yl)-2-(6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl-1-one (intermediate 48) instead of intermediate 42, using (4-chloro-3-methylphenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and using [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (II). The reaction mixture was heated to 90°C. MS (ESI): C 19 H 19 The calculated mass of ClN4O is 354.1; the measured m / z value is 355.2 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0392] Example 40: 1-(azacyclobutane-1-yl)-2-[6-(2-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyrazolium [Pyridin-1-yl]acetone .

[0393] The title compound was prepared in a manner similar to that of Example 17, using 1-(azacyclobutan-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl-1-one (intermediate 13) instead of intermediate 42, using (2-fluoro-3-methylphenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and using [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. The reaction mixture was heated to 90°C. MS (ESI): C 18 H 17 The calculated mass of FN4O is 324.1; the measured m / z value is 325.2 [M+H]. + . 1H NMR (500MHz, DMSO-) d 6) 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).

[0394] Example 41: 1-(azacyclobutane-1-yl)-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4, 3-b]pyridin-1-yl]acetone .

[0395] Similar to Example 6 and Method A, 6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine (intermediate 17) was used instead of intermediate 16 and 1-(azacyclobutan-1-yl)-2-chloroethyl-1-one was used instead of 2-chloro- N , N The title compound was prepared using dimethylacetamide. MS (ESI): C 18 H 15 The calculated mass of F3N4O2 is 376.1; the measured m / z value is 377.1 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0396] Example 42: 1-(azacyclobutane-1-yl)-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]-3-fluoro-pyridine Azo[4,3-b]pyridin-1-yl]acetone .

[0397] The title compound was prepared in a manner similar to Example 5 and Method A, using 6-(3-(difluoromethoxy)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine (intermediate 23) instead of intermediate 16 and using 1-(azacyclobutan-1-yl)-2-chloroethyl-1-one instead of intermediate 1. MS (ESI): C 18 H 14 The calculated mass of F4N4O2 is 394.1; the measured m / z value is 395.1 [M+H] + . 1 H NMR (500MHz, DMSO- d 6) 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, 8.6 Hz, 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).

[0398] Example 43: 1-(azacyclobutane-1-yl)-2-[6-[4-chloro-3-(difluoromethoxy)phenyl)pyrazolo[4, 3-b]pyridin-1-yl]acetone .

[0399] Similar to Example 6 and Method A, 6-[4-chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridine (intermediate 18) was used instead of intermediate 16 and 1-(azacyclobutan-1-yl)-2-chloroethyl-1-one was used instead of 2-chloro- N , N The title compound was prepared using dimethylacetamide. MS (ESI): C 18 H 15 The calculated mass of ClF₂N₄O₂ is 392.1; the measured m / z value is 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, 1.9 Hz, 1H), 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).

[0400] Example 44: 1-(azacyclobutane-1-yl)-2-[6-[4-chloro-3-(difluoromethoxy)phenyl)-3-fluoropyrazole [4,3-b]pyridin-1-yl]acetone .

[0401] The title compound was prepared in a manner similar to Example 5 and Method A, using 6-(4-chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine (intermediate 22) instead of intermediate 16 and 1-(azacyclobutan-1-yl)-2-chloroethyl-1-one instead of intermediate 1. MS (ESI): C 18 H 14 The calculated mass of ClF3N4O2 is 410.1; the measured m / z value is 411.1 [M+H]. + . 1 H NMR (300MHz, DMSO- d 6) 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).

[0402] Example 45: 1-(azacyclobutane-1-yl)-2-[6-(4-fluoro-2-methoxy-phenyl)pyrazolo[4,3-b]pyrazolium [Pyridin-1-yl]acetone .

[0403] The title compound was prepared in a manner similar to Example 17, using 1-(azacyclobutan-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl-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 The calculated mass of FN4O2 is 340.1; the measured m / z value is 341.2 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0404] Example 46: 2-[6-(3-acetyl-4-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(azacyclobutane) Alkyl ethyl ketone .

[0405] The title compound was prepared in a manner similar to that of Example 17, using 1-(azacyclobutan-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl-1-one (intermediate 13) instead of intermediate 42, using (3-acetyl-4-fluorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and using [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (II). The reaction mixture was heated to 90°C. MS (ESI): C 19 H 17 The calculated mass of FN4O2 is 352.1; the measured m / z value is 353.1 [M+H] + . 1H NMR (500MHz, DMSO-) d 6) 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).

[0406] Example 47: 1-(azacyclobutane-1-yl)-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine- 1-yl]ethyl ketone .

[0407] The title compound was prepared in a manner similar to that of Example 17, using 1-(azacyclobutan-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethyl-1-one (intermediate 13) instead of intermediate 42, using (3,4,5-trifluorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and using [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (II). The reaction mixture was heated to 90°C. MS (ESI): C 17 H 13 The calculated mass of F3N4O is 346.1; the measured m / z value is 347.1 [M+H]. + . 1 H NMR (400MHz, DMSO-) d 6) 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).

[0408] Example 48: 1-(azacyclobutane-1-yl)-2-[6-[2-(trifluoromethyl)-4-pyridyl]pyrazolo[4,3- b]pyridin-1-yl]acetone .

[0409] The title compound was prepared in a manner similar to Example 7, using 1-(azacyclobutan-1-yl)-2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl) ethyl-1-one (intermediate 13) instead of intermediate 10 and using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2-(trifluoromethyl)pyridine instead of 4-fluoro-3-methylphenylboronic acid. MS(ESI): C 17 H 14 The calculated mass of F3N5O is 361.1; the measured m / z value is 362.1 [M+H]. + . 1 H NMR (500MHz, DMSO-) d 6) δ 9.08 (d, J = 2.0Hz, 1H), 8.91 (d, J = 5.1Hz, 1H), 8.72 (dd, J = 2.0, 1.0 Hz, 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). Example 49: 2-[6-(5-chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluorozacriane) Alkyl ethyl ketone .

[0410] 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 The calculated mass of ClFN4OS is 350.0; the measured m / z value is 351.1 [M+H]. + . 1 H NMR (300MHz, DMSO- d 6) 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).

[0411] Example 50: 2-[6-(5-chloro-2-thienyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazinoyl) Heterocyclic butane-1-yl)ethyl ketone .

[0412] 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-fluoroazacyclobutan-1-yl)ethyl-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-dioxacyclopentaborane. MS (ESI): C 15 H 11 The calculated mass of ClF2N4OS is 368.0; the measured m / z value is 369.0 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0413] Example 51: 2-[6-[5-(difluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoro (Zyrocyclobutane-1-yl)ethyl ketone .

[0414] 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-dioxacyclopentaborane (intermediate 8) instead of 2-[4-chloro-3-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane. MS(ESI): C 16 H 13 The calculated mass of F3N4OS is 366.1; the measured m / z value is 367.1 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0415] Example 52: 2-[6-[5-(difluoromethyl)-2-thienyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]-1- (3-Fluorozylidene-1-yl)acetone .

