WO2023278483A1

WO2023278483A1 - Compounds having 1h-pyrazolo[4,3-c]pyridin-6-aminos as therapeutic agents

Info

Publication number: WO2023278483A1
Application number: PCT/US2022/035367
Authority: WO
Inventors: Volodymyr KYSIL; Vladislav Zenonovich Parchinsky; Alexei Pushechnikov; Alexandre Vasilievich IVACHTCHENKO; Nikolay Savchuk
Original assignee: Lomond Therapeutics, Inc.
Priority date: 2021-07-01
Filing date: 2022-06-28
Publication date: 2023-01-05
Also published as: TW202317561A

Abstract

The present invention is generally directed to inhibitors of hematopoietic progenitor kinase 1 (HPK1), leucine rich repeat kinase 2 (LRRK2) protein, FMS-like tyrosine kinase 3 (FLT3) gene, interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), and Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2) useful in the treatment of diseases and disorders modulated by said HPK1, LRRK2, FLT3, IRAK1, IRAK4,and JAKs, having the Formula (I):

Description

COMPOUNDS HAVING 1H-PYRAZOLO[4,3-C]PYRIDIN-6-AMINO AS THERAPEUTIC AGENTS Cross-Reference to Related Applications [0001] This application claims priority to and the benefit of U.S. Provisional Patent Application Serial No. 63/217,581 filed July 1, 2021, entitled “Compounds having 1H- Pyrazolo[4,3-c]pyridin-6-amino as Therapeutic Agents,” the disclosure of which is incorporated herein by reference in its entirety for all purposes. Field of Invention [0002] The present invention is directed to inhibitors of hematopoietic progenitor kinase 1 (HPK1), leucine rich repeat kinase 2 (LRRK2) protein, FMS-like tyrosine kinase 3 (FLT3) gene, interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), and Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). The inhibitors described herein can be useful in the treatment of diseases or disorders associated with HPK1, LRRK2, FLT3, IRAK1, IRAK4, and JAKs, such as cancer, autoimmune disease, inflammatory disease, viral infection, male fertility control, benign hyperplasia, sepsis, vascular disorder, atherosclerotic disease, and neurodegenerative disorder. In particular, the invention is concerned with compounds and pharmaceutical compositions inhibiting HPK1, LRRK2, FLT3, IRAK1, IRAK4, and JAKs, methods of treating diseases or disorders associated with HPK1, LRRK2, FLT3, IRAK1, IRAK4, and JAKs, and methods of synthesizing these compounds. Background of the Invention [0003] Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted Ste20 serine/threonine kinase. HPK1 kinase activity can be induced by activation signals generated by various different cell surface receptors found in hematopoietic cells upon ligand engagement. Ligand engagement or antibody-mediated crosslinking of T cell receptors (TCR), B cell antigen receptor (BCR), transforming growth factor β receptor (TGF-βR), erythropoietin receptor (EPOR), and Fas can induce HPK1 kinase activity. Each receptor utilizes unique, but sometimes overlapping, signaling mechanisms to activate HPK1. HPK1 acts as a down- modulator of T and B cell functions through the AP-1, NFKB, Erk2, and Fas pathways. For example, HPK1 has been implicated as a negative regulator of signal transduction in T-cells through phosphorylation and activation of the T-cell receptor adaptor protein SLP-76, which leads to subsequent downregulation of the AP-1 and Erk2 pathways. In B- cells, HPK1 downregulates B-cell receptor (BCR) signaling through phosphorylation of the SLP-76 paralog BLINK. [0004] Thus, HPK1 is viewed as a possible target for therapeutic intervention. For example, it has been reported that HPK1 can be a novel target for cancer immunotherapy (Sawasdikosol et al., Immunol Res.2012 Dec;54(1-3):262-5). Specifically, targeted disruption of HPK1 alleles confers T cells with an elevated Th1 cytokine production in response to TCR engagement. HPK1 (-/-) T cells proliferate more rapidly than the haplotype-matched wild-type counterpart and are resistant to prostaglandin E2 (PGE(2))-mediated suppression. Most strikingly, mice that received adoptive transfer of HPK1 (-/-) T cells became resistant to lung tumor growth. Also, the loss of HPK1 from dendritic cells (DCs) endows them with superior antigen presentation ability, enabling HPK1 (-/-) DCs to elicit a more potent anti-tumor immune response when used as cancer vaccine. [0005] While full-length HPK1 can promote TCR-mediated activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, the catalytically inactive cleavage product HPK1-C can suppress NF-κB activation upon TCR restimulation, leading to activation-induced cell death (AICD) (Brenner et al., EMBO J. 2005, 24:4279). Taking together the catalytic and non-catalytic roles of HPK1, it is possible that blocking the HPK1 kinase activity with a small-molecule inhibitor may promote activation of B-and T- cells, leading to superior anti-tumor immunity, while also facilitating AICD, helping to maintain peripheral immune tolerance. [0006] Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transduce cytokine signaling from membrane receptors to STAT transcription factors. Four JAK family members are described, JAK1, JAK2, JAK3, and TYK2. Upon binding of the cytokine to its receptor, JAK family members auto- and/or transphosphorylate each other, followed by phosphorylation of STATs that then migrate to the nucleus to modulate transcription. JAK-STAT intracellular signal transduction serves the interferons, most interleukins, as well as a variety of cytokines and endocrine factors such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF and PRL. A combination of genetic models and small molecule JAK inhibitor research revealed the therapeutic potential of JAK inhibitors (JAKinibs). [0007] Using TYK2 knock out mice, it has been shown that IL-6, IL-10, IL-11, IL12, IL- 13, IL-19, IL-20, IL-22, IL-23, IL-27, IL-28, IL-29, IL-31, IL-35, and/or type 1 interferons signaling are dependent on TYK2. However, it has recently been shown that JAK1 is a key driver in IFNa, IL6, IL10, and IL22 signaling, TYK2 is involved in type I interferons (including IFNa, IFNb), IL23 and IL12 signaling. Since the activity of IL12 and IL23 is particularly increased in patients with auto-immune diseases such as psoriasis, systemic lupus erythematosus (SLE), psoriatic arthritis, and/or inflammatory bowel disorders, selective TYK2 inhibition may be particularly advantageous in the treatment of these diseases while avoiding JAK2 dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling. Additionally, due to its involvement in type I interferons (including IFNa, IFNb) signaling, TYK2 inhibition may be particularly useful in the treatment of the cytokine storm associated with COVID-19 infections. [0008] Furthermore, a variant of TYK2 gene described in the general human population, with a modification in one amino acid in the kinase domain of TYK2 which invalidates its kinase activity, is associated with the decreased risk of autoimmune and inflammatory diseases. [0009] Leucine rich repeat kinase 2 (LRRK2) is a member of the ROCO protein family and all members of this family share five conserved domains. There is evidence to show that the increased LRRK2 kinase activity is associated with neuronal toxicity in cell culture models (Smith et al., 2006 Nature Neuroscience 9: 1231-1233) and kinase inhibitor compounds protect against LRRK2-mediated cell death (Lee et al., 2010 Nat. Med.16: 998-1000). [0010] Additional evidence links LRRK2 function and dysfunction with autophagy- lysosomal pathways (Manzoni and Lewis, 2013 Faseb J. 27:3234-3429). LRRK2 proteins confer defects in chaperone-mediated autophagy that negatively impact the ability of cells to degrade alpha-synuclein (Orenstein et al., 2013 Nature Neurosci. 16394-406). In other cell models, selective LRRK2 inhibitors have been shown to stimulate macroautophagy (Manzoni et al., 2013 BBA Mol. Cell Res. 1833: 2900-2910). These data suggest that small molecule inhibitors of LRRK2 kinase activity may have utility in the treatment of diseases characterized by defects in cellular proteostasis that result from aberrant autophagy/lysosomal degradation pathways including forms of Parkinson's disease associated with GBA mutations (Swan and Saunders-Pullman 2013 Curr. Neurol. Neurosci Rep.13: 368), other alpha-synucleinopathies, tauopathies, Alzheimer's disease (Li et al., 2010 Neurodegen. Dis. 7: 265-271) and other neurodegenerative diseases (Nixon 2013 Nat. Med.19: 983-997). [0011] Other studies have also shown that overexpression of the G2019S mutant form of LRRK2 confers defects in subventricular zone (SVZ) neuroprogenitor cell proliferation and migration in transgenic mouse models (Winner et al., 2011 Neurobiol. Dis. 41: 706-716) and reduces neurite length and branching cell culture models (Dachsel et al., 2010 Parkinsonism & Related Disorders 16: 650-655). Moreover, it was reported that agents that promote SVZ neuroprogenitor cell proliferation and migration also improve neurological outcomes following ischemic injury in rodent models of stroke (Zhang et al., 2010 J. Neurosci. Res.88: 3275-3281). These findings suggest that compounds that inhibit aberrant activity of LRRK2 may have utility for the treatments designed to stimulate restoration of CNS functions following neuronal injury, such as ischemic stroke, traumatic brain injury, spinal cord injury. [0012] Mutations in LRRK2 have also been identified that are clinically associated with the transition from mild cognitive impairment (MCI) to Alzheimer's disease (WO2007149798). These data suggest that inhibitors of LRRK2 kinase activity may be useful for the treatment diseases such as Alzheimer's disease, other dementias and related neurodegenerative disorders. [0013] Aberrant regulation of normal LRRK2 proteins is also observed in some disease tissues and models of disease. Normal mechanisms of translational control of LRRK2 by miR- 205 are perturbed in some sporadic PD cases, where significant decreases in miR-205 levels in PD brain samples concur with elevated LRRK2 protein levels in those samples (Cho et al., (2013) Hum. Mol. Gen.22: 608-620). Therefore, LRRK2 inhibitors may be used in treatment of sporadic PD patients who have elevated levels of normal LRRK2 proteins. In an experimental model of Parkinson's disease in marmosets, an elevation of LRRK2 mRNA is observed in a manner that correlates with the level of L-Dopa induced dyskinesia (Hurley, M. J et al., 2007 Eur. J. Neurosci.26: 171-177). This suggests that LRRK2 inhibitors may have a utility in amelioration of such dyskinesias. [0014] Significantly elevated levels of LRRK2 mRNA have been reported in ALS patient muscle biopsy samples (Shtilbans et al., 2011 Amyotrophic Lateral Sclerosis 12: 250-256) It is suggested that elevated levels of LRRK2 kinase activity may be a characteristic feature of ALS. Therefore, this observation indicated that LRRK2 inhibitor may have utility for treatment of ALS. [0015] There is also evidence indicating that LRRK2 kinase activity may play a role in mediating microglial proinflammatory responses (Moehle et al., 2012, J. Neuroscience 32:1602-1611). This observation suggests a possible utility of LRRK2 inhibitors for treatment of aberrant neuroinflammatory mechanisms that contribute a range of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, ischemic stroke, traumatic brain injury and spinal cord injury. Some evidence also indicates that LRRK2 plays a role in regulating neuronal progenitor differentiation in vitro (Milosevic, J. et al., 2009 Mol. Neurodegen. 4: 25). This evidence suggests that inhibitors of LRRK2 may have a utility in production of neuronal progenitor cells in vitro for consequent therapeutic application in cell based-treatment of CNS disorders. [0016] Meta-analysis of three genome wide associated scans for Crohn's disease identified a number of loci associated with the disease, including the locus containing the LRRK2 gene (Barrett et al., 2008, Nature Genetics, 40: 955-962). Evidence has also emerged that LRRK2 is an IFN-γ target gene that may be involved in signaling pathways relevant to Crohn's disease pathogenesis (Gardet et al., 2010, J. Immunology, 185: 5577-5585). These findings suggest that inhibitors of LRRK2 may have utility in the treatment of Crohn's disease. [0017] As an IFN-γ target gene, LRRK2 may also play a role in T cell mechanisms that underlie other diseases of the immune system such as multiple sclerosis and rheumatoid arthritis. Further potential utility of LRRK2 inhibitors comes from the reported finding that B lymphocytes constitute a major population of LRRK2 expressing cells (Maekawa et al. 2010, BBRC 392: 431-435). This suggests that LRRK2 inhibitors may be effective in treatment of diseases of the immune system for which B cell depletion is, or may be, effective in diseases such as lymphomas, leukemias, multiple sclerosis (Ray et al., 2011 J. Immunol. 230: 109), rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis, bullous skin disorders, type 1 diabetes mellitus, Sjogren's syndrome, Devic's disease and inflammatory myopathies (Engel et al., 2011 Pharmacol. Rev. 63: 127-156; Homam et al., 2010 J. Clin. Neuromuscular Disease 12: 91-102). [0018] The FMS-like tyrosine kinase 3 (FLT3) gene encodes a membrane bound receptor tyrosine kinase that affects hematopoiesis leading to hematological disorders and malignancies. Activation of FLT3 receptor tyrosine kinases is initiated through the binding of the FLT3 ligand (FLT3L) to the FLT3 receptor, also known as Stem cell tyrosine kinase-1 (STK-1) and fetal liver kinase-2 (flk-2), which is expressed on hematopoietic progenitor and stem cells. [0019] FLT3 is one of the most frequently mutated genes in hematological malignancies, present in approximately 30% of adult acute myeloid leukemia (AML). The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy. FLT3 mutations have been detected in approximately 2% of patients diagnosed with intermediate and high-risk myelodysplastic syndrome (MDS). Like MDS, the number of FLT3 mutations in patients with acute promyelocytic leukemia (APL) is small. The most common FLT3 mutations are internal tandem duplications (ITDs) that lead to in-frame insertions within the juxtamembrane domain of the FLT3 receptor. FLT3-ITD mutations have been reported in 15–35% of adult AML patients. Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. A FLT3-ITD mutation is an independent predictor of poor patient prognosis and is associated with increased relapse risk after standard chemotherapy, and decreased disease free and overall survival. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Less frequent are FLT3 point mutations that arise in the activation loop of the FLT3 receptor. The most commonly affected codon is aspartate 835 (D835). Nucleotide substitutions of the D835 residue occur in approximately 5–10% of adult acute myeloid leukemia patients. [0020] The heightened frequency of constitutively activated mutant FLT3 in adult AML has made the FLT3 gene a highly attractive drug target in this tumor type. Several FLT3 inhibitors with varying degrees of potency and selectivity for the target have been or are currently being investigated and examined in AML patients. [0021] Toll-like receptors (TLRs)/Interleukin 1-receptor (IL-1R) signaling engages IRAK4 and IRAK1 phosphorylation to drive downstream events such as NF-κB and interferon signaling in inflammation response and this process has been recently implicated in tumorigenesis. Moreover, pharmacologic inhibition of IRAK1/4 has been shown to be efficacious in targeting MDS and acute lymphoblastic leukemia (ALL) that carry IRAK1 activation through NF-κB-dependent or in-dependent mechanism. [0022] Accordingly, there is a need for new compounds which would effectively and selectively inhibit hematopoietic progenitor kinase 1 (HPK1), leucine rich repeat kinase 2 (LRRK2) protein, FMS-like tyrosine kinase 3 (FLT3) gene, interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), and Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2), thus allowing the design of specific treatments and dosages tailored to the pathology. Summary of the Invention [0023] A first aspect of the invention relates to compounds of Formula (I):