[0416] 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-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 15) and 2-(5-(difluoromethyl)thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (intermediate 8) instead of 2-[4-chloro-3-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane. MS (ESI): C 16 H 12 The calculated mass of F4N4OS is 384.1; the measured m / z value is 385.1 [M+H].+ . 1 H NMR (300MHz, DMSO- d 6) 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).

[0417] Example 53: 1-(3-fluorozacriane-1-yl)-2-[6-[5-(trifluoromethyl)-2-thienyl]pyrazol [4,3-b]pyridin-1-yl]acetone .

[0418] 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-fluorozacricyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 10 and using 4,4,5,5-tetramethyl-2-(5-(trifluoromethyl)thiophen-2-yl)-1,3,2-dioxacyclopentaborane instead of 4-fluoro-3-methylboronic acid. MS(ESI): C 16 H 12 The calculated mass of F4N4OS is 384.1; the measured m / z value is 385.1 [M+H]. + . 1 H NMR (500MHz, DMSO-) d 6) 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).

[0419] Example 54: 1-(3-fluoroazacyclobutane-1-yl)-2-[3-fluoro-6-[5-(trifluoromethyl)-2-thienyl]pyridine Azo[4,3-b]pyridin-1-yl]acetone .

[0420] The title compound was prepared in a manner similar to Example 9, using 2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 15) and 4,4,5,5-tetramethyl-2-(5-(trifluoromethyl)thiophen-2-yl)-1,3,2-dioxacyclopentaborane instead of 4-fluoro-3-methylboronic acid. MS (ESI): C 16 H 11 The calculated mass of F5N4OS is 402.1; the measured m / z value is 403.0 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6)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 = 17.1Hz, 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).

[0421] Example 55: 1-(3-fluorozacricyclobutane-1-yl)-2-[6-(3-fluorophenyl)pyrazolo[4,3-b]pyridine-1- [Base] Ethyl ketone .

[0422] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 10 and using 3-fluorophenylboronic acid instead of 4-fluoro-3-methylboronic acid. MS (ESI): C 17 H 14 The calculated mass of F₂N₄O is 328.1; the measured m / z value is 329.1 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0423] Example 56: 1-(3-fluorozacriane-1-yl)-2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridine-1- [Base] Ethyl ketone .

[0424] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 10 and using 4-fluorophenylboronic acid instead of 4-fluoro-3-methylboronic acid. MS (ESI): C 17 H 14 The calculated mass of F₂N₄O is 328.1; the measured m / z value is 329.2 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0425] Example 57: 2-[6-(3-chlorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluorozahexacyclobutane-1-yl] ethyl ketone .

[0426] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 10 and using 3-chlorophenylboronic acid instead of 4-fluoro-3-methylphenylboronic acid. MS (ESI): C 17 H 14 The calculated mass of ClFN4O is 344.1; the measured m / z value is 345.1 [M+H] + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0427] Example 58: 1-(3-fluorozacriane-1-yl)-2-[6-(m-tolyl)pyrazolo[4,3-b]pyridine-1- [Base] Ethyl ketone .

[0428] The title compound was prepared in a manner similar to Example 17, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluorozacricyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 42, using m-tolylboronic acid instead of 2,4-difluorophenylboronic acid, and using [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. MS (ESI): C 18 H 17 The calculated mass of FN4O is 324.1; the measured m / z value is 325.2 [M+H]. + .1 H NMR (500MHz, DMSO- d 6) 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).

[0429] Example 59: 1-(3-fluorozacriane-1-yl)-2-[6-[3-(fluoromethyl)phenyl]pyrazolo[4,3-b]pyrazol [Pyridin-1-yl]acetone .

[0430] The title compound was prepared in a manner similar to that of 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 using DCM instead of DMF. MS(ESI): C 18 H 16 The calculated mass of F₂N₄O is 342.1; the measured m / z value is 343.2 [M+H]. + . 1 H NMR (500MHz, DMSO-) d 6) 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).

[0431] Example 60: 2-[6-[3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazaheterocyclic) (butan-1-yl) ethyl ketone .

[0432] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluorozacricyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 10 and using 2-(3-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane instead of 4-fluoro-3-methylboronic acid. MS(ESI): C 18 H 15 The calculated mass of F3N4O is 360.1; the measured m / z value is 361.1 [M+H]. + . 1 H NMR (300MHz, DMSO-) d 6) 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).

[0433] Example 61: 2-[6-[3-(1,1-difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazines) Heterocyclic butane-1-yl)ethyl ketone .

[0434] Similar to Example 6, Method A, 3-(1,1-difluoroethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine (intermediate 20) was used instead of intermediate 16 and 2-chloro-1-(3-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 1) was used instead of 2-chloro- N , N The title compound was prepared using dimethylacetamide. MS (ESI): C 19 H 17 The calculated mass of F3N4O is 374.1; the measured m / z value is 375.1 [M+H]. + . 1 H NMR (300MHz, DMSO- d 6) 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).

[0435] Example 62: 2-[6-[3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazino-1-yl) Cyclobutan-1-yl)ethyl ketone .

[0436] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluorozacricyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 10 and using 2-(3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane instead of 4-fluoro-3-methylphenylboronic acid. MS(ESI): C 18 H 15 The calculated mass of F3N4O2 is 376.1; the measured m / z value is 377.1 [M+H]. + . 1 H NMR (500MHz, DMSO-) d 6) 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 – 7.25(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).

[0437] Example 63: 2-[6-(2,3-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazacyclobutane) Alkyl ethyl ketone .

[0438] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazacyclobutan-1-yl)ethyl-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 The calculated mass of F3N4O is 346.1; the measured m / z value is 347.1 [M+H]. + . 1 H NMR (300MHz, DMSO- d 6) 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).

[0439] Example 64: 2-[6-(2,4-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazacyclobutane) Alkyl ethyl ketone .

[0440] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 10 and using 2,4-difluorophenylboronic acid instead of 4-fluoro-3-methylboronic acid. MS (ESI): C 17 H 13 The calculated mass of F3N4O is 346.1; the measured m / z value is 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).

[0441] Example 65: 2-[6-(3,4-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazacyclobutane) Alkyl ethyl ketone .

[0442] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 10 and using 3,4-difluorophenylboronic acid instead of 4-fluoro-3-methylboronic acid. MS (ESI): C 17 H 13 The calculated mass of F3N4O is 346.1; the measured m / z value is 347.1 [M+H]. + . 1 H NMR (300MHz, DMSO- d 6) 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).

[0443] Example 66: 2-[6-(3,5-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazacyclobutane) Alkyl ethyl ketone .

[0444] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 10 and using 3,5-difluorophenylboronic acid instead of 4-fluoro-3-methylboronic acid. MS (ESI): C 17 H 13 The calculated mass of F3N4O is 346.1; the measured m / z value is 347.1 [M+H]. + . 1 H NMR (300MHz, DMSO- d 6) 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).