and pharmaceutically acceptable salts, isomers, solvates, prodrugs, and tautomers thereof, wherein: X₁ is selected from N and CR_6a; X₂ is selected from N and CR_6b; X₃ is selected from N and CR_6c; R₁ is selected from C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more R₇; R2 and R₃ are each independently selected from hydrogen, halo, –OH, –CN, –NO2, amino, alkylamino, dialkylamino, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, and C₁–C₆ haloalkoxy; each R₄ is independently selected from hydrogen, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10- membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more R8; or, each R₄, together with the nitrogen atom to which they are attached, come together to form 3- to 10-membered heterocyclyl or heteroaryl, wherein the heterocyclyl or heteroaryl may further comprise one or more atom selected from N, O, and S, wherein the heterocyclyl or heteroaryl are optionally substituted with one or more R8; R₅ is selected from hydrogen, halo, –OH, –CN, –NO₂, –N(R₉)₂, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or moreR₁0; each of R_6a, R_6b, and R_6c are independently selected from hydrogen, halo, –OH, –CN, –NO2, amino, alkylamino, dialkylamino, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, –C(O)NR₁₅R₁₅, –C(O)OR₁₅, –NR₁₅C(O)R₁₅, – OC(O)R₁₅, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more halo, –OH, –CN, –NO₂, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl; each R7 is independently selected from halo, –OH, –CN, –NO2, amino, alkylamino, dialkylamino, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₁₀ cycloalkyl, aryl, 3- to 10- membered heterocyclyl, and heteroaryl; each R₈ is independently selected from halo, –OH, –CN, –NO₂, amino, alkylamino, dialkylamino, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, –C(O)R₁₂, –C(O)NR_NR₁₂, –C(O)OR₁₂, –NR_NC(O)R₁₂, –NR_NC(O)NR_NR₁₂, –OC(O)R₁₂, –OC(O)OR₁₂, –S(O)2R₁₂, –S(O)2NRNR₁₂, C₃–C₁₀ cycloalkyl, aryl, 3- to 10- membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or moreR₁3; each R9 is independently selected from hydrogen, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10- membered heterocyclyl, and heteroaryl, wherein the cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more halo, –OH, –CN, –NO₂, amino, alkylamino, dialkylamino, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C1– C₆ alkoxy, C₁–C₆ haloalkoxy, –C(O)R₁₁, –C(O)NHR₁₁, –C(O)OR₁₁, –NR_NC(O)R₁₁, – NRNC(O)R11, –NRNC(O)NRNR11, –OC(O)R11, and –OC(O)OR11; each R₁₀ is independently selected from halo, –OH, –CN, –NO₂, –N(R₉)₂, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, and C₁–C₆ haloalkoxy; each R₁₁ is independently selected from hydrogen, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, and C₁–C₆ haloalkoxy; each R₁₂ is independently selected from C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, and 3- to 10- membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl are optionally substituted with one or more halo, –OH, –CN, –NO₂, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, –C(O)R₁₄, –C(O)NRNR₁₄, –C(O)OR₁₄, –NRNC(O)R₁₄, –OC(O)R₁₄, C₃–C₁₀ cycloalkyl, aryl, and 3- to 10-membered heterocyclyl; each R₁₃ is independently selected from halo, –OH, –CN, –NO₂, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl; each R₁₄ is independently selected from C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, and C₁–C₆ haloalkoxy; each R₁₅ is independently selected from hydrogen, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10- membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more halo, –OH, –CN, –NO₂, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl; each RN is independently selected from hydrogen, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₁₀ cycloalkyl, and aryl; wherein, whenR₁ is phenyl or pyridinyl, then R5 is –N(R9)2, wherein at least one R9 is not hydrogen; and wherein, (1) when R5 is hydrogen, each R₄, together with the nitrogen atom to which they are attached, come together to form piperazinyl; or (2) when R5 is hydrogen and X3 is CR_6c, R_6c is not hydrogen. [0024] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. [0025] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of hematopoietic progenitor kinase 1 (HPK1). The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of HPK1 an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0026] Another aspect of the invention is directed to a method of inhibiting hematopoietic progenitor kinase 1 (HPK1). The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0027] Another aspect of the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting hematopoietic progenitor kinase 1 (HPK1). [0028] Another aspect of the present invention relates to the use of compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease associated with inhibiting hematopoietic progenitor kinase 1 (HPK1). [0029] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of leucine rich repeat kinase 2 (LRRK2) protein. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of LRRK2 an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0030] Another aspect of the invention is directed to a method of inhibiting leucine rich repeat kinase 2 (LRRK2) protein. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0031] Another aspect of the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting leucine rich repeat kinase 2 (LRRK2) protein. [0032] Another aspect of the present invention relates to the use of compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease associated with inhibiting leucine rich repeat kinase 2 (LRRK2) protein. [0033] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of FMS-like tyrosine kinase 3 (FLT3) gene. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of FLT3 an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0034] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3) gene. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0035] Another aspect of the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3) gene. [0036] Another aspect of the present invention relates to the use of compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease associated with inhibiting FMS-like tyrosine kinase 3 (FLT3) gene. [0037] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of interleukin-1 receptor-associated kinase 1 (IRAK1). The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of IRAK1 an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0038] Another aspect of the invention is directed to a method of inhibiting interleukin-1 receptor-associated kinase 1 (IRAK1). The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0039] Another aspect of the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting interleukin-1 receptor-associated kinase 1 (IRAK1). [0040] Another aspect of the present invention relates to the use of compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease associated with inhibiting interleukin-1 receptor-associated kinase 1 (IRAK1). [0041] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of interleukin-1 receptor-associated kinase 4 (IRAK4). The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of IRAK4 an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0042] Another aspect of the invention is directed to a method of inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4). The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0043] Another aspect of the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4). [0044] Another aspect of the present invention relates to the use of compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease associated with inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4). [0045] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of JAKs an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0046] Another aspect of the invention is directed to a method of inhibiting Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0047] Another aspect of the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). [0048] Another aspect of the present invention relates to the use of compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease associated with inhibiting Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). [0049] Another aspect of the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. [0050] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0051] Another aspect of the present invention relates to the use of compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein. [0052] The present invention further provides methods of treating a disease or disorder associated with modulation of hematopoietic progenitor kinase 1 (HPK1), comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0053] The present invention provides inhibitors of hematopoietic progenitor kinase 1 (HPK1) that are therapeutic agents in the treatment of diseases and disorders. [0054] The present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known hematopoietic progenitor kinase 1 (HPK1) inhibitors. The present disclosure also provides agents with novel mechanisms of action toward protein tyrosine phosphatase enzymes in the treatment of various types of diseases. [0055] The present invention further provides methods of treating a disease or disorder associated with modulation of leucine rich repeat kinase 2 (LRRK2) protein, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0056] The present invention provides inhibitors of leucine rich repeat kinase 2 (LRRK2) protein that are therapeutic agents in the treatment of diseases and disorders. [0057] The present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known leucine rich repeat kinase 2 (LRRK2) protein inhibitors. The present disclosure also provides agents with novel mechanisms of action toward LRRK2 in the treatment of various types of diseases. [0058] The present invention further provides methods of treating a disease or disorder associated with modulation of FMS-like tyrosine kinase 3 (FLT3) gene, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0059] The present invention provides inhibitors of FMS-like tyrosine kinase 3 (FLT3) gene that are therapeutic agents in the treatment of diseases and disorders. [0060] The present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known FMS-like tyrosine kinase 3 (FLT3) gene inhibitors. The present disclosure also provides agents with novel mechanisms of action toward FLT3 in the treatment of various types of diseases. [0061] The present invention further provides methods of treating a disease or disorder associated with modulation of interleukin-1 receptor-associated kinase 1 (IRAK1), comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0062] The present invention provides inhibitors of interleukin-1 receptor-associated kinase 1 (IRAK1) that are therapeutic agents in the treatment of diseases and disorders. [0063] The present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known interleukin-1 receptor-associated kinase 1 (IRAK1) inhibitors. The present disclosure also provides agents with novel mechanisms of action toward IRAK1 in the treatment of various types of diseases. [0064] The present invention further provides methods of treating a disease or disorder associated with modulation of interleukin-1 receptor-associated kinase 4 (IRAK4), comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0065] The present invention provides inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4) that are therapeutic agents in the treatment of diseases and disorders. [0066] The present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors. The present disclosure also provides agents with novel mechanisms of action toward IRAK4 in the treatment of various types of diseases. [0067] The present invention further provides methods of treating a disease or disorder associated with modulation of Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2), comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0068] The present invention provides inhibitors of Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2), that are therapeutic agents in the treatment of diseases and disorders. [0069] The present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known Janus kinase (JAK) inhibitors. The present disclosure also provides agents with novel mechanisms of action toward JAKs in the treatment of various types of diseases. [0070] The present invention further provides methods of treating a disease, disorder, or condition selected from cancer, an autoimmune disease, an inflammatory disease, a viral infection, male fertility control, a benign hyperplasia, sepsis, a vascular disorder, an atherosclerotic disease, and a neurodegenerative disorder, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0071] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing compounds described herein (e.g., a method comprising one or more steps described in General Procedures A–E). [0072] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Examples 1–143 and A–C). [0073] In some aspects, the present disclosure provides a method of preparing compounds of the present disclosure. [0074] In some aspects, the present disclosure provides a method of preparing compounds of the present disclosure, comprising one or more steps described herein. [0075] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control. [0076] Other features and advantages of the disclosure will be apparent from the following detailed description and claims Detailed Description of the Invention [0077] The present disclosure relates to compounds and compositions that are capable of inhibiting the activity of hematopoietic progenitor kinase 1 (HPK1), leucine rich repeat kinase 2 (LRRK2) protein, FMS-like tyrosine kinase 3 (FLT3) gene, interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), and Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). The disclosure features methods of treating, preventing or ameliorating a disease or disorder in which HPK1, LRRK2, FLT3, IRAK1, IRAK4, and/or JAKs play(s) a role by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The methods of the present invention can be used in the treatment of a variety of diseases, disorders, and conditions, including cancer, an autoimmune disease, an inflammatory disease, a viral infection, male fertility control, a benign hyperplasia, sepsis, a vascular disorder, an atherosclerotic disease, and a neurodegenerative disorder.In a first aspect of the invention, the compounds of Formula (I) are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein X1, X2, X3, R,₁ R2, R₃, R₄, and R5 are described herein. [0078] The details of the invention are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. Definitions [0079] The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. [0080] The term "and/or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise. [0081] The term “optionally substituted” is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH₂CN, -O-(C₁-C₆) alkyl, (C₁–C₆) alkyl, ( C₁–C₆) alkoxy, (C₁–C₆) haloalkyl, (C₁–C₆) haloalkoxy, -O-(C₂–C₆) alkenyl, -O-(C₂-C₆) alkynyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, -OH, -OP(O)(OH)₂, -OC(O)(C₁-C₆) alkyl, -C(O)(C₁–C₆) alkyl, -OC(O)O(C₁–C₆) alkyl, -NH₂, -NH((C₁–C₆) alkyl), -N((C₁–C₆) alkyl)₂, -NHC(O)(C₁-C₆) alkyl, -C(O)NH(C₁-C₆) alkyl, -S(O)₂(C₁-C₆) alkyl, -S(O)NH(C₁-C₆) alkyl, and S(O)N((C₁–C₆) alkyl)2. The substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below. [0082] As used herein, the term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms. [0083] As used herein, the term “unsubstituted” means that the specified group bears no substituents. [0084] Unless otherwise specifically defined, the term "aryl" refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C₁-C₆) alkyl, (C₁-C₆) alkyl, -O-(C₂-C₆) alkenyl, -O-(C₂-C₆) alkynyl, ( C₂–C₆) alkenyl, (C₂–C₆) alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C₁–C₆) alkyl, -C(O)(C1- C₆) alkyl, -OC(O)O(C₁-C₆) alkyl, -NH₂, NH((C₁-C₆) alkyl), N((C₁-C₆) alkyl)₂, -S(O)₂-(C₁-C₆) alkyl, -S(O)NH(C₁–C₆) alkyl, and -S(O)N((C₁–C₆) alkyl)2. The substituents can themselves be optionally substituted. Furthermore, when containing two fused rings, the aryl groups herein defined may have a saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like. [0085] Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, Se, or B, the remaining ring atoms being C. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, Se, or B. Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, Se, or B. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3- c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2- c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3- b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ²- pyrrolo[2,1-b]pyrimidine, dibenzo[b,d] thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4] thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3- b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5- a]pyridinyl, benzo [1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3- b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H- benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo [1,5-b][1,2]oxazinyl, 4,5,6,7- tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1- b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring, e.g., a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaromatic ring containing 1 to 3 nitrogens, wherein the saturated or partially unsaturated ring includes 0 to 4 heteroatoms selected from N, O, S, P, Se, or B, and is optionally substituted with one or more oxo. In heteroaryl ring systems containing more than two fused rings, a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2- b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3- e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizine, pyrazolo[1,5-a]pyrimidin-7(4H)-only, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, or benzo[c][1,2]oxaborol-1(3H)-olyl. [0086] “Halogen” or “halo” refers to fluorine, chlorine, bromine, or iodine. [0087] “Alkyl” refers to a straight or branched chain saturated hydrocarbon containing 1– 12 carbon atoms. Examples of a (C₁–C₆) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. [0088] “Alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1–12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups. [0089] “Alkenyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2–12 carbon atoms. The “alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. Alkenyl, as herein defined, may be straight or branched. [0090] “Alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2–12 carbon atoms. The “alkynyl” group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynyl group can be unsubstituted or substituted. [0091] The term “alkylene” or “alkylenyl” refers to a divalent alkyl radical. Any of the above-mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a C₁–C₆ alkylene. An alkylene may further be a C₁–C₄ alkylene. Typical alkylene groups include, but are not limited to, -CH₂-, -CH(CH3)-, -C(CH3)2-, -CH₂CH₂-, -CH₂CH(CH3)-, -CH₂C(CH3)2-, -CH₂CH₂CH₂-, -CH₂CH₂CH₂CH₂-, and the like. [0092] “Cycloalkyl” means a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C₃- C12, C3-C10, or C3-C8). Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, decahydronaphthalenyl, octahydro- 1H-indenyl, cyclopentenyl, cyclohexenyl, cyclohexa-1,4-dienyl, cyclohexa-1,3-dienyl, 1,2,3,4-tetrahydronaphthalenyl, octahydropentalenyl, 3a,4,5,6,7,7a-hexahydro-1H-indenyl, 1,2,3,3a-tetrahydropentalenyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.0]pentanyl, spiro[3.3]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]octanyl, 6-methylbicyclo[3.1.1]heptanyl, 2,6,6-trimethylbicyclo[3.1.1]heptanyl, adamantyl, and derivatives thereof. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non-aromatic. [0093] “Heterocyclyl”, “heterocycle” or “heterocycloalkyl” refers to a saturated or partially unsaturated 3–10 membered monocyclic, 7–12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, Se, or B), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1- 6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6- tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1- azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane- 1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3- azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4- c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H- pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2- azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2- azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa- azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. [0094] The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc. [0095] The term “haloalkoxy” as used herein refers to an alkoxy group, as defined herein, which is substituted one or more halogen. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc. [0096] The term “cyano” as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C≡N. [0097] The term “amine” as used herein refers to primary (R-NH₂, R ^ H), secondary (R₂- NH, R₂ ^ H) and tertiary (R₃-N, R ^ H) amines. A substituted amine is intended to mean an amine where at least one of the hydrogen atoms has been replaced by the substituent. [0098] The term “amino” as used herein means a substituent containing at least one nitrogen atom. Specifically, -NH₂, -NH(alkyl) or alkylamino, -N(alkyl)₂ or dialkylamino, amide-, carbamide-, urea, and sulfamide substituents are included in the term “amino”. [0099] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water. [0100] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. [0101] The present invention also contemplates isotopically labelled compounds of Formula I (e.g., those labeled with ²H and ¹⁴C). Deuterated (i.e., ²H or D) and carbon-14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent. [0102] The disclosure also includes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumerate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p- toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. [0103] A "patient" or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus. [0104] An "effective amount" when used in connection with a compound is an amount effective for treating or preventing a disease or disorder in a subject as described herein. [0105] The term "carrier", as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject. [0106] The term "treating" with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder. [0107] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated. [0108] The term "administer", "administering", or "administration" as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body. [0109] The term "prodrug," as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound. [0110] In some embodiments, the compound is of Formula I-A:

and pharmaceutically acceptable salts, isomers, solvates, prodrugs, or tautomers thereof. [0111] In some embodiments, the compound is of Formula I-B-1, I-B-2, or I-B-3: or a p

harmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof. [0112] In some embodiments, the compound is of Formula I-B-1. [0113] In some embodiments, the compound is of Formula I-B-2. [0114] In some embodiments, the compound is of Formula I-B-3. [0115] In some embodiments, the compound is of Formula I-B-3a, I-B-3b, or I-B-3c:

or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof, wherein X4 and X5 are independently selected from N and CR₁₆, wherein eachR₁₆ is selected from hydrogen, halo, –OH, –CN, –NO₂, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, and wherein at least one of X₄ and X₅ is CR₁₆. [0116] In some embodiments, the compound is of Formula I-B-3a. [0117] In some embodiments, the compound is of Formula I-B-3b. [0118] In some embodiments, the compound is of Formula I-B-3c. [0119] In some embodiments, X₄ is N. In some embodiments, X₄ is CR₁₆. [0120] In some embodiments, X5 is N. In some embodiments, X5 is CR₁₆. [0121] In some embodiments, each of X₄ and X₅ are CR₁₆. In some embodiments, X₄ is N and X5 is CR₁₆. In some embodiments, X4 is CR₁₆ and X5 is N. [0122] In some embodiments, R₁₆ is hydrogen. In some embodiments, R₁₆ is halo. In some embodiments, R₁₆ is fluoro. In some embodiments, R₁₆ is chloro. In some embodiments, R₁₆ is bromo. In some embodiments, R₁₆ is iodo. In some embodiments, R₁₆ is –OH. In some embodiments, R₁₆ is –CN. In some embodiments, R₁₆ is –NO2. In some embodiments, R₁₆ is C₁–C₆ alkyl. In some embodiments, R₁₆ is methyl. In some embodiments, R₁₆ is ethyl. In some embodiments, R₁₆ is propyl. In some embodiments, R₁₆ is isopropyl. In some embodiments, R₁₆ is butyl. In some embodiments, R₁₆ is isobutyl. In some embodiments, R₁₆ is sec-butyl. In some embodiments, R₁₆ is tert-butyl. In some embodiments, R₁₆ is pentyl. In some embodiments, R₁₆ is isopentyl. In some embodiments, R₁₆ is sec-pentyl. In some embodiments, R₁₆ is neopentyl. In some embodiments, R₁₆ is hexyl. In some embodiments, R₁₆ is isohexyl. In some embodiments, R₁₆ is C₂–C₆ alkenyl. In some embodiments, R₁₆ is C₂–C₆ alkynyl. In some embodiments, R₁₆ is C₁–C₆ haloalkyl. In some embodiments, R₁₆ is –CHF₂. In some embodiments, R₁₆ is –CF₃. In some embodiments, R₁₆ is C₁–C₆ alkoxy. In some embodiments, R₁₆ is C₁–C₆ haloalkoxy. In some embodiments, R₁₆ is C₃–C₁₀ cycloalkyl. In some embodiments, R₁₆ is aryl. In some embodiments, R₁₆ is 3- to 10-membered heterocyclyl. [0123] In some embodiments, the compound is of Formula I-C:

or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof. [0124] In some embodiments, the compound is of Formula I-D: or a pharmaceu

tically acceptable salt, isomer, solvate, prodrug, or tautomer thereof, wherein m is an integer selected from 0, 1, 2, 3, 4, 5, and 6. [0125] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. [0126] In some embodiments, the compound is of Formula I-D-1:

or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof. [0127] In some embodiments, the compound is of Formula I-E:

or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof. [0128] In some embodiments, the compound is of Formula I-F:

or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5, and o is an integer selected from 0, 1, 2, 3, or 4. [0129] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. [0130] In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4. [0131] In some embodiments, the compound is of Formula I-F-1, I-F-2, I-F-3, or I-F-4:

or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5, and o is an integer selected from 0, 1, 2, 3, or 4. [0132] In some embodiments, the compound is of Formula I-F-1. [0133] In some embodiments, the compound is of Formula I-F-2. [0134] In some embodiments, the compound is of Formula I-F-3. [0135] In some embodiments, the compound is of Formula I-F-4. [0136] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. [0137] In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4. [0138] In some embodiments, the compound is of Formula I-G:

or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof, wherein p and q are each an integer independently selected from 1, 2, and 3, and o is an integer selected from 0, 1, 2, 3, 4, or 5. [0139] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. [0140] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. [0141] In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4. In some embodiments, o is 5. [0142] In some embodiments, the compound is of Formula I-G-1, I-G-2, I-G-3, or I-G-4:

or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof, wherein o is an integer selected from 0, 1, 2, 3, 4, or 5. [0143] In some embodiments, the compound is of Formula I-G-1. [0144] In some embodiments, the compound is of Formula I-G-2. [0145] In some embodiments, the compound is of Formula I-G-3. [0146] In some embodiments, the compound is of Formula I-G-4. [0147] In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4. In some embodiments, o is 5. [0148] In some embodiments, X₁ is N. In some embodiments, X₁ is CR_6a. [0149] In some embodiments, X2 is N. In some embodiments, X2 is CR6a. [0150] In some embodiments, X₃ is N. In some embodiments, X₃ is CR_6a. [0151] In some embodiments, at least one of X1, X2, and X3 is N. In some embodiments, one of X₁, X₂, and X₃ is N. In some embodiments, two of X₁, X₂, and X₃ are N. In some embodiments, each of X1, X2, and X3 are N. [0152] In some embodiments, R₁ is C₁–C₆ alkyl. In some embodiments, R₁ is methyl. In some embodimentsR, ₁ is ethyl. In some embodiments,R₁ is propyl. In some embodiments, R₁ is isopropyl. In some embodiments, R₁ is butyl. In some embodiments, R₁ is isobutyl. In some embodimentsR, ₁ is sec-butyl. In some embodimentsR, ₁ is tert-butyl. In some embodiments, R₁ is pentyl. In some embodiments, R₁ is isopentyl. In some embodiments, R₁ is sec-pentyl. In some embodiments,R₁ is neopentyl. In some embodiments,R₁ is hexyl. In some embodimentsR, ₁ is isohexyl. In some embodiments,R₁ is C₂–C₆ alkenyl. In some embodiments, R₁ is C₂–C₆ alkynyl. In some embodiments, R₁ is C₃–C₁₀ cycloalkyl. In some embodimentsR, ₁ is C₃–C₁₀ cycloalkyl substituted with one or more R7. In some embodiments, R₁ is aryl. In some embodiments, R₁ is aryl substituted with one or more R₇. In some embodimentsR, ₁ is phenyl substituted with one or more R7. In some embodiments,R₁ is 3- to 10-membered heterocyclyl. In some embodiments, R₁ is 3- to 10-membered heterocyclyl substituted with one or more R7. In some embodimentsR, ₁ is heteroaryl. In some embodiments, R₁ is heteroaryl substituted with one or more R₇. [0153] In some embodiments, R₁ is phenyl, R5 is –N(R9)2, and at least one R9 is not hydrogen. [0154] In some embodiments,R₁ is pyridinyl, R5 is –N(R9)2, and at least one R9 is not hydrogen. [0155] In some embodimentsR, ₁ is selected from

, , ,

, , , , , , , , , and

[0156] In some embodiments,R₁ is

hydrogen, halo, –OH, –CN, –NO₂, amino, alkylamino, dialkylamino, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, and C₁–C₆ haloalkoxy; [0157] In some embodiments, R2 is hydrogen. In some embodiments, R2 is halo. In some embodiments, R2 is fluoro. In some embodiments, R2 is chloro. In some embodiments, R2 is bromo. In some embodiments, R2 is iodo. In some embodiments, R2 is –OH. In some embodiments, R₂ is –CN. In some embodiments, R₂ is –NO₂. In some embodiments, R₂ is amino. In some embodiments, R2 is alkylamino. In some embodiments, R2 is dialkylamino. In some embodiments, R₂ is C₁–C₆ alkyl. In some embodiments, R₂ is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is propyl. In some embodiments, R2 is isopropyl. In some embodiments, R₂ is butyl. In some embodiments, R₂ is isobutyl. In some embodiments, R2 is sec-butyl. In some embodiments, R2 is tert-butyl. In some embodiments, R₂ is pentyl. In some embodiments, R₂ is isopentyl. In some embodiments, R₂ is sec-pentyl. In some embodiments, R2 is neopentyl. In some embodiments, R2 is hexyl. In some embodiments, R₂ is isohexyl. In some embodiments, R₂ is C₂–C₆ alkenyl. In some embodiments, R2 is C₂–C₆ alkynyl. In some embodiments, R2 is C₁–C₆ haloalkyl. In some embodiments, R₂ is C₁–C₆ alkoxy. In some embodiments, R₂ is C₁–C₆ haloalkoxy. [0158] In some embodiments, R₃ is hydrogen. In some embodiments, R₃ is halo. In some embodiments, R₃ is fluoro. In some embodiments, R₃ is chloro. In some embodiments, R₃ is bromo. In some embodiments, R₃ is iodo. In some embodiments, R₃ is –OH. In some embodiments, R₃ is –CN. In some embodiments, R₃ is –NO₃. In some embodiments, R₃ is amino. In some embodiments, R₃ is alkylamino. In some embodiments, R₃ is dialkylamino. In some embodiments, R₃ is C₁–C₆ alkyl. In some embodiments, R₃ is methyl. In some embodiments, R₃ is ethyl. In some embodiments, R₃ is propyl. In some embodiments, R₃ is isopropyl. In some embodiments, R₃ is butyl. In some embodiments, R₃ is isobutyl. In some embodiments, R₃ is sec-butyl. In some embodiments, R₃ is tert-butyl. In some embodiments, R₃ is pentyl. In some embodiments, R₃ is isopentyl. In some embodiments, R₃ is sec-pentyl. In some embodiments, R₃ is neopentyl. In some embodiments, R₃ is hexyl. In some embodiments, R₃ is isohexyl. In some embodiments, R₃ is C₂–C₆ alkenyl. In some embodiments, R₃ is C₂–C₆ alkynyl. In some embodiments, R₃ is C₁–C₆ haloalkyl. In some embodiments, R₃ is C₁–C₆ alkoxy. In some embodiments, R₃ is C₁–C₆ haloalkoxy. [0159] In some embodiments, R₂ and R₃ are each hydrogen. [0160] In some embodiments, at least one R₄ is hydrogen. In some embodiments, at least one R₄ is C₁–C₆ alkyl. In some embodiments, at least one R₄ is C₁–C₆ alkyl substituted with one or more R8. In some embodiments, at least one R₄ is methyl. In some embodiments, at least one R₄ is ethyl. In some embodiments, at least one R₄ is propyl. In some embodiments, at least one R₄ is isopropyl. In some embodiments, at least one R₄ is butyl. In some embodiments, at least one R₄ is isobutyl. In some embodiments, at least one R₄ is sec-butyl. In some embodiments, at least one R₄ is tert-butyl. In some embodiments, at least one R₄ is pentyl. In some embodiments, at least one R₄ is isopentyl. In some embodiments, at least one R₄ is sec-pentyl. In some embodiments, at least one R₄ is neopentyl. In some embodiments, at least one R₄ is hexyl. In some embodiments, at least one R₄ is isohexyl. In some embodiments, at least one R₄ is C₂–C₆ alkenyl. In some embodiments, at least one R₄ is C2– C₆ alkenyl substituted with one or more R₈. In some embodiments, at least one R₄ is C₂–C₆ alkynyl. In some embodiments, at least one R₄ is C₂–C₆ alkynyl substituted with one or more R₈. In some embodiments, at least one R₄ is C₁–C₆ haloalkyl. In some embodiments, at least one R₄ is C₁–C₆ alkoxy. In some embodiments, at least one R₄ is C₁–C₆ alkoxy substituted with one or more R₈. In some embodiments, at least one R₄ is C₁–C₆ haloalkoxy. In some embodiments, at least one R₄ is C₃–C₁₀ cycloalkyl. In some embodiments, at least one R₄ is C₃–C₁₀ cycloalkyl substituted with one or more R₈. In some embodiments, at least one R₄ is aryl. In some embodiments, at least one R₄ is aryl substituted with one or more R8. In some embodiments, at least one R₄ is 3- to 10-membered heterocyclyl. In some embodiments, at least one R₄ is 3- to 10-membered heterocyclyl substituted with one or more R8. In some embodiments, at least one R₄ is heteroaryl. In some embodiments, at least one R₄ is heteroaryl substituted with one or more R8. [0161] In some embodiments, each R₄, together with the nitrogen atom to which they are attached, come together to form 3- to 10-membered heterocyclyl, wherein the heterocyclyl may further comprise one or more atom selected from N, O, and S. In some embodiments, each R₄, together with the nitrogen atom to which they are attached, come together to form 3- to 10- membered heterocyclyl, wherein the heterocyclyl may further comprise one or more atom selected from N, O, and S, and wherein the heterocyclyl is optionally substituted with one or more R8. In some embodiments, each R₄, together with the nitrogen atom to which they are attached, come together to form heteroaryl, wherein the heteroaryl may further comprise one or more atom selected from N, O, and S. In some embodiments, each R₄, together with the nitrogen atom to which they are attached, come together to form heteroaryl, wherein the heteroaryl may further comprise one or more atom selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more R₈. [0162] In some embodiments, each R₄, together with the nitrogen atom to which they are attached, come together to form piperidinyl optionally substituted with one or more R₈. [0163] In some embodiments, each R₄, together with the nitrogen atom to which they are attached, come together to form piperazinyl optionally substituted with one or more R₈. [0164] In some embodiments, each R₄, together with the nitrogen atom to which they are attached, come together to form morpholinyl optionally substituted with one or more R₈. [0165] In some embodiments, each R₄, together with the nitrogen atom to which they are attached, come together to form octahydropyrrolo[3,4-c]pyrrolyl optionally substituted with one or more R8. [0166] In some embodiments, one R₄ is hydrogen and one R₄ is C₁–C₆ alkyl. [0167] In some embodiments, one R₄ is hydrogen and one R₄ is C₁–C₆ alkyl substituted with one or more R₈. [0168] In some embodiments, one R₄ is hydrogen and one R₄ is C₁–C₆ alkyl substituted with –OH. [0169] In some embodiments, one R₄ is hydrogen and one R₄ is C₁–C₆ alkyl substituted with aryl. [0170] In some embodiments, one R₄ is hydrogen and one R₄ is C₁–C₆ alkyl substituted with phenyl. [0171] In some embodiments, one R₄ is hydrogen and one R₄ is C₁–C₆ alkyl substituted with C₃–C₁₀ cycloalkyl. [0172] In some embodiments, one R₄ is hydrogen and one R₄ is C₁–C₆ alkyl substituted with cyclopropyl. [0173] In some embodiments, one R₄ is hydrogen and one R₄ is C₁–C₆ alkyl substituted with –OH and phenyl. [0174] In some embodiments, at least one R₄ is selected from hydrogen,

,

and

[0175] In some embodiments, R5 is halo. In some embodiments, R5 is fluoro. In some embodiments, R₅ is chloro. In some embodiments, R₅ is bromo. In some embodiments, R₅ is iodo. In some embodiments, R5 is –OH. In some embodiments, R5 is –CN. In some embodiments, R₅ is –NO₂. In some embodiments, R₅ is –N(R₉)₂. In some embodiments, R₅ is C₁–C₆ alkyl. In some embodiments, R5 is C₁–C₆ alkyl substituted with one or more R10. In some embodiments, R₅ is methyl. In some embodiments, R₅ is ethyl. In some embodiments, R5 is propyl. In some embodiments, R5 is isopropyl. In some embodiments, R5 is butyl. In some embodiments, R₅ is isobutyl. In some embodiments, R₅ is sec-butyl. In some embodiments, R5 is tert-butyl. In some embodiments, R5 is pentyl. In some embodiments, R5 is isopentyl. In some embodiments, R₅ is sec-pentyl. In some embodiments, R₅ is neopentyl. In some embodiments, R5 is hexyl. In some embodiments, R5 is isohexyl. In some embodiments, R₅ is C₂–C₆ alkenyl. In some embodiments, R₅ is C₂–C₆ alkenyl substituted with one or more R10. In some embodiments, R5 is C₂–C₆ alkynyl. In some embodiments, R5 is C2– C₆ alkynyl substituted with one or more R₁₀. In some embodiments, R₅ is C₁–C₆ haloalkyl. In some embodiments, R5 is C₁–C₆ alkoxy. In some embodiments, R5 is C₁–C₆ alkoxy substituted with one or more R₁₀. In some embodiments, R₅ is C₁–C₆ haloalkoxy. In some embodiments, R5 is C₃–C₁₀ cycloalkyl. In some embodiments, R5 is C₃–C₁₀ cycloalkyl substituted with one or more R₁₀. In some embodiments, R₅ is aryl. In some embodiments, R₅ is aryl substituted with one or more R10. In some embodiments, R5 is phenyl. In some embodiments, R5 is phenyl substituted with one or more R₁₀. In some embodiments, R₅ is 3- to 10-membered heterocyclyl. In some embodiments, R5 is 3- to 10-membered heterocyclyl substituted with one or more R10. In some embodiments, R₅ is heteroaryl. In some embodiments, R₅ is heteroaryl substituted with one or more R10. [0176] In some embodiments, R₅ is hydrogen and each R₄, together with the nitrogen atom to which they are attached, come together to form piperazinyl. [0177] In some embodiments, R₅ is hydrogen, X₃ is CR_6c, and R_6c is not hydrogen. [0178] In some embodiments, R₅ is selected from hydrogen, methyl,

,

[0179] In some embodiments, R6a is hydrogen. In some embodiments, R6a is halo. In some embodiments, R_6a is fluoro. In some embodiments, R_6a is chloro. In some embodiments, R_6a is bromo. In some embodiments, R6a is iodo. In some embodiments, R6a is –OH. In some embodiments, R_6a is –CN. In some embodiments, R_6a is –NO₂. In some embodiments, R_6a is amino. In some embodiments, R6a is alkylamino. In some embodiments, R6a is dialkylamino. In some embodiments, R_6a is C₁–C₆ alkyl. In some embodiments, R_6a is methyl. In some embodiments, R6a is ethyl. In some embodiments, R6a is propyl. In some embodiments, R6a is isopropyl. In some embodiments, R6a is butyl. In some embodiments, R6a is isobutyl. In some embodiments, R_6a is sec-butyl. In some embodiments, R_6a is tert-butyl. In some embodiments, R6a is pentyl. In some embodiments, R6a is isopentyl. In some embodiments, R6a is sec-pentyl. In some embodiments, R_6a is neopentyl. In some embodiments, R_6a is hexyl. In some embodiments, R6a is isohexyl. In some embodiments, R6a is C₂–C₆ alkenyl. In some embodiments, R_6a is C₂–C₆ alkynyl. In some embodiments, R_6a is C₁–C₆ haloalkyl. In some embodiments, R6a is C₁–C₆ alkoxy. In some embodiments, R6a is C₁–C₆ haloalkoxy. In some embodiments, R_6a is –C(O)NR₁₅R₁₅. In some embodiments, R_6a is –C(O)OR₁₅. In some embodiments, R6a is –NR₁₅C(O)R₁₅. In some embodiments, R6a is –OC(O)R₁₅. In some embodiments, R_6a is C₃–C₁₀ cycloalkyl. In some embodiments, R_6a is aryl. In some embodiments, R6a is 3- to 10-membered heterocyclyl. In some embodiments, R6a is heteroaryl. In some embodiments, R_6a is selected from C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more halo, –OH, –CN, –NO2, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10- membered heterocyclyl, and heteroaryl. [0180] In some embodiments, R6b is hydrogen. In some embodiments, R6b is halo. In some embodiments, R_6b is fluoro. In some embodiments, R_6b is chloro. In some embodiments, R_6b is bromo. In some embodiments, R6b is iodo. In some embodiments, R6b is –OH. In some embodiments, R_6b is –CN. In some embodiments, R_6b is –NO₂. In some embodiments, R_6b is amino. In some embodiments, R6b is alkylamino. In some embodiments, R6b is dialkylamino. In some embodiments, R_6b is C₁–C₆ alkyl. In some embodiments, R_6b is methyl. In some embodiments, R6b is ethyl. In some embodiments, R6b is propyl. In some embodiments, R6b is isopropyl. In some embodiments, R_6b is butyl. In some embodiments, R_6b is isobutyl. In some embodiments, R6b is sec-butyl. In some embodiments, R6b is tert-butyl. In some embodiments, R_6b is pentyl. In some embodiments, R_6b is isopentyl. In some embodiments, R_6b is sec-pentyl. In some embodiments, R6b is neopentyl. In some embodiments, R6b is hexyl. In some embodiments, R_6b is isohexyl. In some embodiments, R_6b is C₂–C₆ alkenyl. In some embodiments, R6b is C₂–C₆ alkynyl. In some embodiments, R6b is C₁–C₆ haloalkyl. In some embodiments, R_6b is C₁–C₆ alkoxy. In some embodiments, R_6b is C₁–C₆ haloalkoxy. In some embodiments, R6b is –C(O)NR₁₅R₁₅. In some embodiments, R6b is –C(O)OR₁₅. In some embodiments, R_6b is –NR₁₅C(O)R₁₅. In some embodiments, R_6b is –OC(O)R₁₅. In some embodiments, R6b is C₃–C₁₀ cycloalkyl. In some embodiments, R6b is aryl. In some embodiments, R_6b is 3- to 10-membered heterocyclyl. In some embodiments, R_6b is heteroaryl. In some embodiments, R6b is selected from C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more halo, –OH, –CN, –NO₂, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10- membered heterocyclyl, and heteroaryl. [0181] In some embodiments, R6c is hydrogen. In some embodiments, R6c is halo. In some embodiments, R_6c is fluoro. In some embodiments, R_6c is chloro. In some embodiments, R_6c is bromo. In some embodiments, R6c is iodo. In some embodiments, R6c is –OH. In some embodiments, R_6c is –CN. In some embodiments, R_6c is –NO₂. In some embodiments, R_6c is amino. In some embodiments, R6c is alkylamino. In some embodiments, R6c is dialkylamino. In some embodiments, R_6c is C₁–C₆ alkyl. In some embodiments, R_6c is methyl. In some embodiments, R6c is ethyl. In some embodiments, R6c is propyl. In some embodiments, R6c is isopropyl. In some embodiments, R6c is butyl. In some embodiments, R6c is isobutyl. In some embodiments, R6c is sec-butyl. In some embodiments, R6c is tert-butyl. In some embodiments, R6c is pentyl. In some embodiments, R6c is isopentyl. In some embodiments, R6c is sec-pentyl. In some embodiments, R_6c is neopentyl. In some embodiments, R_6c is hexyl. In some embodiments, R6c is isohexyl. In some embodiments, R6c is C₂–C₆ alkenyl. In some embodiments, R_6c is C₂–C₆ alkynyl. In some embodiments, R_6c is C₁–C₆ haloalkyl. In some embodiments, R6c is C₁–C₆ alkoxy. In some embodiments, R6c is C₁–C₆ haloalkoxy. In some embodiments, R_6c is –C(O)NR₁₅R₁₅. In some embodiments, R_6c is –C(O)OR₁₅. In some embodiments, R6c is –NR₁₅C(O)R₁₅. In some embodiments, R6c is –OC(O)R₁₅. In some embodiments, R_6c is C₃–C₁₀ cycloalkyl. In some embodiments, R_6c is aryl. In some embodiments, R6c is 3- to 10-membered heterocyclyl. In some embodiments, R6b is heteroaryl. In some embodiments, R_6c is selected from C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more halo, –OH, –CN, –NO2, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10- membered heterocyclyl, and heteroaryl. [0182] In some embodiments, at least one of R6a, R6b, and R6c is hydrogen. In some embodiments, at least one of R_6a, R_6b, and R_6c is C₁–C₆ alkyl. In some embodiments, at least one of R6a, R6b, and R6c is methyl. [0183] In some embodiments, at least one R₄ is hydrogen, X₃ is CR_6c, and R_6c is not hydrogen. [0184] In some embodiments, at least one of R_6a, R_6b, and R_6c is –C(O)NR₁₅R₁₅. [0185] In some embodiments, at least one of R6a, R6b, and R6c is –C(O)OR₁₅. [0186] In some embodiments, at least one of R_6a, R_6b, and R_6c is heteroaryl. [0187] In some embodiments, at least one of R6a, R6b, and R6c is selected from hydrogen,