[0445] Example 67: 2-[6-(3-chloro-2-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluorozacriane) Alkyl ethyl ketone .

[0446] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 10 and using 3-chloro-2-fluorophenylboronic acid instead of 4-fluoro-3-methylboronic acid. MS (ESI): C 17 H 13 The calculated mass of ClF₂N₄O is 362.1; the measured m / z value is 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).

[0447] Example 68: 2-[6-(3-chloro-4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazacyclobutane) Alkyl ethyl ketone .

[0448] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 10 and using 3-chloro-4-fluorophenylboronic acid instead of 4-fluoro-3-methylboronic acid. MS (ESI): C 17 H 13 The calculated mass of ClF₂N₄O is 362.1; the measured m / z value is 363.1 [M+H]. + . 1 H NMR (300MHz, DMSO- d 6) 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).

[0449] Example 69: 1-(3-chloroazacyclobutane-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazol [4,3 -b ]pyridin-1-yl] acetone .

[0450] The title compound was prepared in a manner similar to Example 1, using 3-azacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 18 H 14 The calculated mass of ClF3N4O is 394.1; the measured m / z value is 395.1 [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), 7.93 – 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).

[0451] Example 70: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]- 1-(3-Fluorozyne-1-yl)ethyl ketone .

[0452] Similar to Example 6 and Method A, 6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridine (intermediate 21) was used instead of intermediate 16 and 2-chloro-1-(3-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 1) was used instead of 2-chloro- N , N The title compound was prepared using dimethylacetamide. MS (ESI): C 18 H 13 The calculated mass of F5N4O is 396.1; the measured m / z value is 397.1 [M+H]. + . 1 H NMR (300MHz, DMSO- d 6) 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 – 5.31 (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).

[0453] Example 71: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-methyl-pyrazolo[4,3] -b ]Pyridine-1- 1-(3-Fluorozylidene-1-yl)ethyl ketone .

[0454] In a manner similar to Example 13, 2-(6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3] -b The title compound was prepared by replacing intermediate 27 with pyridin-1-yl)acetic acid (intermediate 32) and using 3-fluoroazacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 19 H 16 The calculated mass of F4N4O is 392.1; the measured m / z value is 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).

[0455] Example 72: 2-[6-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1- (3-Fluorozylidene-1-yl)acetone .

[0456] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 10 and using 2-(3-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane instead of 4-fluoro-3-methylphenylboronic acid. MS (ESI): C 19 H 16 The calculated mass of F4N4O is 392.1; the measured m / z value is 393.1 [M+H]. + . 1 H NMR (300MHz, DMSO-) d 6) 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).

[0457] Example 73: 2-[6-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridine-1- 1-(3-Fluorozylidene-1-yl)ethyl ketone .

[0458] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 15) instead of intermediate 10 and using 2-(3-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane instead of 4-fluoro-3-methylphenylboronic acid. MS (ESI): C 19 H 15 The calculated mass of F5N4O is 410.1; the measured m / z value is 411.1 [M+H]. + . 1 HNMR (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).

[0459] Example 74: 2-[6-[4-chloro-3-(1,1-difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1- (3-Fluorozylidene-1-yl)acetone .

[0460] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 10 and using 2-(4-chloro-3-(1,1-difluoroethyl))-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane instead of 4-fluoro-3-methylphenylboronic acid. MS (ESI): C 19 H 16 The calculated mass of ClF3N4O is 408.1; the measured m / z value is 409.1 [M+H]. + . 1 H NMR (300MHz, DMSO-) d 6) 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), 5.61 – 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).

[0461] Example 75: 2-[6-[4-chloro-3-(1,1-difluoroethyl)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridine-1- 1-(3-Fluorozylidene-1-yl)ethyl ketone .

[0462] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 15) instead of intermediate 10 and using 2-(4-chloro-3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane instead of 4-fluoro-3-methylphenylboronic acid. MS (ESI): C 19 H 15 The calculated mass of ClF4N4O is 426.1; the measured m / z value is 427.1 [M+H]. + . 1 HNMR (300MHz, DMSO- d 6) 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).

[0463] Example 76: 2-[6-[4-chloro-3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoro) (Zyrocyclobutane-1-yl)ethyl ketone .

[0464] 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-fluorozacricyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 10 and using 2-(4-chloro-3-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane instead of 4-fluoro-3-methylboronic acid. MS(ESI): C 18 H14 The calculated mass of ClF3N4O is 394.1; the measured m / z value is 395.2 [M+H]. + . 1 H NMR (500MHz, DMSO-) d 6) 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),7.31 (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).

[0465] Example 77: 2-[6-(4-chloro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluorozapiroline) (butan-1-yl) ethyl ketone .

[0466] 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-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 42, using (4-chloro-3-methylphenyl)boronic acid instead of 2,4-difluorophenylboronic acid, and using [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. The reaction mixture was heated to 90°C. MS (ESI): C 18 H 16 The calculated mass of ClFN4O is 358.1; the measured m / z value is 359.1 [M+H]. + . 1 HNMR (500MHz, DMSO- d 6) 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).

[0467] Example 78: 1-(3-fluorozacricyclobutane-1-yl)-2-[6-(4-fluoro-2-methoxy-phenyl)pyrazolo[4,3- b]pyridin-1-yl]acetone .

[0468] The title compound was prepared in a manner similar to Example 17, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluorozacricyclobutan-1-yl)ethyl-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 The calculated mass of F₂N₄O₂ is 358.1; the measured m / z value is 359.1 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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 (td, 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).

[0469] Example 79: 2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3- (Fluoro-1-butane-1-yl)ethyl ketone .

[0470] 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 The calculated mass of F4N4O2 is 394.1; the measured m / z value is 395.1 [M+H] + . 1 H NMR (500MHz, DMSO- d 6) δ 8.88 (d, J =1.9Hz, 1H), 8.44 – 8.39 (m, 1H), 8.36 (d, J = 1.1Hz, 1H), 7.83 (dd, J = 7.5,2.3Hz, 1H), 7.78 – 7.71 (m, 1H), 7.60 (dd, J = 10.5, 8.6Hz, 1H), 7.38 (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).

[0471] Example 80: 2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridine-1- 1-(3-Fluorozylidene-1-yl)ethyl ketone .

[0472] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 15) instead of intermediate 10 and using 2-(3-(difluoromethoxy)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane instead of 4-fluoro-3-methylphenylboronic acid. MS (ESI): C 18 H 13 The calculated mass of F5N4O2 is 412.1; the measured m / z value is 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).

[0473] Example 81: 2-[6-[4-chloro-3-(difluoromethoxy)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]- 1-(3-Fluorozyne-1-yl)ethyl ketone .

[0474] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 15) instead of intermediate 10 and using 2-(4-chloro-3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane instead of 4-fluoro-3-methylphenylboronic acid. MS (ESI): C 18 H 13 The calculated mass of ClF4N4O2 is 428.1; the measured m / z value is 429.1 [M+H] + . 1 H NMR (500MHz, DMSO-) d 6) 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 =73.2Hz, 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).

[0475] Example 82: 2-[6-(2,4-difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazines) Heterocyclic butane-1-yl)ethyl ketone .

[0476] 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-fluorozacricyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 10 and using 2-(2,4-difluoro-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane instead of 4-fluoro-3-methylboronic acid. MS(ESI): C 18 H 15 The calculated mass of F3N4O is 360.1; the measured m / z value is 361.1 [M+H]. + . 1 H NMR (300MHz, DMSO-) d 6) 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).

[0477] Example 83: 2-[6-(3,4-difluoro-5-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3-fluoroazino) Heterocyclic butane-1-yl)ethyl ketone .

[0478] 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-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 10 and using 2-(3,4-difluoro-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane instead of 4-fluoro-3-methylboronic acid. MS(ESI): C 18 H 15The calculated mass of F3N4O is 360.1; the measured m / z value is 361.1 [M+H]. + . 1 H NMR (500MHz, DMSO-) d 6) 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).

[0479] Example 84: 1-(3-fluorozacriane-1-yl)-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyrazolium [Pyridin-1-yl]acetone .

[0480] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoroazacyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 10 and using 3,4,5-trifluorophenylboronic acid instead of 4-fluoro-3-methylboronic acid. MS (ESI): C 17 H 12 The calculated mass of F4N4O is 364.1; the measured m / z value is 365.1 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0481] Example 85: 1-(3-fluorozacricyclobutane-1-yl)-2-[6-[2-(trifluoromethyl)-4-pyridyl]pyrazol [4,3-b]pyridin-1-yl]acetone .

[0482] The title compound was prepared in a manner similar to Example 7, using 2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluorozacricyclobutan-1-yl)ethyl-1-one (intermediate 12) instead of intermediate 10 and using 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2-(trifluoromethyl)pyridine instead of 4-fluoro-3-methylphenylboronic acid. MS (ESI): C 17 H 13 The calculated mass of F4N5O is 379.1; the measured m / z value is 380.1 [M+H]. + . 1 H NMR (500MHz, DMSO-) d 6) 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).

[0483] Example 86: 1-(3-methylazacyclobutane-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-] b]pyridin-1-yl]acetone trifluoroacetate .

[0484] The title compound was prepared in a manner similar to that of Example 16, using 3-methylazacyclobutane instead of 3-fluoroazacyclobutane hydrochloride and DCM instead of DMF. MS (ESI): C 19 H 17 The calculated mass of F3N4O is 374.1; the measured m / z value is 375.2 [M+H]. + . 1 H 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).

[0485] Example 87: (racemic) 1-(2-methylazacyclobutane-1-yl)-2-[6-[3-(trifluoromethyl)phenyl] Pyrazolo[4,3-b]pyridin-1-yl]acetone .

[0486] The title compound was prepared in a manner similar to that of Example 15, using 2-methylazacyclobutane hydrochloride instead of 1-methylazacyclobutane-3-amine and DCM instead of DMF. MS (ESI): C 19 H 17 The calculated mass of F3N4O is 374.1; the measured m / z value is 375.2 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0487] Example 88: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-methyl) (1-yl)-(azonylbutane-1-yl)ethyl ketone .

[0488] The title compound was prepared in a manner similar to Example 5 and Method A, using 2-chloro-1-(3-methylazacyclobutan-1-yl)ethyl-1-one (intermediate 6) instead of 2-chloro-1-(3-fluoroazacyclobutan-1-yl)ethylone. MS (ESI): C19 H 17 The calculated mass of F3N4O is 374.1; the measured m / z value is 375.1 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6)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).

[0489] Example 89: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]- 1-(3-Methylazacyclobutan-1-yl)ethyl ketone .

[0490] The title compound was prepared in a manner similar to Example 6 and 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-methylazacyclobutan-1-yl)ethyl-1-one (intermediate 6) instead of 4-fluoro-3-methylphenylboronic acid. MS (ESI): C 19 H 16 The calculated mass of F4N4O is 392.1; the measured m / z value is 393.1 [M+H]. + . 1 H NMR (300MHz, DMSO- d 6) 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).

[0491] Example 90: (racemic) 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]Pyridine-1- 1-(2-methylazacyclobutan-1-yl)ethyl ketone .

[0492] The title compound was prepared in a manner similar to that of Example 1, using 2-methylazacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 19 H 17 The calculated mass of F3N4O is 374.1; the measured m / z value is 375.1 [M+H]. + . 1 H NMR (400MHz, CDCl3) 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).

[0493] Example 91: 2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3- Methylazon-1-yl)ethyl ketone .

[0494] Similar to Example 6 and Method A, 6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine (intermediate 17) was used instead of intermediate 16 and 2-chloro-1-(3-methylazacyclobutan-1-yl)ethyl-1-one (intermediate 6) was used instead of 2-chloro-N , N The title compound was prepared using dimethylacetamide. MS (ESI): C 19 H 17 The calculated mass of F3N4O2 is 390.1; the measured m / z value is 391.1 [M+H] + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0495] Example 92: 2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridine-1- 1-(3-methylazacyclobutane-1-yl)ethyl ketone .

[0496] The title compound was prepared in a manner similar to Example 5 and Method A, using 6-(3-(difluoromethoxy)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine (intermediate 23) instead of intermediate 16 and using 2-chloro-1-(3-methylazacyclobutan-1-yl)ethyl-1-one (intermediate 6) instead of intermediate 1. MS (ESI): C 19 H 16 The calculated mass of F4N4O2 is 408.1. The measured m / z value is 409.2 [M+H] + . 1 H NMR (300MHz, DMSO- d 6) 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).

[0497] Example 93: 2-[6-[4-chloro-3-(difluoromethoxy)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]- 1-(3-Methylazacyclobutan-1-yl)ethyl ketone .

[0498] The title compound was prepared in a manner similar to Example 5 and Method A, using 6-(4-chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine (intermediate 22) instead of intermediate 16 and using 2-chloro-1-(3-methylazacyclobutan-1-yl)ethyl-1-one (intermediate 6) instead of intermediate 1. MS (ESI): C 19 H 16 The calculated mass of ClF3N4O2 is 424.1; the measured m / z value is 425.1 [M+H] + . 1 H NMR (300MHz, DMSO- d 6) 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).

[0499] Example 94: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-(3-ethyl alkynylazine-1-yl)acetone .

[0500] The title compound was prepared in a manner similar to Example 2, using 3-ethynylazetane (intermediate 33) instead of 3-methyleneazetane. MS (ESI): C 20 H 15 The calculated mass of F3N4O is 384.1; the measured m / z value is 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).

[0501] Example 95: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-(3-ethyl alkenylazine-1-yl)ethyl ketone .

[0502] The title compound was prepared in a manner similar to Example 2, using 3-vinylazacyclobutane instead of 3-methyleneazacyclobutane. MS (ESI): C 20 H 17 The calculated mass of F3N4O is 386.1; the measured m / z value is 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).