[0188] In some embodiments, R_6c is selected from hydrogen,

,

and

[0189] In some embodiments, R₂, R₃, and at least one of R_6a, R_6b, and R_6c are each hydrogen. [0190] In some embodiments, at least one R₇ is halo. In some embodiments, at least one R7 is fluoro. In some embodiments, at least one R7 is chloro. In some embodiments, at least one R₇ is bromo. In some embodiments, at least one R₇ is iodo. In some embodiments, at least one R7 is –OH. In some embodiments, at least one R7 is –CN. In some embodiments, at least one R₇ is –NO₂. In some embodiments, at least one R₇ is amino. In some embodiments, at least one R7 is alkylamino. In some embodiments, at least one R7 is dialkylamino. In some embodiments, at least one R₇ is C₁–C₆ alkyl. In some embodiments, at least one R₇ is methyl. In some embodiments, at least one R7 is ethyl. In some embodiments, at least one R7 is propyl. In some embodiments, at least one R7 is isopropyl. In some embodiments, at least one R7 is butyl. In some embodiments, at least one R7 is isobutyl. In some embodiments, at least one R7 is sec-butyl. In some embodiments, at least one R7 is tert-butyl. In some embodiments, at least one R7 is pentyl. In some embodiments, at least one R7 is isopentyl. In some embodiments, at least one R7 is sec-pentyl. In some embodiments, at least one R7 is neopentyl. In some embodiments, at least one R₇ is hexyl. In some embodiments, at least one R₇ is isohexyl. In some embodiments, at least one R7 is C₂–C₆ alkenyl. In some embodiments, at least one R₇ is C₂–C₆ alkynyl. In some embodiments, at least one R₇ is C₁–C₆ haloalkyl. In some embodiments, at least one R7 is C₁–C₆ alkoxy. In some embodiments, at least one R7 is C₁–C₆ haloalkoxy. In some embodiments, at least one R₇ is C₃–C₁₀ cycloalkyl. In some embodiments, at least one R7 is aryl. In some embodiments, at least one R7 is 3- to 10- membered heterocyclyl. In some embodiments, at least one R₇ is heteroaryl. [0191] In some embodiments, at least one R₈ is halo. In some embodiments, at least one R₈ is fluoro. In some embodiments, at least one R₈ is chloro. In some embodiments, at least one R₈ is bromo. In some embodiments, at least one R₈ is iodo. In some embodiments, at least one R₈ is –OH. In some embodiments, at least one R₈ is –CN. In some embodiments, at least one R₈ is –NO2. In some embodiments, at least one R₈ is amino. In some embodiments, at least one R₈ is alkylamino. In some embodiments, at least one R₈ is dialkylamino. In some embodiments, at least one R₈ is –C(O)R₁₂. In some embodiments, at least one R₈ is – C(O)NR_NR₁₂. In some embodiments, at least one R₈ is –C(O)OR₁₂. In some embodiments, at least one R₈ is –NRNC(O)R₁₂. In some embodiments, at least one R₈ is –NRNC(O)NRNR₁₂. In some embodiments, at least one R₈ is –OC(O)R₁₂. In some embodiments, at least one R₈ is – OC(O)OR₁₂. In some embodiments, at least one R₈ is –S(O)2R₁₂. In some embodiments, at least one R₈ is –S(O)₂NR_NR₁₂. In some embodiments, at least one R₈ is C₁–C₆ alkyl. In some embodiments, at least one R₈ is C₁–C₆ alkyl substituted with one or more R₁₃. In some embodiments, at least one R₈ is methyl. In some embodiments, at least one R₈ is ethyl. In some embodiments, at least one R₈ is propyl. In some embodiments, at least one R₈ is isopropyl. In some embodiments, at least one R₈ is butyl. In some embodiments, at least one R₈ is isobutyl. In some embodiments, at least one R₈ is sec-butyl. In some embodiments, at least one R₈ is tert-butyl. In some embodiments, at least one R₈ is pentyl. In some embodiments, at least one R₈ is isopentyl. In some embodiments, at least one R₈ is sec-pentyl. In some embodiments, at least one R₈ is neopentyl. In some embodiments, at least one R₈ is hexyl. In some embodiments, at least one R₈ is isohexyl. In some embodiments, at least one R₈ is C₂–C₆ alkenyl. In some embodiments, at least one R₈ is C₂–C₆ alkenyl substituted with one or more R_13. In some embodiments, at least one R₈ is C₂–C₆ alkynyl. In some embodiments, at least one R₈ is C₂–C₆ alkynyl substituted with one or more R₁₃. In some embodiments, at least one R₈ is C₁–C₆ haloalkyl. In some embodiments, at least one R₈ is C₁– C6 alkoxy. In some embodiments, at least one R₈ is C₁–C₆ alkoxy substituted with one or more R_13. In some embodiments, at least one R₈ is C₁–C₆ haloalkoxy. In some embodiments, at least one R₈ is C₃–C₁₀ cycloalkyl. In some embodiments, at least one R₈ is C₃–C₁₀ cycloalkyl substituted with one or more R_13. In some embodiments, at least one R₈ is aryl. In some embodiments, at least one R₈ is aryl substituted with one or more R₁₃. In some embodiments, at least one R₈ is 3- to 10-membered heterocyclyl. In some embodiments, at least one R₈ is 3- to 10-membered heterocyclyl substituted with one or more R₁₃. In some embodiments, at least one R₈ is heteroaryl. In some embodiments, at least one R₈ is heteroaryl substituted with one or more R₁₃. [0192] In some embodiments, at least one R₉ is hydrogen. In some embodiments, at least one R9 is C₁–C₆ alkyl. In some embodiments, at least one R9 is C₁–C₆ alkyl substituted with one or more R_13. In some embodiments, at least one R₉ is methyl. In some embodiments, at least one R9 is ethyl. In some embodiments, at least one R9 is propyl. In some embodiments, at least one R₉ is isopropyl. In some embodiments, at least one R₉ is butyl. In some embodiments, at least one R9 is isobutyl. In some embodiments, at least one R9 is sec-butyl. In some embodiments, at least one R₉ is tert-butyl. In some embodiments, at least one R₉ is pentyl. In some embodiments, at least one R9 is isopentyl. In some embodiments, at least one R₉ is sec-pentyl. In some embodiments, at least one R₉ is neopentyl. In some embodiments, at least one R9 is hexyl. In some embodiments, at least one R9 is isohexyl. In some embodiments, at least one R₉ is C₂–C₆ alkenyl. In some embodiments, at least one R₉ is C₂– C6 alkynyl. In some embodiments, at least one R9 is C₁–C₆ haloalkyl. In some embodiments, at least one R₉ is C₁–C₆ alkoxy. In some embodiments, at least one R₉ is C₁–C₆ haloalkoxy. In some embodiments, at least one R9 is C₃–C₁₀ cycloalkyl. In some embodiments, at least one R₉ is aryl. In some embodiments, at least one R₉ is 3- to 10-membered heterocyclyl. In some embodiments, at least one R9 is heteroaryl. In some embodiments, at least one R9 is selected from C₃–C₁₀ cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more halo, –OH, –CN, –NO2, amino, alkylamino, dialkylamino, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, –C(O)R11, –C(O)NHR11, – C(O)OR11, –NRNC(O)R11, –NRNC(O)R11, –NRNC(O)NRNR11, –OC(O)R11, and –OC(O)OR11. [0193] In some embodiments, at least one R₁₀ is halo. In some embodiments, at least one R10 is fluoro. In some embodiments, at least one R10 is chloro. In some embodiments, at least one R₁₀ is bromo. In some embodiments, at least one R₁₀ is iodo. In some embodiments, at least one R10 is –OH. In some embodiments, at least one R10 is –CN. In some embodiments, at least one R₁₀ is –NO₂. In some embodiments, at least one R₁₀ is –N(R₉)₂. In some embodiments, at least one R10 is C₁–C₆ alkyl. In some embodiments, at least one R10 is methyl. In some embodiments, at least one R₁₀ is ethyl. In some embodiments, at least one R₁₀ is propyl. In some embodiments, at least one R10 is isopropyl. In some embodiments, at least one R₁₀ is butyl. In some embodiments, at least one R₁₀ is isobutyl. In some embodiments, at least one R10 is sec-butyl. In some embodiments, at least one R10 is tert-butyl. In some embodiments, at least one R₁₀ is pentyl. In some embodiments, at least one R₁₀ is isopentyl. In some embodiments, at least one R10 is sec-pentyl. In some embodiments, at least one R10 is neopentyl. In some embodiments, at least one R₁₀ is hexyl. In some embodiments, at least one R10 is isohexyl. In some embodiments, at least one R10 is C₂–C₆ alkenyl. In some embodiments, at least one R₁₀ is C₂–C₆ alkynyl. In some embodiments, at least one R₁₀ is C₁– C6 haloalkyl. In some embodiments, at least one R10 is C₁–C₆ alkoxy. In some embodiments, at least one R₁₀ is C₁–C₆ haloalkoxy. [0194] In some embodiments, at least one R11 is hydrogen. In some embodiments, at least one R₁₁ is C₁–C₆ alkyl. In some embodiments, at least one R₁₁ is methyl. In some embodiments, at least one R11 is ethyl. In some embodiments, at least one R11 is propyl. In some embodiments, at least one R₁₁ is isopropyl. In some embodiments, at least one R₁₁ is butyl. In some embodiments, at least one R11 is isobutyl. In some embodiments, at least one R11 is sec- butyl. In some embodiments, at least one R₁₁ is tert-butyl. In some embodiments, at least one R11 is pentyl. In some embodiments, at least one R11 is isopentyl. In some embodiments, at least one R₁₁ is sec-pentyl. In some embodiments, at least one R₁₁ is neopentyl. In some embodiments, at least one R11 is hexyl. In some embodiments, at least one R11 is isohexyl. In some embodiments, at least one R₁₁ is C₂–C₆ alkenyl. In some embodiments, at least one R₁₁ is C₂–C₆ alkynyl. In some embodiments, at least one R11 is C₁–C₆ haloalkyl. In some embodiments, at least one R₁₁ is C₁–C₆ alkoxy. In some embodiments, at least one R₁₁ is C₁– C6 haloalkoxy. [0195] In some embodiments, at least one R₁₂ is C₁–C₆ alkyl. In some embodiments, at least one R₁₂ is methyl. In some embodiments, at least one R₁₂ is ethyl. In some embodiments, at least one R₁₂ is propyl. In some embodiments, at least one R₁₂ is isopropyl. In some embodiments, at least one R₁₂ is butyl. In some embodiments, at least one R₁₂ is isobutyl. In some embodiments, at least one R₁₂ is sec-butyl. In some embodiments, at least one R₁₂ is tert- butyl. In some embodiments, at least one R₁₂ is pentyl. In some embodiments, at least one R₁₂ is isopentyl. In some embodiments, at least one R₁₂ is sec-pentyl. In some embodiments, at least one R₁₂ is neopentyl. In some embodiments, at least one R₁₂ is hexyl. In some embodiments, at least one R₁₂ is isohexyl. In some embodiments, at least one R₁₂ is C₂–C₆ alkenyl. In some embodiments, at least one R₁₂ is C₂–C₆ alkynyl. In some embodiments, at least one R₁₂ is C₁–C₆ haloalkyl. In some embodiments, at least one R₁₂ is C₁–C₆ alkoxy. In some embodiments, at least one R₁₂ is C₁–C₆ haloalkoxy. In some embodiments, at least one R₁₂ is C₃–C₁₀ cycloalkyl. In some embodiments, at least one R₁₂ is aryl, and 3- to 10-membered heterocyclyl. In some embodiments, at least one R₁₂ is selected from C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, C₃–C₁₀ cycloalkyl, aryl, and 3- to 10-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl are optionally substituted with one or more halo, –OH, –CN, –NO2, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, –C(O)R₁₄, –C(O)NRNR₁₄, –C(O)OR₁₄, –NRNC(O)R₁₄, –OC(O)R₁₄, C₃–C₁₀ cycloalkyl, aryl, and 3- to 10- membered heterocyclyl. [0196] In some embodiments, at least one R₁₃ is halo. In some embodiments, at least one R₁₃ is fluoro. In some embodiments, at least one R₁₃ is chloro. In some embodiments, at least one R₁₃ is bromo. In some embodiments, at least one R₁₃ is iodo. In some embodiments, at least one R₁₃ is –OH. In some embodiments, at least one R₁₃ is –CN. In some embodiments, at least one R₁₃ is –NO2. In some embodiments, at least one R₁₃ is C₁–C₆ alkyl. In some embodiments, at least one R₁₃ is methyl. In some embodiments, at least one R₁₃ is ethyl. In some embodiments, at least one R₁₃ is propyl. In some embodiments, at least one R₁₃ is isopropyl. In some embodiments, at least one R₁₃ is butyl. In some embodiments, at least one R₁₃ is isobutyl. In some embodiments, at least one R₁₃ is sec-butyl. In some embodiments, at least one R₁₃ is tert-butyl. In some embodiments, at least one R₁₃ is pentyl. In some embodiments, at least one R₁₃ is isopentyl. In some embodiments, at least one R₁₃ is sec-pentyl. In some embodiments, at least one R₁₃ is neopentyl. In some embodiments, at least one R₁₃ is hexyl. In some embodiments, at least one R₁₃ is isohexyl. In some embodiments, at least one R₁₃ is C₂–C₆ alkenyl. In some embodiments, at least one R₁₃ is C₂–C₆ alkynyl. In some embodiments, at least one R₁₃ is C₁–C₆ haloalkyl. In some embodiments, at least one R₁₃ is C₁–C₆ alkoxy. In some embodiments, at least one R₁₃ is C₁–C₆ haloalkoxy. In some embodiments, at least one R₁₃ is C₃–C₁₀ cycloalkyl. In some embodiments, at least one R₁₃ is aryl. In some embodiments, at least one R₁₃ is 3- to 10-membered heterocyclyl. In some embodiments, at least one R₁₃ is heteroaryl. [0197] In some embodiments, at least one R₁₄ is C₁–C₆ alkyl. In some embodiments, at least one R₁₄ is methyl. In some embodiments, at least one R₁₄ is ethyl. In some embodiments, at least one R₁₄ is propyl. In some embodiments, at least one R₁₄ is isopropyl. In some embodiments, at least one R₁₄ is butyl. In some embodiments, at least one R₁₄ is isobutyl. In some embodiments, at least one R₁₄ is sec-butyl. In some embodiments, at least one R₁₄ is tert- butyl. In some embodiments, at least one R₁₄ is pentyl. In some embodiments, at least one R₁₄ is isopentyl. In some embodiments, at least one R₁₄ is sec-pentyl. In some embodiments, at least one R₁₄ is neopentyl. In some embodiments, at least one R₁₄ is hexyl. In some embodiments, at least one R₁₄ is isohexyl. In some embodiments, at least one R₁₄ is C₂–C₆ alkenyl. In some embodiments, at least one R₁₄ is C₂–C₆ alkynyl. In some embodiments, at least one R₁₄ is C₁–C₆ haloalkyl. In some embodiments, at least one R₁₄ is C₁–C₆ alkoxy. In some embodiments, at least one R₁₄ is C₁–C₆ haloalkoxy. [0198] In some embodiments, at least one R₁₅ is C₁–C₆ alkyl. In some embodiments, at least one R₁₅ is methyl. In some embodiments, at least one R₁₅ is ethyl. In some embodiments, at least one R₁₅ is propyl. In some embodiments, at least one R₁₅ is isopropyl. In some embodiments, at least one R₁₅ is butyl. In some embodiments, at least one R₁₅ is isobutyl. In some embodiments, at least one R₁₅ is sec-butyl. In some embodiments, at least one R₁₅ is tert- butyl. In some embodiments, at least one R₁₅ is pentyl. In some embodiments, at least one R₁₅ is isopentyl. In some embodiments, at least one R₁₅ is sec-pentyl. In some embodiments, at least one R₁₅ is neopentyl. In some embodiments, at least one R₁₅ is hexyl. In some embodiments, at least one R₁₅ is isohexyl. In some embodiments, at least one R₁₅ is C₂–C₆ alkenyl. In some embodiments, at least one R₁₅ is C₂–C₆ alkynyl. In some embodiments, at least one R₁₅ is C₁–C₆ haloalkyl. In some embodiments, at least one R₁₅ is C₁–C₆ alkoxy. In some embodiments, at least one R₁₅ is C₁–C₆ haloalkoxy. In some embodiments, at least one R₁₅ is C₃–C₁₀ cycloalkyl. In some embodiments, at least one R₁₅ is aryl. In some embodiments, at least one R₁₅ is 3- to 10-membered heterocyclyl. In some embodiments, at least one R₁₅ is heteroaryl. In some embodiments, at least one R₁₅ is selected from C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ alkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more halo, –OH, –CN, –NO2, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl. [0199] In some embodiments, at least one R_N is hydrogen. In some embodiments, at least one RN is C₁–C₆ alkyl. In some embodiments, at least one RN is methyl. In some embodiments, at least one R_N is ethyl. In some embodiments, at least one R_N is propyl. In some embodiments, at least one RN is isopropyl. In some embodiments, at least one RN is butyl. In some embodiments, at least one R_N is isobutyl. In some embodiments, at least one R_N is sec-butyl. In some embodiments, at least one RN is tert-butyl. In some embodiments, at least one RN is pentyl. In some embodiments, at least one R_N is isopentyl. In some embodiments, at least one RN is sec-pentyl. In some embodiments, at least one RN is neopentyl. In some embodiments, at least one R_N is hexyl. In some embodiments, at least one R_N is isohexyl. In some embodiments, at least one RN is C₂–C₆ alkenyl. In some embodiments, at least one RN is C2– C₆ alkynyl. In some embodiments, at least one R_N is C₃–C₁₀ cycloalkyl. In some embodiments, at least one RN is aryl. [0200] In some embodiments, X1 is N; X2 is N; X3 is CR6c; R1 is C₁–C₆ alkyl; R2 is hydrogen; R₃ is hydrogen; R₄ is hydrogen; R₄ is C₁–C₆ alkyl substituted with one or more R₈; R5 is hydrogen; R6c is –C(O)NR₁₅R₁₅; R8 is –OH; R8 is aryl; R₁₅ is hydrogen; and R₁₅ is C₁–C₆ alkyl. [0201] In some embodiments, X1 is N; X2 is N; X3 is CR6c; R1 is C₁–C₆ alkyl; R2 is hydrogen; R₃ is hydrogen; R₄ is hydrogen; R₄ is C₁–C₆ alkyl substituted with one or more R₈; R5 is hydrogen; R6c is –C(O)OR₁₅; R8 is –OH; and R₁₅ is C₁–C₆ alkyl. [0202] In some embodiments, X₁ is N; X₂ is N; X₃ is CR_6c; R₁ is C₁–C₆ alkyl; R₂ is hydrogen; R₃ is hydrogen; each R₄, together with the nitrogen atom to which they are attached, come together to form 3- to 10-membered heterocyclyl; R₅ is hydrogen; R_6c is –C(O)NR₁₅R₁₅; R8 is –OH; R8 is aryl; R₁₅ is hydrogen; and R₁₅ is C₃–C₁₀ cycloalkyl. [0203] In some embodiments, X₁ is N; X₂ is N; X₃ is CR_6c; R₁ is C₁–C₆ alkyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is hydrogen; R₄ is C₁–C₆ alkyl substituted with one or more R8; R₅ is hydrogen; R_6c is –C(O)NR₁₅R₁₅; R₈ is –OH; R₈ is aryl; R₁₅ is hydrogen; and R₁₅ is C₁–C₆ alkyl substituted with aryl. [0204] In some embodiments, X1 is N; X2 is N; X3 is CR6c; R1 is C₁–C₆ alkyl; R2 is hydrogen; R₃ is hydrogen; R₄ is hydrogen; R₄ is C₁–C₆ alkyl substituted with one or more R8; R5 is hydrogen; R6c is –C(O)OR₁₅; R8 is –OH; and R₁₅ is C₁–C₆ alkyl. [0205] In some embodiments, X₁ is N; X₂ is N; X₃ is CR_6c; R₁ is C₁–C₆ alkyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is hydrogen; R₄ is C₁–C₆ alkyl substituted with one or more R8; R₅ is hydrogen; R_6c is heteroaryl ; R₈ is –OH; and R₈ is aryl. [0206] Non-limiting illustrative compounds of the present disclosure include: N-{2-[4-(dimethylamino)piperidin-1-yl]-6-(pyrrolidin-1-yl)pyrimidin-4-yl}-1-(propan-2- yl)-1H-pyrazolo[4,3-c]pyridin-6-amine; N²-(2-methoxyethyl)-N²-methyl-N⁴-[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-6- (pyrrolidin-1-yl)pyrimidine-2,4-diamine; N-[2-(4-methylpiperidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-amine; N-[2-(3,3-difluoropiperidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-amine; N²-butyl-N²-methyl-N⁴-[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-6-(pyrrolidin-1- yl)pyrimidine-2,4-diamine; N²-cyclohexyl-N²-methyl-N⁴-[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-6- (pyrrolidin-1-yl)pyrimidine-2,4-diamine; N-[2-(4-phenylpiperidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-amine; {1-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1- yl)pyrimidin-2-yl]piperidin-4-yl}methanol; 2-phenyl-2-{[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-2-(pyrrolidin-1- yl)pyrimidin-4-yl]amino}ethanol; {1-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1- yl)pyrimidin-4-yl]piperidin-4-yl}methanol; N-[4-(3,3-difluoropiperidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-amine; N⁴-butyl-N⁴-methyl-N²-[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-6-(pyrrolidin-1- yl)pyrimidine-2,4-diamine; N⁴-(2-methoxyethyl)-N⁴-methyl-N²-[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-6- (pyrrolidin-1-yl)pyrimidine-2,4-diamine; N-[4-(4-phenylpiperidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-amine; N-[2-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-amine; N-[6-(piperazin-1-yl)-2-(pyrrolidin-1-yl)pyrimidin-4-yl]-1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-amine; N²-butyl-N²-methyl-6-(piperazin-1-yl)-N⁴-[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]pyrimidine-2,4-diamine; N-[2-(4-aminopiperidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-amine; N-[2-(3-aminoazetidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-amine; 1-(propan-2-yl)-N-{2-[3-(propan-2-yl)piperazin-1-yl]-6-(pyrrolidin-1-yl)pyrimidin-4-yl}- 1H-pyrazolo[4,3-c]pyridin-6-amine; N-{2-[(3S)-3-methylpiperazin-1-yl]-6-(pyrrolidin-1-yl)pyrimidin-4-yl}-1-(propan-2-yl)- 1H-pyrazolo[4,3-c]pyridin-6-amine; N-[2-(1,4-diazepan-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-amine; N-[6-(1,4-diazepan-1-yl)-2-(pyrrolidin-1-yl)pyrimidin-4-yl]-1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-amine; N-{6-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2-(pyrrolidin-1-yl)pyrimidin-4- yl}-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine; N-[2,6-di(piperazin-1-yl)pyrimidin-4-yl]-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- amine; N-[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1-(propan-2-yl)-1H-imidazo[4,5- c]pyridin-6-amine; N-[2-(3-aminopyrrolidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-amine; 1-[4-(piperazin-1-yl)-6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}pyrimidin-2-yl]pyrrolidin-3-ol; N-(piperidin-4-yl)-N'-[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-2-(pyrrolidin-1- yl)pyrimidine-4,6-diamine; N-[2-(2-methylpyrrolidin-1-yl)-6-(piperazin-1-yl)pyrimidin-4-yl]-1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-amine; N-{2-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6-(pyrrolidin-1-yl)pyrimidin-4- yl}-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine; N-{2-[(2S)-2-methylpiperazin-1-yl]-6-(pyrrolidin-1-yl)pyrimidin-4-yl}-1-(propan-2-yl)- 1H-pyrazolo[4,3-c]pyridin-6-amine; N-[4-(4-aminopiperidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-amine; 1-[6-(piperazin-1-yl)-2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}pyrimidin-4-yl]pyrrolidin-3-ol; N-[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-amine; N-[4-(1,4-diazepan-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-amine; N-[4-(3-aminopyrrolidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-amine; N⁴-(piperidin-4-yl)-N²-[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-6-(pyrrolidin-1- yl)pyrimidine-2,4-diamine; N-[4-(2-methylpyrrolidin-1-yl)-6-(piperazin-1-yl)pyrimidin-2-yl]-1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-amine; N-{4-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6-(pyrrolidin-1-yl)pyrimidin-2- yl}-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine; 1-cyclopentyl-N-[6-(piperazin-1-yl)-2-(pyrrolidin-1-yl)pyrimidin-4-yl]-1H-pyrazolo[4,3- c]pyridin-6-amine; 1-(cyclohex-2-en-1-yl)-N-[6-(piperazin-1-yl)-2-(pyrrolidin-1-yl)pyrimidin-4-yl]-1H- pyrazolo[4,3-c]pyridin-6-amine; N-[6-(piperazin-1-yl)-2-(pyrrolidin-1-yl)pyrimidin-4-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H- pyrazolo[4,3-c]pyridin-6-amine; 1-(cyclobutylmethyl)-N-[6-(piperazin-1-yl)-2-(pyrrolidin-1-yl)pyrimidin-4-yl]-1H- pyrazolo[4,3-c]pyridin-6-amine; 1-(cyclohexylmethyl)-N-[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1H- pyrazolo[4,3-c]pyridin-6-amine; 1-cyclopentyl-N-[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1H-pyrazolo[4,3- c]pyridin-6-amine; N-[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H- pyrazolo[4,3-c]pyridin-6-amine; 1-(cyclohex-2-en-1-yl)-N-[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1H- pyrazolo[4,3-c]pyridin-6-amine; 