[0503] Example 96: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-[3- [( Z [-prop-1-enyl]azacyclobutan-1-yl] ethyl ketone .

[0504] Using a method similar to Example 2, ( Z The title compound was prepared by substituting 3-(prop-1-en-1-yl)azacyclobutane (intermediate 34) for 3-methyleneazacyclobutane. MS (ESI): C 21 H 19 The calculated mass of F3N4O is 400.2; the measured m / z value is 401.1 [M+H]. + . 1 H 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).

[0505] Example 97: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-[3- [(fluoromethyl)azacyclobutane-1-yl]acetone .

[0506] The title compound was prepared in a manner similar to that of Example 1, using 3-fluoromethylazacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 19 H 16 The calculated mass of F4N4O is 392.1; the measured m / z value is 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).

[0507] Example 98: 1-[3-(difluoromethyl)azacyclobutane-1-yl]-2-[6-[3-(difluoromethyl)-4-fluoro-benzene] [4,3]pyrazol[4,3] -b ]pyridin-1-yl] acetone .

[0508] The title compound was prepared in a manner similar to Example 1, using 3-(difluoromethyl)azacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 19 H 15 The calculated mass of F5N4O is 410.1; the measured m / z value is 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).

[0509] Example 99: 1-[3-(trifluoromethyl)azacyclobutane-1-yl]-2-[6-[3-(trifluoromethyl)phenyl]pyrazole [4,3-b]pyridin-1-yl]acetone trifluoroacetate .

[0510] The title compound was prepared in a manner similar to that of Example 16, using 3-(trifluoromethyl)azacyclobutane hydrochloride instead of 3-fluoroazacyclobutane hydrochloride. MS (ESI): C 19 H 14 The calculated mass of F6N4O is 428.1; the measured m / z value is 429.2 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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, 5.4 Hz, 1H).

[0511] Example 100: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-[3- [(trifluoromethyl)azacyclobutane-1-yl]acetone .

[0512] The title compound was prepared in a manner similar to that of Example 1, using 3-trifluoromethylazacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 19 H 14 The calculated mass of F6N4O is 428.1; the measured m / z value is 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).

[0513] Example 101: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-[3- [(Z)-2-Fluorovinyl]azacyclobutane-1-yl]acetone .

[0514] Using a method similar to Example 2, ( Z The title compound was prepared by substituting 3-methyleneazetane (intermediate 36) for 3-fluorovinyl)azacyclobutane. MS (ESI): C 20 H 16 The calculated mass of F4N4O is 404.1; the measured m / z value is 405.1 [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 – 7.82 (m, 1H), 7.78 – 7.70(m, 1H), 7.32 – 7.24(m, 1H), 6.97 (t, J = 54.8Hz, 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).

[0515] Example 102: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-[3- (2,2-Difluorovinyl)azacyclobutane-1-yl]acetone .

[0516] The title compound was prepared in a manner similar to Example 2, using 3-(2,2-difluorovinyl)azacyclobutane (intermediate 35) instead of 3-methyleneazacyclobutane. MS (ESI): C 20 H 15 The calculated mass of F5N4O is 422.1; the measured m / z value is 423.1 [M+H]. + . 1 H 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).

[0517] Example 103: 1-(3-methoxyazacyclobutane-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazol [4,3-b]pyridin-1-yl]acetone .

[0518] The title compound was prepared in a manner similar to that of Example 16, using 3-methoxyazacyclobutane hydrochloride instead of 3-fluoroazacyclobutane hydrochloride and DCM instead of DMF. MS (ESI): C 19 H 17 The calculated mass of F3N4O2 is 390.1; the measured m / z value is 391.2 [M+H]. + . 1 H NMR (400MHz, DMSO- d 6) 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).

[0519] Example 104: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-(3- Methoxyazine-1-yl)ethyl ketone .

[0520] The title compound was prepared in a manner similar to that of Example 1, using 3-methoxyazacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 19 H 17 The calculated mass of F3N4O2 is 390.1; the measured m / z value is 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).

[0521] Example 105: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-(3- ethoxyazine-1-yl)ethyl ketone .

[0522] The title compound was prepared in a manner similar to that of Example 1, using 3-ethoxyazacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 20 H 19The calculated mass of F3N4O2 is 404.1; the measured m / z value is 405.1 [M+H]. + . 1 H NMR (400MHz, CDCl3) δ 8.80 (d, J = 1.9Hz, 1H), 8.29 (d, J = 1.0Hz, 1H), 7.94 (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).

[0523] Example 106: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-[3- [(methoxymethyl)azacyclobutane-1-yl]acetone .

[0524] The title compound was prepared in a manner similar to that of Example 1, using 3-(methoxymethyl)azacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 20 H 19 The calculated mass of F3N4O2 is 404.1; the measured m / z value is 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).

[0525] Example 107: 1-[3-(methoxymethyl)azacyclobutane-1-yl]-2-[6-[3-(trifluoromethyl)phenyl]pyridine Azo[4,3-b]pyridin-1-yl]acetone .

[0526] The title compound was prepared in a manner similar to that of Example 16, using 3-(methoxymethyl)azacyclobutane hydrochloride instead of 3-fluoroazacyclobutane hydrochloride and DCM instead of DMF. MS (ESI): C 20 H 19 The calculated mass of F3N4O2 is 404.2; the measured m / z value is 405.2 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0527] Example 108: (racemic) 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]Pyridine-1- 1-[3-(1-hydroxyethyl)azacyclobutane-1-yl] ethyl ketone ; The title compound was prepared in a manner similar to Example 1, using 1-(azacyclobutane-3-yl)ethane-1-ol instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 20 H 19 The calculated mass of F3N4O2 is 404.1; the measured m / z value is 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), 6.97 (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).

[0528] Example 109: 1-[3-(difluoromethoxy)azacyclobutane-1-yl]-2-[6-[3-(difluoromethyl)-4-fluoro- [Phenyl]pyrazolo[4,3] -b ]pyridin-1-yl] acetone .

[0529] The title compound was prepared in a manner similar to Example 1, using 3-(difluoromethoxy)azacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 19 H 15 The calculated mass of F5N4O2 is 426.1; the measured m / z value is 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).

[0530] Example 110: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-[3- [(trifluoromethoxy)azacyclobutane-1-yl]acetone.

[0531] The title compound was prepared in a manner similar to Example 1, using 3-(trifluoromethoxy)azacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 19 H 14 The calculated mass of F6N4O2 is 444.1; the measured m / z value is 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).

[0532] Example 111: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-(3- Hydroxy-azacyclobutane-1-yl)ethyl ketone .

[0533] The title compound was prepared in a manner similar to that of Example 1, using aziridine-3-ol instead of 3-(trifluoromethyl)aziridine-3-ol. MS (ESI): C 18 H 15 The calculated mass of F3N4O2 is 376.1; the measured m / z value is 377.1 [M+H]. + . 1 H NMR (400MHz, CDCl3) δ 8.80 (d, J = 1.9Hz, 1H), 8.29 (d, J = 1.0Hz, 1H),7.95 – 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).