1-(cyclobutylmethyl)-N-[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1H- pyrazolo[4,3-c]pyridin-6-amine; 1-benzyl-N-[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1H-pyrazolo[4,3- c]pyridin-6-amine; 1-cyclohexyl-N-[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1H-pyrazolo[4,3- c]pyridin-6-amine; N-[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1-(pyridin-3-ylmethyl)-1H- pyrazolo[4,3-c]pyridin-6-amine; 1-phenyl-N-[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1H-pyrazolo[4,3- c]pyridin-6-amine; 3-methyl-6-{[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]amino}-1-(propan-2-yl)- 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one; N-(2-methoxyethyl)-4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide; N-(2-methoxyethyl)-4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-2-yl]piperazine-1-carboxamide; N-(2-methoxyethyl)-4-[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-2- (pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide; 1-(2-methoxyethyl)-3-{1-[6-(piperazin-1-yl)-2-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}pyrimidin-4-yl]pyrrolidin-3-yl}urea; 4-[2-{[1-(cyclohexylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1- yl)pyrimidin-4-yl]-N-(2-methoxyethyl)piperazine-1-carboxamide; N-(2-methoxyethyl)-4-[6-(2-methylpyrrolidin-1-yl)-2-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}pyrimidin-4-yl]piperazine-1-carboxamide; N-(2-methoxyethyl)-4-[2-(morpholin-4-yl)-6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin- 6-yl]amino}pyrimidin-4-yl]piperazine-1-carboxamide; N-(2-methoxyethyl)-4-[2-(piperidin-1-yl)-6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin- 6-yl]amino}pyrimidin-4-yl]piperazine-1-carboxamide; 4-{2-[(1-cyclohexyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino]-6-(pyrrolidin-1-yl)pyrimidin- 4-yl}-N-(2-methoxyethyl)piperazine-1-carboxamide; 4-(2-[butyl(methyl)amino]-6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}pyrimidin-4-yl)-N-(2-methoxyethyl)piperazine-1-carboxamide; 4-[2-(2,6-dimethylmorpholin-4-yl)-6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}pyrimidin-4-yl]-N-(2-methoxyethyl)piperazine-1-carboxamide; 4-{6-[(1-ethyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino]-2-(pyrrolidin-1-yl)pyrimidin-4-yl}- N-(2-methoxyethyl)piperazine-1-carboxamide; N-(2-methoxyethyl)-4-[6-{[1-(2-methylpropyl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-2- (pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide; N-(2-methoxyethyl)-4-[2-(pyrrolidin-1-yl)-6-{[1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}pyrimidin-4-yl]piperazine-1-carboxamide; 4-{6-[(1-cyclohexyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino]-2-(pyrrolidin-1-yl)pyrimidin- 4-yl}-N-(2-methoxyethyl)piperazine-1-carboxamide; N-(2-methoxyethyl)-2,5-dimethyl-4-[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-2-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide; (2S)-N-(2-methoxyethyl)-2-methyl-4-[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-2-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide; (2S)-N-(2-methoxyethyl)-2-methyl-4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperazine-1-carboxamide; 1-(2-methoxyethyl)-3-{1-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-2-yl]piperidin-4-yl}urea; 1-(2-methoxyethyl)-3-{1-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-4-yl]piperidin-4-yl}urea; 1-(2-methoxyethyl)-3-{1-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-2-yl]azetidin-3-yl}urea; 1-(2-methoxyethyl)-3-{1-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-4-yl]azetidin-3-yl}urea; N-(2-methoxyethyl)-2-(propan-2-yl)-4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperazine-1-carboxamide; N-(2-methoxyethyl)-4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-2-yl]-1,4-diazepane-1-carboxamide; N-(2-methoxyethyl)-4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-4-yl]-1,4-diazepane-1-carboxamide; N-(2-methoxyethyl)-4-[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-2- (pyrrolidin-1-yl)pyrimidin-4-yl]-1,4-diazepane-1-carboxamide; N-(2-methoxyethyl)-2-(propan-2-yl)-4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide; 4-{6-[(1-cyclopentyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino]-2-(pyrrolidin-1-yl)pyrimidin- 4-yl}-N-(2-methoxyethyl)piperazine-1-carboxamide; 4-{2-[(1-cyclopentyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino]-6-(pyrrolidin-1-yl)pyrimidin- 4-yl}-N-(2-methoxyethyl)piperazine-1-carboxamide; 4,4'-(6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}pyrimidine-2,4- diyl)bis[N-(2-methoxyethyl)piperazine-1-carboxamide]; 4-[2-(3-hydroxypyrrolidin-1-yl)-6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}pyrimidin-4-yl]-N-(2-methoxyethyl)piperazine-1-carboxamide; 4-[6-(3-hydroxypyrrolidin-1-yl)-2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}pyrimidin-4-yl]-N-(2-methoxyethyl)piperazine-1-carboxamide; 1-(2-methoxyethyl)-3-{1-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-4-yl]pyrrolidin-3-yl}urea; 1-(2-methoxyethyl)-3-{1-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-2-yl]pyrrolidin-3-yl}urea; N-(2-methoxyethyl)-4-{[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-2- (pyrrolidin-1-yl)pyrimidin-4-yl]amino}piperidine-1-carboxamide; N-(2-methoxyethyl)-4-[6-(pyrrolidin-1-yl)-2-{[1-(tetrahydro-2H-pyran-4-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]amino}pyrimidin-4-yl]piperazine-1-carboxamide; 4-[2-{[1-(cyclohex-2-en-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1- yl)pyrimidin-4-yl]-N-(2-methoxyethyl)piperazine-1-carboxamide; 4-[2-{[1-(cyclobutylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1- yl)pyrimidin-4-yl]-N-(2-methoxyethyl)piperazine-1-carboxamide; N-(2-methoxyethyl)-4-{[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-4-yl]amino}piperidine-1-carboxamide; 4-{2-[(1-benzyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino]-6-(pyrrolidin-1-yl)pyrimidin-4- yl}-N-(2-methoxyethyl)piperazine-1-carboxamide; (3aR,6aS)-N-(2-methoxyethyl)-5-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]hexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide; (3aR,6aS)-N-(2-methoxyethyl)-5-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]hexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxamide; N-(2-methoxyethyl)-4-[2-{[1-(propan-2-yl)-1H-imidazo[4,5-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide; (3S)-N-(2-methoxyethyl)-3-methyl-4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperazine-1-carboxamide; N-(2-methoxyethyl)-4-[2-{[1-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide; N-(2-methoxyethyl)-4-{2-[(1-phenyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino]-6-(pyrrolidin- 1-yl)pyrimidin-4-yl}piperazine-1-carboxamide; 4-{6-[(1-cyclohexyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino]-2-(pyrrolidin-1-yl)pyrimidin- 4-yl}-N-(3-methoxypropyl)piperazine-1-carboxamide; N-(3-methoxypropyl)-4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide; N-(2-phenylethyl)-4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-2-yl]piperazine-1-carboxamide; N-(2-phenylethyl)-4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide; N-(3-methylbutyl)-4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-2-yl]piperazine-1-carboxamide; N-(3-methylbutyl)-4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide; N-(3-ethoxypropyl)-4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide; N-tert-butyl-4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin- 1-yl)pyrimidin-4-yl]piperazine-1-carboxamide; N-benzyl-4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1- yl)pyrimidin-4-yl]piperazine-1-carboxamide; 4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1- yl)pyrimidin-4-yl]-N-(tetrahydrofuran-2-ylmethyl)piperazine-1-carboxamide; 2-methoxy-1-{4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-4-yl]piperazin-1-yl}ethenone; 2-methoxy-1-{4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-2-yl]piperazin-1-yl}ethenone; 2-methoxy-1-{4-[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-2- (pyrrolidin-1-yl)pyrimidin-4-yl]piperazin-1-yl}ethenone; 2-methoxy-N-{1-[6-(piperazin-1-yl)-2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}pyrimidin-4-yl]pyrrolidin-3-yl}acetamide; 1-{4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1- yl)pyrimidin-2-yl]piperazin-1-yl}pent-4-yn-1-one; 1-{4-[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-2-(pyrrolidin-1- yl)pyrimidin-4-yl]piperazin-1-yl}pent-4-yn-1-one; 1-{4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1- yl)pyrimidin-4-yl]piperazin-1-yl}pent-4-yn-1-one; N-{1-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1- yl)pyrimidin-2-yl]piperidin-4-yl}pent-4-ynamide; N-{1-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1- yl)pyrimidin-4-yl]piperidin-4-yl}pent-4-ynamide; N-{1-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1- yl)pyrimidin-2-yl]azetidin-3-yl}pent-4-ynamide; N-{1-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1- yl)pyrimidin-4-yl]azetidin-3-yl}pent-4-ynamide; 1-{4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1- yl)pyrimidin-2-yl]-1,4-diazepan-1-yl}pent-4-yn-1-one; 1-{4-[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-2-(pyrrolidin-1- yl)pyrimidin-4-yl]-1,4-diazepan-1-yl}pent-4-yn-1-one; 1-{4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1- yl)pyrimidin-4-yl]-1,4-diazepan-1-yl}pent-4-yn-1-one; 1-[(3aR,6aS)-5-[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-2-(pyrrolidin- 1-yl)pyrimidin-4-yl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]pent-4-yn-1-one; 3-[1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl]-1-{4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperazin-1-yl}propan-1-one; 3-[1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl]-1-{4-[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-2-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazin-1-yl}propan-1-one; ethyl 7-(4-{2-[(1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino]-6-pyrrolidin-1- ylpyrimidin-4-yl}piperazin-1-yl)-7-oxoheptanoate; ethyl 7-(4-{4-[(1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino]-6-pyrrolidin-1- ylpyrimidin-2-yl}piperazin-1-yl)-7-oxoheptanoate; cyclohexyl{4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin- 1-yl)pyrimidin-2-yl]piperazin-1-yl}methanone; (4-ethylphenyl){4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-2-yl]piperazin-1-yl}methanone; (3,4-dimethylphenyl){4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-2-yl]piperazin-1-yl}methanone; {4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1- yl)pyrimidin-2-yl]piperazin-1-yl}(thiophen-2-yl)methanone; 2-ethyl-1-{4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1- yl)pyrimidin-2-yl]piperazin-1-yl}butan-1-one; 2-(1H-indol-3-yl)-1-{4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-2-yl]piperazin-1-yl}ethanone; N-(2-oxo-2-{4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin- 1-yl)pyrimidin-4-yl]piperazin-1-yl}ethyl)acetamide; N-{2-[4-(cyclopropylsulfonyl)piperazin-1-yl]-6-(pyrrolidin-1-yl)pyrimidin-4-yl}-1- (propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine; N-[2-{4-[4-(dimethylamino)benzyl]piperazin-1-yl}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1- (propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine; N-{2-[4-(cyclohexylmethyl)piperazin-1-yl]-6-(pyrrolidin-1-yl)pyrimidin-4-yl}-1-(propan- 2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine; tert-butyl 4-[2-(2,6-dimethylmorpholin-4-yl)-6-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}pyrimidin-4-yl]piperazine-1-carboxylate; tert-butyl 4-[2-(morpholin-4-yl)-6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}pyrimidin-4-yl]piperazine-1-carboxylate; tert-butyl 4-[2-(piperidin-1-yl)-6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}pyrimidin-4-yl]piperazine-1-carboxylate; tert-butyl 4-(2-[butyl(methyl)amino]-6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}pyrimidin-4-yl)piperazine-1-carboxylate; (S)-4-((2-hydroxy-1-phenylethyl)amino)-N-isopropyl-2-((1-isopropyl-1H-pyrazolo[4,3- c]pyridin-6-yl)amino)pyrimidine-5-carboxamide; 2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-4-(piperazin-1-yl)pyrimidine-5- carboxamide; ethyl 2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-4-(piperazin-1-yl)pyrimidine- 5-carboxylate; ethyl 2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-4-(4-((2- methoxyethyl)carbamoyl)piperazin-1-yl)pyrimidine-5-carboxylate; (S)-N-cyclopentyl-4-((2-hydroxy-1-phenylethyl)amino)-2-((1-isopropyl-1H-pyrazolo[4,3- c]pyridin-6-yl)amino)pyrimidine-5-carboxamide; (S)-N-benzyl-4-((2-hydroxy-1-phenylethyl)amino)-2-((1-isopropyl-1H-pyrazolo[4,3- c]pyridin-6-yl)amino)pyrimidine-5-carboxamide; (S)-4-((2-hydroxy-1-phenylethyl)amino)-N-isobutyl-2-((1-isopropyl-1H-pyrazolo[4,3- c]pyridin-6-yl)amino)pyrimidine-5-carboxamide; ethyl 4-((1-(hydroxymethyl)cyclopropyl)amino)-2-((1-isopropyl-1H-pyrazolo[4,3- c]pyridin-6-yl)amino)pyrimidine-5-carboxylate; ethyl 4-((1-hydroxy-2-methylpropan-2-yl)amino)-2-((1-isopropyl-1H-pyrazolo[4,3- c]pyridin-6-yl)amino)pyrimidine-5-carboxylate; (S)-2-((2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-5-(1,3,4-oxadiazol-2- yl)pyrimidin-4-yl)amino)-2-phenylethan-1-ol; (S)-2-((5-(3-(difluoromethyl)-1,2,4-oxadiazol-5-yl)-2-((1-isopropyl-1H-pyrazolo[4,3- c]pyridin-6-yl)amino)pyrimidin-4-yl)amino)-2-phenylethan-1-ol; (S)-2-((2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-5-(3-(trifluoromethyl)- 1,2,4-oxadiazol-5-yl)pyrimidin-4-yl)amino)-2-phenylethan-1-ol; (S)-2-((5-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)-2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin- 6-yl)amino)pyrimidin-4-yl)amino)-2-phenylethan-1-ol; (S)-2-((5-(3-ethyl-1,2,4-oxadiazol-5-yl)-2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6- yl)amino)pyrimidin-4-yl)amino)-2-phenylethan-1-ol; (S)-2-isopropyl-4-(2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-5-(1,3,4- oxadiazol-2-yl)pyrimidin-4-yl)-N-(2-methoxyethyl)piperazine-1-carboxamide; 4-(2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-5-(1,3,4-oxadiazol-2- yl)pyrimidin-4-yl)-N-(2-methoxyethyl)piperazine-1-carboxamide; (S)-1-isopropyl-N-(4-(3-isopropylpiperazin-1-yl)-5-(1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)- 1H-pyrazolo[4,3-c]pyridin-6-amine; N-(5-(1,3,4-oxadiazol-2-yl)-4-(piperazin-1-yl)pyrimidin-2-yl)-1-isopropyl-1H- pyrazolo[4,3-c]pyridin-6-amine; (1-((2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-5-(1,3,4-oxadiazol-2- yl)pyrimidin-4-yl)amino)cyclopropyl)methanol; (1-((2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-5-(1,3,4-oxadiazol-2- yl)pyrimidin-4-yl)amino)cyclopentyl)methanol; (1-((2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-5-(1,3,4-oxadiazol-2- yl)pyrimidin-4-yl)amino)cyclohexyl)methanol; (1-((2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-5-(1,3,4-oxadiazol-2- yl)pyrimidin-4-yl)amino)cyclobutyl)methanol; 2-((2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-5-(1,3,4-oxadiazol-2- yl)pyrimidin-4-yl)amino)-2-methylpropan-1-ol; ethyl 4-((1-(hydroxymethyl)cyclopentyl)amino)-2-((1-isopropyl-1H-pyrazolo[4,3- c]pyridin-6-yl)amino)pyrimidine-5-carboxylate; ethyl 4-((1-(hydroxymethyl)cyclohexyl)amino)-2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin- 6-yl)amino)pyrimidine-5-carboxylate; and ethyl 4-((1-(hydroxymethyl)cyclobutyl)amino)-2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin- 6-yl)amino)pyrimidine-5-carboxylate; or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof. [0207] In some embodiments, the compound is selected from: (S)-4-((2-hydroxy-1-phenylethyl)amino)-N-isopropyl-2-((1-isopropyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxamide; ethyl 2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-4-(piperazin- 1-yl)pyrimidine-5-carboxylate; (S)-N-cyclopentyl-4-((2-hydroxy-1-phenylethyl)amino)-2-((1-isopropyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxamide; (S)-N-benzyl-4-((2-hydroxy-1-phenylethyl)amino)-2-((1-isopropyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxamide; (S)-4-((2-hydroxy-1-phenylethyl)amino)-N-isobutyl-2-((1-isopropyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxamide; ethyl 4-((1-(hydroxymethyl)cyclopropyl)amino)-2-((1-isopropyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxylate; ethyl 4-((1-hydroxy-2-methylpropan-2-yl)amino)-2-((1-isopropyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxylate; and (S)-2-((2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-5-(1,3,4- oxadiazol-2-yl)pyrimidin-4-yl)amino)-2-phenylethan-1-ol; or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof. [0208] In some embodiments, the compound is (S)-4-((2-hydroxy-1-phenylethyl)amino)- N-isopropyl-2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5- carboxamide or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof. [0209] In some embodiments, the compound is ethyl 2-((1-isopropyl-1H-pyrazolo[4,3- c]pyridin-6-yl)amino)-4-(piperazin-1-yl)pyrimidine-5-carboxylate or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof. [0210] In some embodiments, the compound is (S)-N-cyclopentyl-4-((2-hydroxy-1- phenylethyl)amino)-2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5- carboxamide or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof. [0211] In some embodiments, the compound is (S)-N-benzyl-4-((2-hydroxy-1- phenylethyl)amino)-2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5- carboxamide or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof. [0212] In some embodiments, the compound is (S)-4-((2-hydroxy-1-phenylethyl)amino)- N-isobutyl-2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxamide or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof. [0213] In some embodiments, the compound is ethyl 4-((1- (hydroxymethyl)cyclopropyl)amino)-2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6- yl)amino)pyrimidine-5-carboxylate or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof. [0214] In some embodiments, the compound is ethyl 4-((1-hydroxy-2-methylpropan-2- yl)amino)-2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxylate or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof. [0215] In some embodiments, the compound is (S)-2-((2-((1-isopropyl-1H-pyrazolo[4,3- c]pyridin-6-yl)amino)-5-(1,3,4-oxadiazol-2-yl)pyrimidin-4-yl)amino)-2-phenylethan-1-ol or a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof. [0216] It should be understood that all isomeric forms are included within the present invention, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration. All tautomeric forms are also intended to be included. [0217] Compounds of the invention, and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers and prodrugs thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. [0218] The compounds of the invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry. [0219] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chiral HPLC column. [0220] It is also possible that the compounds of the invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention. [0221] All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I)incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds. [0222] The compounds of Formula I may form salts which are also within the scope of this invention. Reference to a compound of the Formula herein is understood to include reference to salts thereof, unless otherwise indicated. [0223] The present invention relates to compounds which are modulators of hematopoietic progenitor kinase 1 (HPK1). [0224] In one embodiment, the compounds of the present invention are inhibitors of hematopoietic progenitor kinase 1 (HPK1). [0225] In some embodiments, the compounds of Formula I are selective inhibitors of hematopoietic progenitor kinase 1 (HPK1). [0226] The present invention relates to compounds which are modulators of hematopoietic progenitor kinase 1 (HPK1). [0227] In one embodiment, the compounds of the present invention are inhibitors of hematopoietic progenitor kinase 1 (HPK1). [0228] In some embodiments, the compounds of Formula I are selective inhibitors of hematopoietic progenitor kinase 1 (HPK1). [0229] The present invention relates to compounds which are modulators of leucine rich repeat kinase 2 (LRRK2) protein. [0230] In one embodiment, the compounds of the present invention are inhibitors of leucine rich repeat kinase 2 (LRRK2) protein. [0231] In some embodiments, the compounds of Formula I are selective inhibitors of leucine rich repeat kinase 2 (LRRK2) protein. [0232] The present invention relates to compounds which are modulators of FMS-like tyrosine kinase 3 (FLT3) gene. [0233] In one embodiment, the compounds of the present invention are inhibitors of FMS- like tyrosine kinase 3 (FLT3) gene. [0234] In some embodiments, the compounds of Formula I are selective inhibitors of FMS- like tyrosine kinase 3 (FLT3) gene. [0235] The present invention relates to compounds which are modulators of interleukin-1 receptor-associated kinase 1 (IRAK1). [0236] In one embodiment, the compounds of the present invention are inhibitors of interleukin-1 receptor-associated kinase 1 (IRAK1). [0237] In some embodiments, the compounds of Formula I are selective inhibitors of interleukin-1 receptor-associated kinase 1 (IRAK1). [0238] The present invention relates to compounds which are modulators of interleukin-1 receptor-associated kinase 4 (IRAK4). [0239] In one embodiment, the compounds of the present invention are inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4). [0240] In some embodiments, the compounds of Formula I are selective inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4). [0241] The present invention relates to compounds which are modulators of Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). [0242] In one embodiment, the compounds of the present invention are inhibitors of Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). [0243] In some embodiments, the compounds of Formula I are selective inhibitors of Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). [0244] The invention is directed to compounds as described herein and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof. Method of Synthesizing the Compounds [0245] The compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below. [0246] The compounds of Formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of those skilled in the art will recognize if a stereocenter exists in the compounds of Formula (I). Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994). [0247] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes. Preparation of Compounds [0248] The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Suitable methods include but are not limited to those methods described below. Compounds of the present invention can be synthesized by following the steps outlined in General Procedures A–E which comprise different sequences of assembling intermediates or compounds. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated below. [0249] GENERAL PROCEDURE A

[0250] GENERAL PROCEDURE B

[0251] GENERAL PROCEDURE C

[0252] GENERAL PROCEDURE D

[0253] GENERAL PROCEDURE E

wherein Z1 and Z2 are independently C₁–C₆ alkyl optionally substituted with one or more R8. [0254] GENERAL PROCEDURE F

Methods of Using the Disclosed Compounds [0255] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of hematopoietic progenitor kinase 1 (HPK1). The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of HPK1 an effective amount the compositions and compounds of Formula (I). [0256] In another aspect, the present invention is directed to a method of inhibiting hematopoietic progenitor kinase 1 (HPK1). The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I). [0257] Another aspect of the present invention relates to a method of treating, preventing, inhibiting or eliminating a disease or disorder in a patient associated with the inhibition of hematopoietic progenitor kinase 1 (HPK1), the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I). In one embodiment, the disease may be, but not limited to, cancer. [0258] The present invention also relates to the use of an inhibitor of hematopoietic progenitor kinase 1 (HPK1) for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a disease or condition mediated by HPK1, wherein the medicament comprises a compound of Formula (I). [0259] In another aspect, the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by hematopoietic progenitor kinase 1 (HPK1), wherein the medicament comprises a compound of Formula (I). [0260] Another aspect of the present invention relates to a compound of Formula (I) for use in the manufacture of a medicament for treating a disease associated with inhibiting hematopoietic progenitor kinase 1 (HPK1). [0261] In another aspect, the present invention relates to the use of a compound of Formula (I) in the treatment of a disease associated with inhibiting hematopoietic progenitor kinase 1 (HPK1). [0262] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of leucine rich repeat kinase 2 (LRRK2) protein. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of LRRK2 an effective amount the compositions and compounds of Formula (I). [0263] In another aspect, the present invention is directed to a method of inhibiting leucine rich repeat kinase 2 (LRRK2) protein. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I). [0264] Another aspect of the present invention relates to a method of treating, preventing, inhibiting or eliminating a disease or disorder in a patient associated with the inhibition of leucine rich repeat kinase 2 (LRRK2) protein, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I). [0265] The present invention also relates to the use of an inhibitor of leucine rich repeat kinase 2 (LRRK2) protein for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a disease or condition mediated by LRRK2, wherein the medicament comprises a compound of Formula (I). [0266] In another aspect, the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by leucine rich repeat kinase 2 (LRRK2) protein, wherein the medicament comprises a compound of Formula (I). [0267] Another aspect of the present invention relates to a compound of Formula (I) for use in the manufacture of a medicament for treating a disease associated with inhibiting leucine rich repeat kinase 2 (LRRK2) protein. [0268] In another aspect, the present invention relates to the use of a compound of Formula (I) in the treatment of a disease associated with inhibiting leucine rich repeat kinase 2 (LRRK2) protein. [0269] In some embodiments, the leucine rich repeat kinase 2 (LRRK2) protein is a mutant LRRK2 protein. [0270] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of FMS-like tyrosine kinase 3 (FLT3) gene. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of FLT3 an effective amount the compositions and compounds of Formula (I). [0271] In another aspect, the present invention is directed to a method of inhibiting FMS- like tyrosine kinase 3 (FLT3) gene. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I). [0272] Another aspect of the present invention relates to a method of treating, preventing, inhibiting or eliminating a disease or disorder in a patient associated with the inhibition of FMS-like tyrosine kinase 3 (FLT3) gene, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I). [0273] The present invention also relates to the use of an inhibitor of FMS-like tyrosine kinase 3 (FLT3) gene for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a disease or condition mediated by FLT3, wherein the medicament comprises a compound of Formula (I). [0274] In another aspect, the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by FMS-like tyrosine kinase 3 (FLT3) gene, wherein the medicament comprises a compound of Formula (I). [0275] Another aspect of the present invention relates to a compound of Formula (I) for use in the manufacture of a medicament for treating a disease associated with inhibiting FMS- like tyrosine kinase 3 (FLT3) gene. [0276] In another aspect, the present invention relates to the use of a compound of Formula (I) in the treatment of a disease associated with inhibiting FMS-like tyrosine kinase 3 (FLT3) gene. [0277] In some embodiments, the FMS-like tyrosine kinase 3 (FLT3) gene is a mutant FLT3 gene. [0278] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of interleukin-1 receptor-associated kinase 1 (IRAK1). The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of IRAK1 an effective amount the compositions and compounds of Formula (I). [0279] In another aspect, the present invention is directed to a method of inhibiting interleukin-1 receptor-associated kinase 1 (IRAK1). The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I). [0280] Another aspect of the present invention relates to a method of treating, preventing, inhibiting or eliminating a disease or disorder in a patient associated with the inhibition of interleukin-1 receptor-associated kinase 1 (IRAK1), the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I). [0281] The present invention also relates to the use of an inhibitor of interleukin-1 receptor- associated kinase 1 (IRAK1) for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a disease or condition mediated by IRAK1, wherein the medicament comprises a compound of Formula (I). [0282] In another aspect, the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by interleukin-1 receptor-associated kinase 1 (IRAK1), wherein the medicament comprises a compound of Formula (I). [0283] Another aspect of the present invention relates to a compound of Formula (I) for use in the manufacture of a medicament for treating a disease associated with inhibiting interleukin-1 receptor-associated kinase 1 (IRAK1). [0284] In another aspect, the present invention relates to the use of a compound of Formula (I) in the treatment of a disease associated with inhibiting interleukin-1 receptor-associated kinase 1 (IRAK1). [0285] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of interleukin-1 receptor-associated kinase 4 (IRAK4). The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of IRAK4 an effective amount the compositions and compounds of Formula (I). [0286] In another aspect, the present invention is directed to a method of inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4). The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I). [0287] Another aspect of the present invention relates to a method of treating, preventing, inhibiting or eliminating a disease or disorder in a patient associated with the inhibition of interleukin-1 receptor-associated kinase 4 (IRAK4), the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I). [0288] The present invention also relates to the use of an inhibitor of interleukin-1 receptor- associated kinase 4 (IRAK4) for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a disease or condition mediated by IRAK4, wherein the medicament comprises a compound of Formula (I). [0289] In another aspect, the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by interleukin-1 receptor-associated kinase 4 (IRAK4), wherein the medicament comprises a compound of Formula (I). [0290] Another aspect of the present invention relates to a compound of Formula (I) for use in the manufacture of a medicament for treating a disease associated with inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4). [0291] In another aspect, the present invention relates to the use of a compound of Formula (I) in the treatment of a disease associated with inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4). [0292] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of JAKs an effective amount the compositions and compounds of Formula (I). [0293] In another aspect, the present invention is directed to a method of inhibiting Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I). [0294] Another aspect of the present invention relates to a method of treating, preventing, inhibiting or eliminating a disease or disorder in a patient associated with the inhibition of Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2), the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I). [0295] The present invention also relates to the use of an inhibitor of Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2) for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a disease or condition mediated by JAKs, wherein the medicament comprises a compound of Formula (I). [0296] In another aspect, the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2), wherein the medicament comprises a compound of Formula (I). [0297] Another aspect of the present invention relates to a compound of Formula (I) for use in the manufacture of a medicament for treating a disease associated with inhibiting Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). [0298] In another aspect, the present invention relates to the use of a compound of Formula (I) in the treatment of a disease associated with inhibiting Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). [0299] In some embodiments, the Janus kinase (JAK) is Janus kinase 1 (JAK1). [0300] In some embodiments, the Janus kinase (JAK) is Janus kinase 2 (JAK2). [0301] In some embodiments, the Janus kinase (JAK) is Janus kinase 3 (JAK3). [0302] In some embodiments, the Janus kinase (JAK) is tyrosine kinase 2 (TYK2). [0303] Another aspect of the invention relates to a method of treating cancer. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I). [0304] Another aspect of the invention relates to a method of treating or preventing cancer. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I). [0305] In one embodiment, the present invention relates to the use of an inhibitor of hematopoietic progenitor kinase 1 (HPK1) for the preparation of a medicament used in treatment, prevention, inhibition or elimination of a disease or disorder associated with cancer. [0306] In some embodiments, the disease, disorder, or condition is selected from cancer, an autoimmune disease, an inflammatory disease, a viral infection, male fertility control, a benign hyperplasia, sepsis, a vascular disorder, an atherosclerotic disease, and a neurodegenerative disorder. [0307] In some embodiments, the disease, disorder, or condition is cancer. [0308] In some embodiments, the cancer is selected from bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer, prostate cancer, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), acute myeloid leukemia (AML), and acute promyelocytic leukemia (APL). [0309] In some embodiments, the disease, disorder, or condition is an autoimmune disease. [0310] In some embodiments, the autoimmune disease is selected from chronic obstructive pulmonary disease (COPD), asthma, bronchitis, lupus, dermatomyositis, Sjogren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus and complications associated therewith, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto’s and autoimmune thyroiditis), contact dermatitis and further eczematous dermatitis, inflammatory bowel disease, interferonopathy, atherosclerosis, and amyotrophic lateral sclerosis. [0311] In some embodiments, the asthma is selected from chronic asthma, inveterate asthma, intrinsic asthma, extrinsic asthma, dust asthma, and infantile asthma. [0312] In some embodiments, the inveterate asthma is selected late asthma and airway hyperreponsiveness. [0313] In some embodiments, the bronchitis is bronchial asthma. [0314] In some embodiments, the lupus is selected from systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis, and lupus nephritis. [0315] In some embodiments, the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis. [0316] In some embodiments, the disease, disorder, or condition is an inflammatory disease. [0317] In some embodiments, the inflammatory disease is selected from rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease, chronic obstructive pulmonary disease (COPD), inflammatory liver disease, inflammatory bowel disease, endotoxin-driven disease state, and related diseases involving cartilage, such as that of the joints. [0318] In some embodiments, the allergic airway disease is selected from asthma and rhinitis. [0319] In some embodiments, the inflammatory liver disease is selected from primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). [0320] In some embodiments, the inflammatory bowel disease is selected from Crohn’s disease and ulcerative colitis. [0321] In some embodiments, the disease, disorder, or condition is a viral infection. [0322] In some embodiments, the viral infection is an infection by a virus selected from human adenovirus, human cytomegalovirus, Kaposi’s sarcoma-associated herpesvirus, hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus, human immunodeficiency virus (HIV), HPS-associated hantaviruses, Sin Nombre virus, rotavirus, echovirus, foot-and-mouth disease virus, coxsackievirus, West Nile virus, Ebola virus, Ross River virus, human papillomavirus, and coronavirus. [0323] In some embodiments, the viral infection is an infection by hepatitis B virus (HBV). [0324] In some embodiments, the viral infection is an infection by human immunodeficiency virus (HIV). [0325] In some embodiments, the disease, disorder, or condition is male fertility control. [0326] In some embodiments, the disease, disorder, or condition is a benign hyperplasia. [0327] In some embodiments, the benign hyperplasia is selected from benign hyperplasia of the prostate gland and benign hyperplasia of the mammary gland. [0328] In some embodiments, the disease, disorder, or condition is sepsis. [0329] In some embodiments, the disease, disorder, or condition is a vascular disorder. [0330] In some embodiments, the vascular disorder is selected from erythromelalgia, peripheral artery disease, renal artery stenosis, Buerger’s disease, Raynaud’s disease, disseminated intravascular coagulation, and cerebrovascular disease. [0331] In some embodiments, the disease, disorder, or condition is an atherosclerotic disorder. [0332] In some embodiments, the atherosclerotic disease is selected from myocardial infarction and stroke. [0333] In some embodiments, the disease, disorder, or condition is a neurodegenerative disorder. [0334] In some embodiments, the neurodegenerative disorder is selected from Alzheimer's disease, vascular disease dementia, frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Lewy body dementia, tangle-predominant senile dementia, Pick's disease (PiD), argyrophilic grain disease, amyotrophic lateral sclerosis (ALS), other motor neuron diseases, Guam parkinsonism-dementia complex, FTDP-17, Lytico-Bodig disease, multiple sclerosis, traumatic brain injury (TBI), and Parkinson's disease. [0335] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. [0336] The disclosed compounds of the invention can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects. [0337] Administration of the disclosed compounds can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes. [0338] Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts. [0339] Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a Compound of the Invention and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200. [0340] Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds. [0341] The disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier. [0342] The disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No.5,262,564 which is hereby incorporated by reference in its entirety. [0343] Disclosed compounds can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled. The disclosed compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the Disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. In one embodiment, disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate. Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection. [0344] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. In some embodiments, the pharmaceutical composition can further comprise an additional pharmaceutically active agent.n some embodiments, the additional therapeutic agent is selected from an immune checkpoint inhibitor, a cell-based therapy, and a cytokine therapy. [0345] In some embodiments, the immune checkpoint antibody is selected from a PD-1 antibody, a PD-L1 antibody, a PD-L2 antibody, a CTLA-4 antibody, a TIM3 antibody, a LAG3 antibody, and a TIGIT antibody. [0346] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody. [0347] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody. [0348] In some embodiments, the cell-based therapy is a cancer vaccine. [0349] In some embodiments, the cancer vaccine is selected from an anti-tumor vaccine or a vaccine based on neoantigens. [0350] Cell-based therapies usually involve the removal of immune cells from a subject suffering from cancer, either from the blood or from a tumor. Immune cells specific for the tumor will be activated, grown, and returned to a subject suffering from cancer where the immune cells provide an immune response against the cancer. [0351] In some embodiments, the immune cells are selected from natural killer cells, lymphokine-activated killer cells, cytotoxic T-cells, and dendritic cells. [0352] In some embodiments, the cancer vaccine is natural killer cell-based. [0353] In some embodiments, the cancer vaccine is lymphokine-activated killer cell-based. [0354] In some embodiments, the cancer vaccine is cytotoxic T-cell-based. [0355] In some embodiments, the cancer vaccine is dendritic cell-based. [0356] In some embodiments, the cell-based therapy is selected from CAR-T therapy (e.g., chimeric antigen receptor T-cells which are T-cells engineered to target specific antigens), TIL therapy (e.g., administration of tumor-infiltrating lymphocytes), and TCR gene therapy. [0357] In some embodiments, the cytokine therapy is interleukin-2 therapy. [0358] In some embodiments, the cytokine therapy is interferon-alpha therapy. [0359] Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume. [0360] The dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. [0361] Effective dosage amounts of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or, in a range of from one amount to another amount in the list of doses. In one embodiment, the compositions are in the form of a tablet that can be scored. EXAMPLES [0362] The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims. [0363] Abbreviations used in the following examples and elsewhere herein are: AcCl acetyl chloride AcOH acetic acid atm atmosphere br broad anh. anhydrous aq. aqueous BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene BSA bovine serum albumin BuLi butyl lithium CDI N,N'-carbonyldiimidazole CC column chromatography (e.g. silica CC) CO2 carbon dioxide COSY correlation spectroscopy CPBA chloroperbenzoic acid (e.g. m-CPBA) CSI chlorosulfonyl isocyanate DCM dichloromethane DDQ 2,3-dichloro-5,6-dicyano-1.4-quinone DIAD diisopropyl azodicarboxylate DIPEA N,N-diisopropylethylamine DMAc N,N-dimethyl acetamide DMAP N,N-dimethylpyridin-4-amine DME 1,2-Dimethoxyethane DMEDA N,N′-Dimethylethylenediamine DMEM Dulbecco’s modified Eagle’s medium DMF N,N-dimethyl formamide DMSO dimethyl sulfoxide DTT dithiothreitol EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide EDTA ethylenedi-aminetetraacetic acid ESI electrospray ionization Et-I iodoethane Et₂O diethyl ether EtOAc ethyl acetate EtOH ethanol FA formic acid FBS fetal bovine serum FC flash chromatography (e.g. silica FC) h hour(s) Hal halogen HEPES 4-(2-hydroxyethyl)piperazine-l- ethanesulfonic acid Het heteryl HOBt 1-hydroxybenzotriazole HATU [bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC high pressure (or performance) liquid chromatography t-BuOK potassium tert-butoxide ΙΝFγ interferon gamma LCMS liquid chromatography mass spectrometry LHMDS Lithium bis(trimethylsilyl)amide m multiplet M molar MeCN acetonitrile 2-MeTHF 2-methyl tetrahydrofuran MeOH methanol MHz megahertz min minutes MS molecular sieves MsCl methanesulfonyl chloride MsCl methanesulfonic acid n-BuLi butyl lithium NBS N-bromosuccinimide NEt₃ Triethylamine NIS N-iodosuccinimide NMR nuclear magnetic resonance NOE nuclear Overhauser effect NOESY nuclear Overhauser effect correlation spectroscopy PBS phosphate-buffered saline PEG polyethylene glycol pin pinacolate ppm parts per million quant. Quantitative rac racemic mixture rt room temperature Rt retention time sat. saturated STAB sodium triacetoxyborohydride T3P Propylphosphonic anhydride TBAB tetrabutylammonium bromide TBTU O-(Benzotriazol-1-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate TosMIC toluenesulfonylmethyl isocyanide tBuBrettPhos [(2-Di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′- Pd G3 triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulfonate t-BuOH tert-butanol TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TsCl toluenesulfonyl chloride (e.g. p- TsCl) TsOH toluenesulfonic acid (e.g. p-TsOH) X-Phos Dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′- biphenyl]-2-yl]phosphane [0364] Purity and identity of all synthesized compounds were confirmed by LC-MS analysis performed on Shimadzu Analytical 10Avp equipped with PE SCIEX API 165 mass-, Sedex 75 ELSD-, and Shimadzu UV- (254 and 215) detectors. Separation was achieved with C18 column 100 ^ 4.6 mm, 5.0 µm, pore size 100 Å, water-acetonitrile+0.1 TFA, gradient 5 to 87 for 10 min. [0365] Preparative HPLC purification was carried out on Shimadzu instrument equipped with SPD-10Avp detector and FRC-10A fraction collector. Separation was achieved with a column YMC-Pack ODS-AQ 250×20 mm, S-10 µm, 12 nm, gradient solution А – solution B (A: 1000 mL H₂O-226 µL TFA; B: 1000 mL CH3CN-226 µL TFA). [0366] Preparation 1: 6-Chloro-1-(1-methylethyl)-1H-pyrazolo[4,3-c]pyridine

[0367] A suspension of NaH (60%, 4.7 g, 118 mmol) was added portion wise to a stirred and cooled to 0 ⁰C solution of 6-chloro-1H-pyrazolo[4,3-c]pyridine (15.0 g, 98.0 mmol) in DMF (150 mL). The mixture was stirred at 0⁰C for 30 min, then 2-bromopropane (13.0 g, 107.0 mmol) was added dropwise, and stirring was continued for 1 h. The reaction mixture was allowed to warm up to ambient temperature, stirred additionally for 16 h, and poured into vigorously stirring mixture of ice-cooled water and EtOAc. The organic layer was separated, washed with brine, dried over Na₂SO₄, and filtered. The residue after volatiles removal was subjected to silica FC eluting with a mixture of EtOAc (0 to 30%) and DCM to afford the title compound as a first fraction (9.6 g, 50%).¹H-NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.33 (s, 1H), 7.92 (s, 1H), 4.89 - 5.08 (m, 1H), 1.46 (d, J= 6.6 Hz, 6H). [0368] Note: The second fraction was a regio-isomer 6-chloro-2-(1-methylethyl)-2H- pyrazolo[4,3-c]pyridine.¹H-NMR (400 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.79 (s, 1H), 7.66 (s, 1H), 5.00- 4.67 (m, 1H), 1.55 (d, J= 6.6 Hz, 6H). [0369] Preparation 2: 6-chloro-1-(cyclohexylmethyl)-1H-pyrazolo[4,3-c]pyridine

[0370] The compound was synthesized according to the procedure described in Preparation 1 using (bromomethyl)cyclohexane instead of 2-bromopropane.¹H-NMR (400 MHz, DMSO- d6) δ 8.91 (s, 1H), 8.34 (s, 1H), 7.94 (s, 1H), 4.25 (d, J = 7.2 Hz, 2H), 1.96-1.79 (m, 1H), 1.69 – 1.51 (m, 3H), 1.44 (d, J = 12.0 Hz, 2H), 0.86 – 1.20 (m, 5H). [0371] Preparation 3: 6-chloro-1-cyclohexyl-1H-pyrazolo[4,3-c]pyridine