[0534] Example 112: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]- 1-(3-hydroxyazacyclobutane-1-yl)ethyl ketone .

[0535] The title compound was prepared in a manner similar to 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 using aziridine-3-ol instead of 3-(trifluoromethyl)aziridine-3-ol. MS (ESI): C 18 H 14 The calculated mass of F4N4O2 is 394.1; the measured m / z value is 395.1 [M+H] + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0536] Example 113: 1-(3-hydroxyazacyclobutane-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4, 3-b]pyridin-1-yl]acetone trifluoroacetate .

[0537] The title compound was prepared in a manner similar to that of Example 15, using aziridine-3-ol hydrochloride instead of 1-methylaziridine-3-amine. MS (ESI): C 18 H 15The calculated mass of F3N4O2 is 376.1; the measured m / z value is 377.0 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0538] Example 114: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-[3- [(hydroxymethyl)azacyclobutane-1-yl]acetone .

[0539] The title compound was prepared in a manner similar to that of Example 1, using 3-(hydroxymethyl)azacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 19 H 17 The calculated mass of F3N4O2 is 390.1; the measured m / z value is 391.2 [M+H]. + . 1 H 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), 4.16 (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).

[0540] Example 115: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-(4-methyl-2-thienyl)pyrazolo[4, 3-b]pyridin-1-yl]acetone .

[0541] The title compound was prepared in a manner similar to Example 17, using 4-methylthiophene-2-boronate pinacol ester instead of 2,4-difluorophenylboronic acid and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. The reaction mixture was heated to 90°C. MS (ESI): C 16 H 14 The calculated mass of F2N4OS is 348.1; the measured m / z value is 349.1 [M+H]. + . 1 H NMR (400MHz, DMSO-) d 6) 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 – 7.25(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).

[0542] Example 116: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyrazolium [Pyridin-1-yl]acetone .

[0543] In a manner similar to Example 1, 2-(6-(4-fluorophenyl)-1H-pyrazolo[4,3] -b The title compound was prepared by replacing intermediate 16 with pyridin-1-yl)acetic acid (intermediate 31) and using 3,3-difluoroazacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 17 H 13 The calculated mass of F3N4O is 346.1; the measured m / z value is 347.1 [M+H].+ . 1 H NMR (500MHz, CDCl3) δ 8.83 (d, J = 1.9Hz, 1H), 8.31 (d, J = 1.0Hz, 1H), 7.89 (dd, J = 1.9, 1.0Hz, 1H), 7.66 – 7.60 (m, 2H), 7.25 – 7.18 (m, 2H), 5.14 (s, 2H), 4.42-4.26 (m, 4H).

[0544] Example 117: 2-[6-(3-chlorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3,3-difluoroazacyclobutane) Alkyl ethyl ketone .

[0545] 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 using [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. MS (ESI): C 17 H 13 The calculated mass of ClF₂N₄O is 362.1; the measured m / z value is 363.1 [M+H]. + . 1 H NMR (400MHz, DMSO- d 6) 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).

[0546] Example 118: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-(m-tolyl)pyrazolo[4,3-b]pyrazolium [Pyridin-1-yl]acetone .

[0547] The title compound was prepared in a manner similar to Example 17, using m-tolylboronic acid instead of 2,4-difluorophenylboronic acid and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. The reaction mixture was heated to 90°C. MS (ESI): C 18 H 16 The calculated mass of F₂N₄O is 342.1; the measured m / z value is 343.2 [M+H]. + . 1 H NMR (400MHz, DMSO- d 6)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).

[0548] Example 119: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-[3-(difluoromethyl)phenyl]pyrazol [4,3-b]pyridin-1-yl]acetone .

[0549] 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]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. MS (ESI): C 18 H 14 The calculated mass of F4N4O is 378.1; the measured m / z value is 379.0 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0550] Example 120: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazol [4,3-b]pyridin-1-yl]acetone trifluoroacetate .

[0551] The title compound was prepared in a manner similar to that of Example 15, using 3,3-difluoroazacyclobutane hydrochloride instead of 1-methylazacyclobutane-3-amine. MS (ESI): C 18 H 13 The calculated mass of F5N4O is 396.1; the measured m / z value is 397.1 [M+H]. + . 1 H NMR (400MHz, DMSO- d 6) 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).

[0552] Example 121: 3-[1-[2-(3,3-difluoroazacyclobutane-1-yl)-2-oxo-ethyl]pyrazolo[4,3-b]pyrazolium [Pyridine-6-yl]benzyl nitrile .

[0553] The title compound was prepared in a manner similar to Example 17, using (3-cyanophenyl)boronic acid instead of 2,4-difluorophenylboronic acid, using [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and using sodium carbonate instead of cesium carbonate. MS (ESI): C 18 H 13 The calculated mass of F2N5O is 353.1; the measured m / z value is 354.2 [M+H]. + . 1 H NMR (400MHz, DMSO- d6)δ8.98 – 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).

[0554] Example 122: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-[6-(trifluoromethyl)-2-pyridyl]pyridine Azo[4,3-b]pyridin-1-yl]acetone trifluoroacetate 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-tetra(triphenylphosphine) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. MS (ESI): C 17 H 12 The calculated mass of F5N5O is 397.1; the measured m / z value is 398.2 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0555] Example 123: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-[2-(trifluoromethyl)-4-pyridyl]pyridine Azo[4,3-b]pyridin-1-yl]acetone .

[0556] 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]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. The reaction mixture was heated to 90°C. MS (ESI): C 17 H 12 The calculated mass of F5N5O is 397.1; the measured m / z value is 398.1 [M+H]. + . 1 H NMR (400MHz, DMSO-) d 6) 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 – 8.34(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).

[0557] Example 124: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-[5-(trifluoromethyl)-3-pyridyl]pyridine Azo[4,3-b]pyridin-1-yl]acetone .

[0558] The title compound was prepared in a manner similar to that of Example 17, using (5-(trifluoromethyl)pyridin-3-yl)boronic acid instead of 2,4-difluorophenylboronic acid and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. The reaction mixture was heated to 90°C. MS (ESI): C 17 H 12 The calculated mass of F5N5O is 397.1; the measured m / z value is 398.2 [M+H]. + . 1 H NMR (400MHz, DMSO-) d 6) 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 – 8.59 (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).

[0559] Example 125: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-(3,4-difluorophenyl)pyrazolo[4,3- b]pyridin-1-yl]acetone .

[0560] 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]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. MS (ESI): C 17 H 12 The calculated mass of F4N4O is 364.1; the measured m / z value is 365.1 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0561] Example 126: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-(3,5-difluorophenyl)pyrazolo[4,3- b]pyridin-1-yl]acetone .

[0562] The title compound was prepared in a manner similar to that of Example 17, using (3,5-difluorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid. MS (ESI): C 17 H 12 The calculated mass of F4N4O is 364.1; the measured m / z value is 365.1 [M+H]. + . 1 HNMR (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).

[0563] Example 127: 2-[6-(3-chloro-4-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3,3-difluoronitrogen) Heterocyclic butane-1-yl)ethyl ketone .

[0564] 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-tetra(triphenylphosphine) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. MS (ESI): C 17 H 12 The calculated mass of ClF3N4O is 380.1; the measured m / z value is 381.1 [M+H] + . 1 H NMR (500MHz, DMSO-) d 6) 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).

[0565] Example 128: 2-[6-(3-chloro-2-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-(3,3-difluoronitrogen) Heterocyclic butane-1-yl)ethyl ketone .

[0566] The title compound was prepared in a manner similar to Example 17, using (3-chloro-2-fluorophenyl)boronic acid instead of 2,4-difluorophenylboronic acid and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. MS (ESI): C 17 H 12 The calculated mass of ClF3N4O is 380.1; the measured m / z value is 381.1 [M+H] + . 1 H NMR (400MHz, DMSO- d 6) 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).

[0567] Example 129: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-(4-fluoro-3-methyl-phenyl)pyrazol] [4,3-b]pyridin-1-yl]acetone trifluoroacetate .

[0568] The title compound was prepared in a manner similar 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-difluoroazacyclobutane hydrochloride instead of morpholine. MS (ESI): C 18 H 15 The calculated mass of F3N4O is 360.1; the measured m / z value is 361.2 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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 – 7.29(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).

[0569] Example 130: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-(4-fluoro-2-methyl-phenyl)pyrazol] [4,3-b]pyridin-1-yl]acetone trifluoroacetate .

[0570] The title compound was prepared in a manner similar to Example 13, 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 The calculated mass of F3N4O is 360.1; the measured m / z value is 361.1 [M+H]. + . 1 HNMR (500MHz, DMSO- d 6) 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, 2.8Hz, 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).

[0571] Example 131: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-(2-fluoro-3-methyl-phenyl)pyrazol] [4,3-b]pyridin-1-yl]acetone .

[0572] The title compound was prepared in a manner similar to Example 17, using (2-fluoro-3-methylphenyl)boronic acid instead of 2,4-difluorophenylboronic acid and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. The reaction mixture was heated to 90°C. MS (ESI): C 18 H 15The calculated mass of F3N4O is 360.1; the measured m / z value is 361.2 [M+H]. + . 1 H NMR (600MHz, DMSO-) d 6) 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).

[0573] Example 132: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-[2-fluoro-3-(trifluoromethyl)phenyl]pyridine Azo[4,3-b]pyridin-1-yl]acetone .

[0574] 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 The calculated mass of F6N4O is 414.1; the measured m / z value is 415.1 [M+H]. + . 1 H NMR (400MHz, DMSO- d 6) 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).

[0575] Example 133: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]pyrene Azo[4,3-b]pyridin-1-yl]acetone .

[0576] 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-tetra(triphenylphosphine) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. MS (ESI): C 18 H 12 The calculated mass of F6N4O is 414.1; the measured m / z value is 415.1 [M+H]. + . 1 HNMR (400MHz, DMSO- d 6) 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).

[0577] Example 134: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-[2-fluoro-5-(trifluoromethyl)phenyl]pyridine Azo[4,3-b]pyridin-1-yl]acetone .

[0578] 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-tetra(triphenylphosphine) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. MS (ESI): C 18 H 12 The calculated mass of F6N4O is 414.1; the measured m / z value is 415.2 [M+H]. + . 1 HNMR (400MHz, DMSO- d 6) 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).

[0579] Example 135: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-[2-methyl-3-(trifluoromethyl)phenyl] Pyrazolo[4,3-b]pyridin-1-yl]acetone .

[0580] 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-tetra(triphenylphosphine) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. MS (ESI): C 19 H 15 The calculated mass of F5N4O is 410.1; the measured m / z value is 411.2 [M+H]. + . 1 H NMR (400MHz, DMSO- d 6) 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).

[0581] Example 136: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-(4-fluoro-2-methoxy-phenyl)pyrazol] [4,3-b]pyridin-1-yl]acetone .

[0582] The title compound was prepared in a manner similar to that of 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 The calculated mass of F3N4O2 is 376.1; the measured m / z value is 377.1 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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, 6.9 Hz, 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).

[0583] Example 137: 1-(3,3-difluoroazacyclobutane-1-yl)-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4, 3-b]pyridin-1-yl]acetone .

[0584] 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]palladium(II) dichloride (a complex with dichloromethane) instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. The reaction mixture was heated to 90°C. MS (ESI): C 17 H 11 The calculated mass of F5N4O is 382.1; the measured m / z value is 383.1 [M+H]. + . 1 H NMR (500MHz, DMSO-) d 6) δ 8.93 (d, J = 2.0Hz, 1H), 8.48 – 8.46 (m, 1H), 8.39 (d, J = 1.0Hz, 1H),7.91 – 7.83 (m, 2H), 5.40 (s, 2H), 4.73 (t, J = 12.4Hz, 2H), 4.38 (t, J = 12.5Hz, 2H).

[0585] Example 138: 1-(3,3-dimethylazonobutan-1-yl)-2-[6-[3-(trifluoromethyl)phenyl]pyrazol [4,3-b]pyridin-1-yl]acetone trifluoroacetate .

[0586] The title compound was prepared in a manner similar to that of Example 16, using 3,3-dimethylazacyclobutane hydrochloride instead of 3-fluoroazacyclobutane hydrochloride. MS (ESI): C 20H 19 The calculated mass of F3N4O is 388.2; the measured m / z value is 389.2 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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).

[0587] Example 139: 1-(3-fluoro-3-methyl-azacyclobutane-1-yl]-2-[6-[3-(trifluoromethyl)phenyl]pyrazole [4,3-b]pyridin-1-yl]acetone .

[0588] The title compound was prepared in a manner similar to that of Example 16, using 3-fluoro-3-methylazacyclobutane instead of 3-fluoroazacyclobutane hydrochloride and DCM instead of DMF. MS (ESI): C 19 H 16 The calculated mass of F4N4O is 392.1; the measured m / z value is 393.2 [M+H]. + . 1 H NMR (500MHz, DMSO- d 6) 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 – 7.77(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).

[0589] Example 140: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-(3, 3-Dimethylazonylbutane-1-yl)ethyl ketone .

[0590] The title compound was prepared in a manner similar to that of Example 1, using 3,3-dimethylazacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 20 H 19The calculated mass of F3N4O is 388.2; the measured m / z value is 389.1 [M+H]. + . 1 H 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).

[0591] Example 141: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-(3- Fluoro-3-methyl-azacyclobutane-1-yl)ethyl ketone .

[0592] The title compound was prepared in a manner similar to that of Example 1, using 3-fluoro-3-methylazacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 19 H 16 The calculated mass of F4N4O is 392.1; the measured m / z value is 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).

[0593] Example 142: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-(3- Ethyl-3-fluoro-azacyclobutane-1-yl)ethyl ketone .