[0372] The compound was synthesized according to the procedure described in Preparation 1 using bromocyclohexane instead of 2-bromopropane.¹H-NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.33 (s, 1H), 7.97 (s, 1H), 4.73–4.54 (m, 1H), 1.98–1.77 (m, 6H), 1.75-1.63 (m, 1H), 1.39-1.56 (m, 2H), 1.33-1.20 (m, 1H). [0373] Preparation 4: 6-chloro-1-ethyl-1H-pyrazolo[4,3-c]pyridine

[0374] The compound was synthesized according to the procedure described in Preparation 1 using bromoethane instead of 2-bromopropane. ¹H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.34 (s, 1H), 7.92 (s, 1H), 4.44 (q, J = 7.2 Hz, 2H), 1.44-1.33 (m, 3H). [0375] Preparation 5: 6-chloro-1-(2-methylpropyl)-1H-pyrazolo[4,3-c]pyridine

[0376] The compound was synthesized according to the procedure described in Preparation 1 using 1-bromo-2-methylpropane instead of 2-bromopropane. ¹H-NMR (400 MHz, DMSO- d6) δ 9.04 (s, 1H), 8.77 (s, 1H), 7.68 (s, 1H), 4.30 (d, J = 7.3 Hz, 2H), 2.35-2.20 (m, 1H), 0.86 (d, J = 6.7 Hz, 6H). [0377] Preparation 6: 6-chloro-1-cyclopentyl-1H-pyrazolo[4,3-c]pyridine

The compound was synthesized according to the procedure described in Preparation 1 using bromocyclopentane instead of 2-bromopropane.1H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 8.34 (s, 1H), 7.92 (s, 1H), 5.04 – 5.28 (m, 1H), 2.22-2.05 (m, 2H), 1.80 – 2.00 (m, 4H), 1.52 – 1.76 (m, 2H). [0378] Preparation 7: 6-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3- c]pyridine

[0379] The compound was synthesized according to the procedure described in Preparation 1 using tetrahydro-2H-pyran-4-yl methanesulfonate instead of 2-bromopropane.¹H-NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.37 (s, 1H), 8.00 (s, 1H), 5.04-4.84 (m, 1H), 4.09-3.91 (m, 2H), 3.61-3.45 (m, 2H), 2.19-1.99 (m, 2H), 1.92–1.81 (m, 2H). [0380] Preparation 8: 6-chloro-1-cyclohex-2-en-1-yl-1H-pyrazolo[4,3-c]pyridine

[0381] The compound was synthesized according to the procedure described in Preparation 1 using 3-bromocyclohexene instead of 2-bromopropane. ¹H-NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 6.07-5.94 (m, 1H), 5.76-5.63 (m, 1), 5.50-5.30 (m, 1), 2.21-2.00 (m, 3), 1.96-1.79 (m, 2), 1.76-1.62 (m, 1). [0382] Preparation 9: 6-chloro-1-(cyclobutylmethyl)-1H-pyrazolo[4,3-c]pyridine

[0383] The compound was synthesized according to the procedure described in Preparation 1 using (bromomethyl)cyclobutane instead of 2-bromopropane ¹H-NMR (400 MHz, DMSO- d6) δ 8.90 (s, 1H), 8.33 (s, 1H), 7.97 (s, 1H), 4.43 (d, J = 7.2 Hz, 2H), 2.93-2.70 (m, 1), 1.92 – 1.73 (m, 6H). [0384] Preparation 10: 1-benzyl-6-chloro-1H-pyrazolo[4,3-c]pyridine

[0385] The compound was synthesized according to the procedure described in Preparation 1 using benzyl bromide instead of 2-bromopropane. ¹H-NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.17 (s, 1H), 7.18–7.40 (m, 7H), 5.56 (s, 2H). [0386] Preparation 11: 6-chloro-1-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-c]pyridine

[0387] The compound was synthesized according to the procedure described in Preparation 1 using 3-(chloromethyl)pyridine hydrochloride instead of 2-bromopropane. ¹H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.58 (s, 1H), 8.50 (d, J = 4.8Hz, 1H), 8.41 (s, 1H), 8.10 (q, J = 1.0 Hz, 1H), 7.65 ( d, J = 2.1 Hz, 1H), 7.31–7.39 (m, 1H), 5.72 (s, 2H). [0388] Preparation 12: 6-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

[0389] To a stirred mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (1.0 g, 6.0 mmol), Cs2CO3 (3.95 g, 12.0 mmol), and in DMAA (10 mL) was added 2.2.2-trifluoroethyl triflate (1.4 g, 6.0 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 16 h and threated with water (25 mL) and EtOAc (25 mL). The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue after volatiles removing was subjected to silica CC eluting with a mixture of DCM and EtOAc to afford 1.0 g (67%) of the title compound. ¹H-NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.49 (s, 1H), 8.06 (s, 1H), 5-64-5.359M, 1H). [0390] Preparation 13: 6-chloro-1-phenyl-1H-pyrazolo[4,3-c]pyridine

[0391] A mixture of 6-chloro-lH-pyrazolo[4,3-c]pyridine (500 mg, 3.26 mmol), CuI, (0.2 eq, 124 mg) N,N-dimethylglycine (370 mg, 3.59 mmol,), phenyl bromide (537 mg, 3.42mmol,) and potassium carbonate (900 mg, 6.52 mmol) in DMSO (10 mL) was stirred at 100⁰C t for 18h, cooled to an ambient temperature, and filtered. The filtrate was diluted with DCM and washed with H₂O. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was subjected to silica CC eluting wit a mixture of hexane and EtOAc to afford 380 mg (50.8 %) the title compound. ¹H-NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.65 (s, 1H), 7.90 (s, 1H), 7.84–7.76 (m, 2H), 7.66 – 7.56 (m, 2H), 7.47 (t, J = 7.4 Hz, 1H). [0392] Preparation 14: 6-chloro-N⁴-(1-methylethyl)pyridine-3,4-diamine

[0393] Step A: Synthesis of 2-chloro-N-(1-methylethyl)-5-nitropyridin-4-amine [0394] A solution of isopropylamine (6mL, 70 mmol) in THF (28 mL) was added dropwise over 1h to a stirred mixture of 2,4-dichloro-5-nitropyridine (6.75 g, 35 mmol) in THF (170 mL) at ambient temperature. The reaction mixture was stirred for 6 h, diluted with water, and extracted with EtOAc (3x50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford 7.5g (99 %) of the title compound pure enough to be used for the next step. ¹H-NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.08 (s, 1H), 6.74(s, 1H), 3.87-3.71 (m, 1 H), 1.36 (d, J=6.8Hz, 6H), 1.49–1.27 (m, 6H). [0395] Step B: Synthesis of 6-chloro-N⁴-(1-methylethyl)pyridine-3,4-diamine [0396] A solution of NH₄Cl solution (9.35 g, 175 mmol)) in 20mL of water was added a solution of the product obtained at the previous step compound (7.5 g, 35 mmol) in ethanol (200 mL) followed by portion wise addition of Fe powder (9.76 g, 175 mmol) and 0.5 mL of conc. HCl. The reaction mixture was stirred at 70 C for 3 h, cooled down to ambient temperature, and filtered through Celite pad. The filtrate was concentrated under reduced pressure, and the residue was treated with sat. aq. solution of NaHCO3. The organic layer was separated, the aqueous one was extracted with EtOAc (3 x 100mL), combined organic layers were dried over anh. Na2S04 and concentrated under reduced pressure to afford the crude product (5.9 g, 91.5 %) that was used for the next step without further purification. ¹H-NMR (400 MHz, DMSO-d6) δ 7.39 (s, 1H), 6.33 (s, 1H), 5.39 (d, J = 7.2 Hz, 1H), 4.75 (s, 2H), 3.66- 3.57 (m, 1H), 1.55 (d, J =7.2Hz, 6H). [0397] Preparation 15: 6-chloro-1-(1-methylethyl)-1H-imidazo[4,5-c]pyridine

[0398] A mixture of 6-chloro-N⁴-(1-methylethyl)pyridine-3,4-diamine (See Preparation 14) (3 g, 16.1 mmol), triethylortoformate (80 mL, 480 mmol) and TFA (0.72 mL, 9.6 mmol) was stirred and heated at 125 C for 3.5 h and concentrated under reduced pressure. The residue was treated with sat. aq. NaHCO3 and extracted with EtOAc (3 x 70). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue after evaporation was subjected to silica FC eluting with a mixture of EtOAc (10 to 20 %) DCM to afford the compound 4 (2.6 g, 83.8%). ¹H-NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.01 (s, 1H), 7.36 (s, 1H), 4.62-4.54 (m, 1H), 1.60 (d, J = 7.6 Hz, 6H). [0399] Preparation 16: 6-chloro-3-methyl-1-(1-methylethyl)-1,3-dihydro-2H- imidazo[4,5-c]pyridin-2-one

[0400] Step A: Synthesis of 6-chloro-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5- c]pyridin-2-one. [0401] A mixture of 6-chloro-N⁴-(1-methylethyl)pyridine-3,4-diamine (See Preparation 14) (0.85 g, 4.5 mmol) CDI (1.1g, 6.75 mmol), and THF (20 mL) was stirred at ambient temperature for 12 h, diluted with water, and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was subjected to silica FC eluting with a mixture of EtOAc (5 to 20%) and DCM to afford 0.6 g (62%) of the title compound. [0402] Step B: 6-chloro-3-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5- c]pyridin-2-one. A mixture of the product obtained at the previous step (0.56 g, 2.46 mmol), K2CO3 (0.73 g, 4.92 mmoL), methyl iodide (0.5 mL, 7.38 mmol), and DMF (5 mL) was stirred at ambient temperature for 16 h, diluted with water, and extracted twice with EtOAc. Combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was treated with Et2O, formed precipitate was filtered off, washed with Et₂O, and dried to afford 0.17 g (28%) of the title compound. ¹H NMR (400 MHz, CDCl₃) δ 7.98 (s, 1H), 7.07 (s, 1H), 4.73-4.65 (m, 1H), 3.44 (s, 3H), 1.53 (d, J = 6.8 Hz, 6H). [0403] Preparation 17: 1-(1-methylethyl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0404] Step A: Synthesis of N-(2,4-dimethoxybenzyl)-1-(1-methylethyl)-1H-pyrazolo[4,3- c]pyridin-6-amine [0405] A mixture of 6-chloro-1-(1-methylethyl)-1H-pyrazolo[4,3-c]pyridine (See Preparation 1) (7.0 g, 36 mmol), (2,4-dimethoxybenzyl)amine (12.0 g, 72 mmol), Cs₂CO₃ (23.5 g, 72 mmol), BINAP (0.9 g, 1.4 mmol), Pd(OAc)2 (0.3 g, 1.4 mol) and dioxane (70 mL) was stirred at 100⁰C for 12 hours in inert atmosphere, diluted with water, and extracted twice with DCM. Combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue after evaporation was subjected to silica FC eluting with a mixture of EtOAc (0 to 100 %) and DCM to afford 4.4 g (38 %) of the title compound. [0406] Step B: Synthesis of 1-(1-methylethyl)-1H-pyrazolo[4,3-c]pyridin-6-amine [0407] A solution of the compound obtained at Step 1 (4.4 g, 13 mmol) in TFA (5 mL) was heated under reflux for 1 hour, concentrated under reduced pressure, and the residue was treated with sat. aq. NaHCO3 and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine, and dried over sodium sulfate, The residue after solvent removal was purified by re-crystallization from a mixture of EtOAc and hexane to afford 2.1 g (87%) of the title compound. ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 8.49 (s, 1H), 6.31 (br.s, 2H), 4.72-4.53 (m, 1H), 1.41 (d, J= 6.6 Hz, 6H). [0408] Preparation 18: 1-(cyclohexylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0409] The compound was synthesized according to the procedure described in Preparation 17 using 6-chloro-1-(cyclohexylmethyl)-1H-pyrazolo[4,3-c]pyridine instead of 6-chloro-1-(1- methylethyl)-1H-pyrazolo[4,3-c]pyridine. [0410] Preparation 19: 1-cyclohexyl-1H-pyrazolo[4,3-c]pyridin-6-amine

[0411] The compound was synthesized according to the procedure described in Preparation 17 using 6-chloro-1-cyclohexyl-1H-pyrazolo[4,3-c]pyridine instead of 6-chloro-1-(1- methylethyl)-1H-pyrazolo[4,3-c]pyridine. [0412] Preparation 20: 1-ethyl-1H-pyrazolo[4,3-c]pyridin-6-amine

[0413] The compound was synthesized according to the procedure described in Preparation 17 using 6-chloro-1-ethyl-1H-pyrazolo[4,3-c]pyridine instead of 6-chloro-1-(1-methylethyl)- 1H-pyrazolo[4,3-c]pyridine. [0414] Preparation 21: 1-(2-methylpropyl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0415] The compound was synthesized according to the procedure described in Preparation 17 using 6-chloro-1-(2-methylpropyl)-1H-pyrazolo[4,3-c]pyridine instead of 6-chloro-1-(1- methylethyl)-1H-pyrazolo[4,3-c]pyridine. [0416] Preparation 22: 1-cyclopentyl-1H-pyrazolo[4,3-c]pyridin-6-amine

[0417] The compound was synthesized according to the procedure described in Preparation 17 using 6-chloro-1-cyclopentyl-1H-pyrazolo[4,3-c]pyridine instead of 6-chloro-1-(1- methylethyl)-1H-pyrazolo[4,3-c]pyridine. [0418] Preparation 23: 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-6- amine

[0419] The compound was synthesized according to the procedure described in Preparation 17 using 6-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridine instead of 6- chloro-1-(1-methylethyl)-1H-pyrazolo[4,3-c]pyridine. [0420] Preparation 24: 1-cyclohex-2-en-1-yl-1H-pyrazolo[4,3-c]pyridin-6-amine

[0421] The compound was synthesized according to the procedure described in Preparation 17 using 6-chloro-1-cyclohex-2-en-1-yl-1H-pyrazolo[4,3-c]pyridine instead of 6-chloro-1-(1- methylethyl)-1H-pyrazolo[4,3-c]pyridine. [0422] Preparation 25: 1-(cyclobutylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0423] The compound was synthesized according to the procedure described in Preparation 17 using 6-chloro-1-(cyclobutylmethyl)-1H-pyrazolo[4,3-c]pyridine instead of 6-chloro-1-(1- methylethyl)-1H-pyrazolo[4,3-c]pyridine. [0424] Preparation 26: 1-benzyl-1H-pyrazolo[4,3-c]pyridin-6-amine

[0425] The compound was synthesized according to the procedure described in Preparation 17 using 1-benzyl-6-chloro-1H-pyrazolo[4,3-c]pyridine instead of 6-chloro-1-(1-methylethyl)- 1H-pyrazolo[4,3-c]pyridine. [0426] Preparation 27: 1-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0427] The compound was synthesized according to the procedure described in Preparation 17 using 6-chloro-1-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-c]pyridine instead of 6-chloro-1- (1-methylethyl)-1H-pyrazolo[4,3-c]pyridine. [0428] Preparation 28: 1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0429] The compound was synthesized according to the procedure described in Preparation 17 using 6-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine instead of 6-chloro-1- (1-methylethyl)-1H-pyrazolo[4,3-c]pyridine. [0430] Preparation 29: 1-phenyl-1H-pyrazolo[4,3-c]pyridin-6-amine

[0431] The compound was synthesized according to the procedure described in Preparation 17 using 6-chloro-1-phenyl-1H-pyrazolo[4,3-c]pyridine instead of 6-chloro-1-(1- methylethyl)-1H-pyrazolo[4,3-c]pyridine. [0432] Preparation 30: 1-(1-methylethyl)-1H-imidazo[4,5-c]pyridin-6-amine [0433] The compound was synthesized according to the procedure described in Preparation 17 using 6-chloro-1-(1-methylethyl)-1H-imidazo[4,5-c]pyridine instead of 6-chloro-1-(1- methylethyl)-1H-pyrazolo[4,3-c]pyridine. [0434] Preparation 31: 6-amino-3-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5- c]pyridin-2-one

[0435] The compound was synthesized according to the procedure described in Preparation 17 using 6-chloro-3-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one instead of 6-chloro-1-(1-methylethyl)-1H-pyrazolo[4,3-c]pyridine. [0436] Preparation 32: tert-butyl 4-(2,6-dichloropyrimidin-4-yl)piperazine-1-carboxylate (P32-A) and tert-butyl 4-(4,6-dichloropyrimidin-2-yl)piperazine-1-carboxylate (P32-B)

[0437] A solution of tert-butyl piperazine-1-carboxylate 2 (26.47 g, 142 mmol) in MeCN (50 mL) was added dropwise to a stirred solution of 2,4,6-trichloropyrimidine (24.76 g, 135 mmol) and NEt3 (27.27 g, 270 mmol) in MeCN (100 mL) maintaining temperature of the mixture 5 C. Upon addition completion, the mixture was allowed to warm to ambient temperature, stirred 12 h, and concentrated under reduced pressure. The residue was dissolved in DCM, washed with water, brine, dried over anh. Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica CC eluting with DCM to afford 8 g (18 %) of the title compound P32-B and 32.2 g (71 %) of the title compound P32-A. [0438] tert-butyl 4-(2,6-dichloropyrimidin-4-yl)piperazine-1-carboxylate (P32-A). ¹H- NMR (400 MHz, CDCl3) δ 6.42 (s, 1H), 3.7-3.6 (m, 4H), 3.58-3.52 (m, 4H), 1.50 (s, 9H). tert-butyl 4-(4,6-dichloropyrimidin-2-yl)piperazine-1-carboxylate (P32-B).¹H-NMR (400 MHz, CDCl3) δ 6.57 (s, 1H), 3.81 (t, J = 5.3 Hz, 4H), 3.50 (t, J = 5.3 Hz, 4H), 1.50 (s, 9H). [0439] Preparation 33: 2,4-dichloro-6-pyrrolidin-1-ylpyrimidine (P33-A) and 4,6- dichloro-2-pyrrolidin-1-ylpyrimidine (P33-B)

[0440] The compounds were synthesized according to the procedure described in Preparation 32 using pyrrolidine instead of piperazine-1-carboxylate. [0441] 2,4-dichloro-6-pyrrolidin-1-ylpyrimidine (P33-A). ¹H-NMR (400 MHz, CDCl3) δ 6.20 (s, 1H), 3.63 (t, J = 6.6 Hz, 2H), 3.33 (t, J = 6.6 Hz, 2H), 2.12-2.03 (m, 2H), 2.03-194 (m, 2H). [0442] 4,6-dichloro-2-pyrrolidin-1-ylpyrimidine (P33-B). ¹H-NMR (400 MHz, CDCl3) δ 6.52 (s, 1H), 3.61-3.55 (m, 4H), 2.02-1.96 (m, 4H). [0443] Preparation 34: tert-butyl 4-(2,6-dichloropyrimidin-4-yl)-1,4-diazepane-1- carboxylate (P34-A) and tert-butyl 4-(4,6-dichloropyrimidin-2-yl)-1,4-diazepane-1- carboxylate (P34-B)

[0444] The compounds were synthesized according to the procedure described in Preparation 32 using tert-butyl 1,4-diazepane-1-carboxylate instead of piperazine-1- carboxylate. [0445] tert-Butyl 4-(2,6-dichloropyrimidin-4-yl)-1,4-diazepane-1-carboxylate (P34- A).¹H-NMR (400 MHz, CDCl₃) δ 6.36 (s, 1H), 4.04 – 3.20 (m, 8H), 1.94 (q, J = 6.2 Hz, 2H), 1.42 (s, 9H). [0446] tert-Butyl 4-(4,6-dichloropyrimidin-2-yl)-1,4-diazepane-1-carboxylate (P34-B). 1H-NMR (400 MHz, CDCl3) δ 6.55 (s, 1H), 3.87 (d, J = 5.4 Hz, 2H), 3.78 – 3.70 (m, 2H), 3.56 (m, 2H), 3.41 (t, J = 6.2 Hz, 1H), 3.31 (t, J = 6.2 Hz, 1H), 2.01 – 1.91 (m, 2H), 1.45 (d, J = 14.4 Hz, 9H). [0447] Preparation 35: tert-butyl 4-(2-chloro-6-pyrrolidin-1-ylpyrimidin-4-yl)piperazine- 1-carboxylate (P35-A) and tert-butyl 4-(6-chloro-2-pyrrolidin-1-ylpyrimidin-4- yl)piperazine-1-carboxylate (P35-B)