[0594] The title compound was prepared in a manner similar to Example 2, using 3-ethyl-3-fluoro-azacyclobutane instead of 3-methyleneazacyclobutane. MS (ESI): C 20 H 18 The calculated mass of F4N4O is 406.1; the measured m / z value is 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).

[0595] Example 143: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-[3- [Fluoro-3-(fluoromethyl)azacyclobutane-1-yl]ethyl ketone .

[0596] The title compound was prepared in a manner similar to Example 1, using 3-fluoro-3-(fluoromethyl)azacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 19 H 15 The calculated mass of F5N4O is 410.1; the measured m / z value is 411.1 [M+H]. + . 1 H 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,1H), 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).

[0597] Example 144: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-(3- Methoxy-3-methyl-azacyclobutane-1-yl)ethyl ketone .

[0598] The title compound was prepared in a manner similar to that of Example 1, using 3-methoxy-3-methylazacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 20 H 19 The calculated mass of F3N4O2 is 404.1; the measured m / z value is 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), 6.98 (t, J = 54.9Hz, 1H), 5.09 (s, 2H), 4.03 (dd, J = 14.6, 9.7 Hz, 2H), 3.83 (ddd, J = 24.8, 9.7, 1.3Hz, 2H), 3.21 (s, 3H), 1.46 (s, 3H).

[0599] Example 145: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-(3- Ethyl-3-hydroxy-azacyclobutane-1-yl)ethyl ketone .

[0600] The title compound was prepared in a manner similar to Example 1, using 3-ethyl-3-hydroxyazacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 20 H 19 The calculated mass of F3N4O2 is 404.1; the measured m / z value is 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, 1H), 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).

[0601] Example 146: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-(3- Hydroxy-3-methyl-azacyclobutane-1-yl)ethyl ketone .

[0602] The title compound was prepared in a manner similar to Example 1, using 3-hydroxy-3-methylazacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 19 H 17 The calculated mass of F3N4O2 is 390.1; the measured m / z value is 391.2 [M+H]. + [M+H]+. 1 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).

[0603] Example 147: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-[3- Fluoro-3-(hydroxymethyl)azacyclobutane-1-yl]ethyl ketone .

[0604] The title compound was prepared in a manner similar to Example 1, using 3-fluoro-3-hydroxymethylazacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 19 H 16 The calculated mass of F4N4O2 is 408.1. The measured m / z value is 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).

[0605] Example 148: 2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-[3- [Fluoro-3-(methoxymethyl)azacyclobutan-1-yl]ethyl ketone .

[0606] The title compound was prepared in a manner similar to Example 1, using 3-fluoro-3-methoxymethylazacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 20 H 18 The calculated mass of F4N4O2 is 422.1. The measured m / z value is 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).

[0607] Example 149: [6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]-1-(3-hydroxy 2-Methyl-azacyclobutane-1-yl)ethyl ketone .

[0608] The title compound was prepared in a manner similar to that of Example 1, using a diastereomeric mixture of 3-hydroxy-2-methylazacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 19 H 17 The calculated mass of F3N4O2 is 390.1; the measured m / z value is 391.0 [M+H]. + . 1 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 = 54.9Hz, 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).

[0609] Example 150: 1-[2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]nitrogen Heterocyclic butane-3-carboxynitrile .

[0610] The title compound was prepared in a manner similar to that of Example 16, using aziridine-3-carboxynitrile hydrochloride instead of 3-fluoroaziridine hydrochloride and DCM instead of DMF. MS (ESI): C 19 H 14 The calculated mass of F3N5O is 385.1; the measured m / z value is 386.1 [M+H]. + . 1 H NMR (400MHz, DMSO- d 6) 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).

[0611] Example 151: 1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]acetyl [By]-Z-butane-3-carboxynitrile .

[0612] The title compound was prepared in a manner similar to Example 2, using 3-cyanozycyclobutane instead of 3-methyleneozycyclobutane. MS (ESI): C 19 H 14 The calculated mass of F3N5O is 385.1; the measured m / z value is 386.0 [M+H]. + . 1 HNMR (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).

[0613] Example 152: 1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]acetyl 3-methyl-azacyclobutane-3-carboxynitrile .

[0614] The title compound was prepared in a manner similar to that of Example 1, using 3-cyano-3-methylazacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 20 H 16 The calculated mass of F3N5O is 399.1; the measured m / z value is 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).

[0615] Example 153: 1-(3-acetylazonobutane-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyridine Azo[4,3] -b ]pyridin-1-yl] acetone .

[0616] The title compound was prepared in a manner similar to Example 1, using 1-(azacyclobutane-3-yl)ethyl-1-one instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 20 H 17 The calculated mass of F3N4O2 is 402.1; the measured m / z value is 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).

[0617] Example 154: N -[1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl] Acetyl]azacyclobutane-3-yl]acetamide .

[0618] The title compound was prepared in a manner similar to that of Example 1, using 3-acetamidoazacyclobutane instead of 3-(trifluoromethyl)azacyclobutane-3-ol. MS (ESI): C 20 H 18 The calculated mass of F3N5O2 is 417.1; the measured m / z value is 418.2 [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 – 7.83 (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).

[0619] Example 155: 1-[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3] -b ]pyridin-1-yl]acetyl base]- N , N -Dimethyl-azacyclobutane-3-carboxamide .

[0620] Using a manner similar to Example 1 N,N The title compound was prepared by replacing 3-(trifluoromethyl)azacyclobutane-3-ol with dimethylazacyclobutane-3-carboxamide. MS (ESI): C 21 H 20 The calculated mass of F3N5O2 is 431.2; the measured m / ...

Claims

1. A compound, said compound being: ； And its pharmaceutically acceptable salts, hydrates and isotopic variants.

2. The compound according to claim 1, wherein the compound is: ； And its pharmaceutically acceptable salts.

3. The compound according to claim 1, wherein the compound is: 。 4. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt, hydrate or isotopic variant thereof, and a pharmaceutically acceptable excipient.

5. Use of the compound of claim 1 or a pharmaceutically acceptable salt, hydrate, or isotopic variant thereof in the manufacture of a medicament for treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by GluN2B receptor activity, wherein the disease, disorder, or medical condition mediated by GluN2B receptor activity is selected from: bipolar disorder, major depressive disorder, treatment-resistant depression, postpartum depression, seasonal affective disorder, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, cognitive impairment, head injury, spinal cord injury, stroke, epilepsy, movement disorder, amyotrophic lateral sclerosis, neurodegenerative diseases associated with bacteria or chronic infection, pain, diabetic neuropathy, migraine, cerebral ischemia, schizophrenia, encephalitis, autism and autism syndrome disorder, memory and learning disabilities, obsessive-compulsive disorder, attention deficit hyperactivity disorder (ADHD), and addictive disorders.

6. The use according to claim 5, wherein the disease, disorder or medical condition is selected from treatment-resistant depression, major depressive disorder and bipolar disorder.

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