₅ A mixture of tert-butyl 4-(4,6-dichloropyrimidin-2-yl)piperazine-1-carboxylate (20 g, 60 mmol) (See Preparation 32, P30-A), pyrrolidine (6.4 g, 90 mmol), NEt3 (9.1 g, 90 mmol), and MeCN (100 mL) was stirred at ambient temperature for 12 h, cooled, and concentrated under reduced pressure. The residue was dissolved in DCM, washed with water, brine, dried over anh. Na₂SO₄, and concentrated under reduced pressure. The residue was subjected to silica FC eluting with a mixture of Et2O (0 to 5 %) and DCM to afford 2.1 g (9 %) of the title compound P35-A and 17.2 g (78 %) of the title compound P35-B. [0448] tert-butyl 4-(2-chloro-6-pyrrolidin-1-ylpyrimidin-4-yl)piperazine-1-carboxylate (35-A). ¹H-NMR (400 MHz, CDCl3) δ 5.15 (s, 1H), 3.58-3.50 (m, 8H), 3.50-3.32 (m, 4H), 2.05-1.94 (m, 4H), 1.50 (s, 9H). [0449] tert-butyl 4-(6-chloro-2-pyrrolidin-1-ylpyrimidin-4-yl)piperazine-1-carboxylate (P32-B).1H-NMR (400 MHz, CDCl3) δ 5.84 (s, 1H), 3.68-3.35 (m, 12H), 2.00-1.91 (m, 4H), 1.49 (s, 9H). [0450] Preparation 36: tert-butyl 4-[2-chloro-6-(2-methylpyrrolidin-1-yl)pyrimidin-4- yl]piperazine-1-carboxylate (P36-A) and tert-butyl 4-[6-chloro-2-(2-methylpyrrolidin-1- yl)pyrimidin-4-yl]piperazine-1-carboxylate (P36-B)

[0451] The compounds were synthesized according to the procedure described in Preparation 35 using 3-methyl-pyrrolidine instead of pyrrolidine. [0452] tert-butyl 4-[2-chloro-6-(2-methylpyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1- carboxylate (P36-A).¹H-NMR (400 MHz, CDCl₃) δ 5.17 (s, 1H), 4.28-4.17 (m, 1H), 3.62-3.43 (m, 10H), 2.13-1.92 (m, 3H), 1.76-1.69 (m, 1H), 1.50 (s, 9H), 1.24 (d, J = 5.2 Hz, 3H). [0453] tert-butyl 4-[6-chloro-2-(2-methylpyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1- carboxylate (P36-B).¹H-NMR (400 MHz, CDCl3) δ 5.84 (s, 1H), 4.28-4.17 (m, 1H), 3.65-3.41 (m, 10H), 2.11-1.92 (m, 3H), 1.74-1.62 (m, 1H), 1.50 (s, 9H), 1.24 (d, J = 6.3 Hz, 3H). [0454] Preparation 37: tert-butyl 4-[2-chloro-6-(3-hydroxypyrrolidin-1-yl)pyrimidin-4- yl]piperazine-1-carboxylate (P37-A) and tert-butyl 4-[6-chloro-2-(3-hydroxypyrrolidin-1- yl)pyrimidin-4-yl]piperazine-1-carboxylate (P37-B)

[0455] The compounds were synthesized according to the procedure described in Preparation 35 using pyrrolidin-3-ol instead of pyrrolidine. [0456] tert-butyl 4-[2-chloro-6-(3-hydroxypyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1- carboxylate (P37-A).¹H-NMR (400 MHz, CDCl₃) δ 5.18 (s, 1H), 4.60 (m, 1H), 3.64-3.53 (m, 8H), 3.53-3.48 (m, 4H), 2.16-2.02 (m, 2H), 1.49 (s, 9H). [0457] tert-butyl 4-[6-chloro-2-(3-hydroxypyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1- carboxylate (P37-B).¹H-NMR (400 MHz, CDCl3) δ 5.86 (s, 1H), 4.56 (m, 1H), 3.74-3.62 (m, 4H), 3.62-3.56 (m, 4H), 3.52-3.46 (m, 4H), 2.15-1.98 (m, 2H), 1.49 (s, 9H). [0458] Preparation 38: tert-butyl 4-(2-chloro-6-morpholin-4-ylpyrimidin-4-yl)piperazine- 1-carboxylate (P38-A) and tert-butyl 4-(6-chloro-2-morpholin-4-ylpyrimidin-4-yl)piperazine- 1-carboxylate.

[0459] The compounds were synthesized according to the procedure described in Preparation 35 using morpholine instead of pyrrolidine. [0460] tert-butyl 4-(2-chloro-6-morpholin-4-ylpyrimidin-4-yl)piperazine-1-carboxylate (P38-A). This isomer was not isolated. [0461] tert-butyl 4-(6-chloro-2-morpholin-4-ylpyrimidin-4-yl)piperazine-1-carboxylate (P38-B).1H-NMR (400 MHz, CDCl3) δ 6.18 (s, 1H), 3.62-3.53 (m, 10H), 3.39-3.33 (m, 6H), 1.41 (s, 9H). [0462] Preparation 39: tert-butyl 4-(2-chloro-6-piperidin-1-ylpyrimidin-4-yl)piperazine- 1-carboxylate (P39-A) and tert-butyl 4-(6-chloro-2-piperidin-1-ylpyrimidin-4-yl)piperazine-1- carboxylate (P39-B)

[0463] The compounds were synthesized according to the procedure described in Preparation 35 using piperidine instead of pyrrolidine. [0464] tert-butyl 4-(2-chloro-6-piperidin-1-ylpyrimidin-4-yl)piperazine-1-carboxylate (P39-A). This isomer was not isolated. [0465] tert-butyl 4-(6-chloro-2-piperidin-1-ylpyrimidin-4-yl)piperazine-1-carboxylate (P39-B). 1H-NMR (400 MHz, CDCl3) δ 5.81 (s, 1H), 3.73-3.70 (m, 4H), 3.58-3.55 (m, 4H), 3.51-3.48 (m, 4H), 1.67-1.62 (m, 2H), 1.60-1.55 (m, 6H), 1.48 (s, 9H). [0466] Preparation 40: tert-butyl 4-[2-chloro-6-(2,6-dimethylmorpholin-4-yl)pyrimidin- 4-yl]piperazine-1-carboxylate (P40-A) and tert-butyl 4-[6-chloro-2-(2,6-dimethylmorpholin- 4-yl)pyrimidin-4-yl]piperazine-1-carboxylate (P40-B)

[0467] The compounds were synthesized according to the procedure described in Preparation 35 using 2,6-dimethylmorpholine instead of pyrrolidine. [0468] tert-butyl 4-[2-chloro-6-(2,6-dimethylmorpholin-4-yl)pyrimidin-4-yl]piperazine-1- carboxylate (P40-A). 1H-NMR (400 MHz, CDCl3) δ 5.87 (s, 1H), 4.09-4.02 (m, 2H), 3.88- 3.80 (m, 2H), 3.58-3.47 (m, 10H), 1.49 (s, 9H), 1.24 (s, 3H).1.23 (s, 3H). [0469] tert-butyl 4-[6-chloro-2-(2,6-dimethylmorpholin-4-yl)pyrimidin-4-yl]piperazine-1- carboxylate (P40-B). 1H-NMR (400 MHz, CDCl3) δ 5.88 (s, 1H), 4.49-4.45 (m, 2H), 3.66- 3.59 (m, 2H), 3.58-3.56 (m, 4H) 3.52-3.49 (m, 4H), 2.58-2.52 (m, 2H), 1.49 (s, 9H), 1.26 (s, 3H).1.24 (s, 3H). [0470] Preparation 41: tert-butyl 4-{6-[butyl(methyl)amino]-2-chloropyrimidin-4- yl}piperazine-1-carboxylate (P41-A) and tert-butyl 4-{2-[butyl(methyl)amino]-6- chloropyrimidin-4-yl}piperazine-1-carboxylate (P41-B)

[0471] The compounds were synthesized according to the procedure described in Preparation 35 using N-methylbutan-1-amine instead of pyrrolidine. [0472] tert-butyl 4-{6-[butyl(methyl)amino]-2-chloropyrimidin-4-yl}piperazine-1- carboxylate (P41-A). This isomer was not isolated. [0473] tert-butyl 4-{2-[butyl(methyl)amino]-6-chloropyrimidin-4-yl}piperazine-1- carboxylate (P41-B).1H-NMR (400 MHz, CDCl3) δ 5.81 (s, 1H), 3.57-3.47 (m, 10H), 3.08 (s, 3H), 1.64-1.52 (m, 2H), 1.48 (s, 9H), 1.37-1.28 (m, 2H).0.94 (t, J=7.6Hz, 3H). [0474] Preparation 42: di-tert-butyl 4,4'-(2-chloropyrimidine-4,6-diyl)dipiperazine-1- carboxylate (P42-A) and di-tert-butyl 4,4'-(6-chloropyrimidine-2,4-diyl)dipiperazine-1- carboxylate (P42-B)

[0475] The compounds were synthesized according to the procedure described in Preparation 35 using tert-butyl piperazine-1-carboxylate instead of pyrrolidine. [0476] Preparation 43:

^{P43 A P43 B} [0477] A mixture of 2,4-dichloro-6-pyrrolidin-1-ylpyrimidine (3.2 g, 14 mmol) (See Preparation 33-A), tert-butyl azetidin-3-ylcarbamate (2.7 g, 15.4 mmol), NEt3 (4.5 g, 42 mmol), and MeCN (50 mL) was stirred at ambient temperature for 12 h, cooled, and concentrated under reduced pressure. The residue was dissolved in DCM, washed with water, brine, dried over anh. Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica FC eluting with a mixture of Et2O (0 to 5 %) and DCM to afford 0.24 g (4.6 %) of the title compound P43-A and 2.2 g (44 %) of the title compound P43-B. [0478] (P43-A). 1H-NMR (400 MHz, CDCl3) δ 5.00 (br.s, 1H),4.85 (s, 1H), 4.58 (br.s, 1H), 4.32 (t, J=8Hz, 2H), 3.83-3.79 (m, 2H),3.57-3.29 (m, 4H), 2.01-1.93 (m, 4H), 1.46 (s, 9H). [0479] (P43-B). 1H-NMR (400 MHz, CDCl3) δ 5.71 (s, 1H),4.96 (br.s, 1H), 4.52 (br.s, 1H), 4.38 (t, J=9.6Hz, 2H), 3.86-3.82 (m, 2H),3.61-3.18 (m, 4H), 2.01-1.88 (m, 4H), 1.46 (s, 9H). [0480] Preparation 44:

[0481] The compounds were synthesized according to the procedure described in Preparation 43 using tert‐butyl 4‐aminopiperidine‐1‐carboxylate instead of tert-butyl azetidin- 3-ylcarbamate. [0482] (P44-A). 1H-NMR (400 MHz, CDCl3) δ 5.02 (s, 1H),4.65 (d,J-7.7Hz, 1H), 4.02- 3.96 (m, 2H), 3.65-3.01 (m, 5H), 3.01-2.95 (m, 2H), 2.04-1.94 (m, 6H, 1.47 (s, 9H), 1.43-1.33 (m, 2H). [0483] (P44-B).1H-NMR (400 MHz, CDCl3) δ 5.70 (s, 1H), 4.78 (d, J=7.6Hz, 1H), 4.02- 3.91 (m, 3H), 3.55-3.25 (m, 4H), 2.98-2.92 (m, 2H), 2.04-1.93 (m, 6H), 1.46 (s, 9H), 1.39-1.33 (m, 2H). [0484] Preparation 45:

[0485] The compounds were synthesized according to the procedure described in Preparation 43 using tert‐butyl N‐(pyrrolidin‐3‐yl)carbamate instead of tert-butyl azetidin-3- ylcarbamate. [0486] (P45-A). 1H-NMR (400 MHz, CDCl3) δ 4.92 (s, 1H), 4.67 (br.s, 1H), 4.30 (br.s, 1H), 3.71-3.67 (m, 1H), 3.57-3.28 (m, 7H), 2.26-2.19 (m, 1H), 2.00-1.93(m, 5H), 1.45 (s, 9H). [0487] (P45-B). 1H-NMR (400 MHz, CDCl3) δ 5.66 (s, 1H), 4.69 (br.s, 1H), 4.27 (br.s, 1H), 3.80-3.74 (m, 1H), 3.64-3.16 (m, 7H), 2.22-2.14 (m, 1H), 2.01-1.85(m, 5H), 1.44 (s, 9H). [0488] Preparation 46:

[0489] The compounds were synthesized according to the procedure described in Preparation 43 using tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate instead of tert-butyl azetidin-3-ylcarbamate. [0490] (P46-A). 1H-NMR (400 MHz, CDCl3) δ 4.92 (s, 1H), 3.75-3.57 (m, 4H), 3.51- 3.16 (m, 8H), 3.02-2.90 (m, 2H), 2.02-1.90 (m, 4H), 1.46 (s, 9H). [0491] (P46-B).1H-NMR (400 MHz, CDCl3) δ 5.69 (s, 1H), 3.86-3.72 (m, 2H), 3.68-3.43 (m, 6H), 3.41-3.19 (m, 4H), 2.97-2.87 (m, 2H), 2.03-1.91 (m, 4H), 1.46 (s, 9H). [0492] Preparation 47:

[0493] The compounds were synthesized according to the procedure described in Preparation 43 using tert-butyl 2-isopropylpiperazine-1-carboxylate hydrochloride instead of tert-butyl azetidin-3-ylcarbamate. [0494] (P47-A).1H-NMR (400 MHz, DMSO-d6) δ 5.45 (s, 1H), 4.49-4.34 (m, 1H), 4.14- 4.04 (m, 1H), 3.92-3.79 (m, 1H), 3.73-3.57 (m, 1H), 3.43-3.31 (m, 4H), 2.98-2.78 (m, 3H), 1.95-1.84 (m, 4H), 1.83-1.74 (m, 1H), 1.40 (s, 9H), 0.96 (d, J = 6.5 Hz, 3H). 0.75 (d, J = 6.5 Hz, 3H). [0495] (P47-B).1H-NMR (400 MHz, DMSO-d6) δ 5.80 (s, 1H), 4.79-4.65 (m, 1H), 4.55- 4.41 (m, 1H), 3.95-3.78 (m, 1H), 3.74-3.57 (m, 1H), 3.55-3.35 (m, 2H), 3.31-3.17 (m, 3H), 2.91-2.73 (m, 3H), 1.96-1.73 (m, 4H), 1.41 (s, 9H), 1.00 (d, J = 6.6 Hz, 3H). 0.75 (d, J = 7.1 Hz, 3H). [0496] Preparation 48:

[0497] The compounds were synthesized according to the procedure described in Preparation 43 using tert-butyl N-(4-piperidyl)carbamate instead of tert-butyl azetidin-3- ylcarbamate. [0498] (P48-A). 1H-NMR (400 MHz, CDCl3) δ 5.17 (s, 1H),4.48 (br.s, 1H), 4.19 (d, J=18.8Hz, 2H), 3.72-3.65 (m, 1H), 3.48-3.35 (m, 4H),2.88-2.90 (m, 2H), 2.04-1.94 (m, 6H), 1.45 (s, 9H, 1.40-1.29(m, 2H)). [0499] (P48-B).1H-NMR (400 MHz, CDCl3) δ 5.64 (s, 1H), 4.59 (d, J=13.2Hz, 2H), 4.48 (br.s, 1H), 3.72-3.21 (m, 5H), 2.99-2.92 (m, 2H), 2.02-1.90 (m, 6H), 1.44 (s, 9H, 1.36-1.26 (m, 2H)). [0500] Preparation 49:

[0501] The compounds were synthesized according to the procedure described in Preparation 43 using tert-butyl (2S)-2-methylpiperazine-1-carboxylate instead of tert-butyl azetidin-3-ylcarbamate. [0502] (P49-A). This isomer was not isolated. [0503] (P49-B).1H-NMR (400 MHz, DMSO-d6) δ 5.80 (s, 1H), 4.44-4.28 (m, 2H), 4.24- 4.11 (m, 1H), 3.79-3.67 (m, 1H), 3.54-3.32 (m, 4H), 3.12-2.96 (m, 2H), 2.94-2.83 (m, 1H), 1.98-1.77 (m, 4H), 1.41 (s, 9H), 1.03 (d, J = 6.6 Hz, 3H). [0504] Preparation 50:

[0505] The compounds were synthesized according to the procedure described in Preparation 43 using piperidin-4-ylmethanol instead of tert-butyl azetidin-3-ylcarbamate. [0506] (P50-A). 1H-NMR (400 MHz, DMSO-d6) δ 5.43 (s, 1H), 4.29-4.18 (m, 2H), 3.35- 3.32 (m, 5H), 3.24 (d, J = 6.3 Hz, 2H), 2.87-2.70 (m, 2H), 1.93-1.80 (m, 4H), 1.72-1.53 (m, 3H), 1.12-0.93 (m, 2H). [0507] (P50-B).1H-NMR (400 MHz, DMSO-d6) δ 5.75 (s, 1H), 4.63-4.49 (m, 2H), 3.52- 3.37 (m, 2H), 3.32-3.26 (m, 3H), 3.23 (d, J = 6.0 Hz, 2H), 2.83-2.69 (m, 2H), 1.98-1.80 (m, 4H), 1.70-1.63 (m, 2H), 1.61-1.50 (m, 1H), 1.09-0.92 (m, 2H). [0508] Preparation 51:

[0509] The compounds were synthesized according to the procedure described in Preparation 43 using 3,3-difluoropiperidine hydrochloride instead of tert-butyl azetidin-3- ylcarbamate. [0510] (P51-A). 1H-NMR (400 MHz, DMSO-d6) δ 5.58 (s, 1H), 3.90 (t, J = 11.6 Hz, 2H), 3.61-3.53 (m, 2H), 3.39-3.35 (m, 4H), 2.14-2.01 (m, 4H), 1.94-1.82 (m, 2H), 1.72-1.61 (m, 2H). [0511] (P51-B).1H-NMR (400 MHz, DMSO-d6) δ 5.86 (s, 1H), 4.00 (t, J = 12.0 Hz, 2H), 3.76-3.66 (m, 2H), 3.52-3.40 (m, 2H), 3.31-3.22 (m, 2H), 2.13-1.99 (m, 2H), 1.97-1.81 (m, 4H), 1.72-1.61 (m, 2H). [0512] Preparation 52:

[0513] The compounds were synthesized according to the procedure described in Preparation 43 using N-methylbutan-1-amine instead of tert-butyl azetidin-3-ylcarbamate. [0514] (P52-A). 1H-NMR (400 MHz, DMSO-d6) δ 5.21 (s, 1H), 3.57-3.38 (m, 4H), 3.29- 3.19 (m, 2H), 2.92 (s, 3H), 1.93-1.83 (m, 4H), 1.52-1.41 (m, 2H), 1.29-1.19 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H). [0515] (P52-B). 1H-NMR (400 MHz, DMSO-d6) δ 5.74 (s, 1H), 3.57-3.38 (m, 4H), 3.29- 3.19 (m, 2H), 2.99 (s, 3H), 1.99-1.81 (m, 4H), 1.58-1.45 (m, 2H), 1.32-1.19 (m, 2H), 0.90 (t, J = 8.4 Hz, 3H). [0516] Preparation 53:

[0517] The compounds were synthesized according to the procedure described in Preparation 43 using (2-methoxyethyl)methylamine instead of tert-butyl azetidin-3- ylcarbamate. [0518] (P53-A). No NMR data for this compound; it was isolated in 6% yield and identified by LCMS. [0519] (P53-B).1H-NMR (400 MHz, DMSO-d6) δ: 5.77 (s, 1H), 3.66 (t, J = 5.6 Hz, 2H), 3.49 (t, J = 5.3 Hz, 2H), 3.47-3.36 (m, 2H), 3.34-3.26 (m, 2H), 3.24 (s, 3H), 3.04 (s, 3H), 1.98- 1.74 (m, 4H). [0520] Preparation 54:

[0521] The compounds were synthesized according to the procedure described in Preparation 43 using 4-phenylpiperidine instead of tert-butyl azetidin-3-ylcarbamate. [0522] (P54-A). 1H-NMR (400 MHz, DMSO-d6) δ: 7.38-7.12 (m, 5H), 5.51 (s, 1H), 4.47- 4.29 (m, 2H), 3.44-3.32 (m, 4H), 2.98-2.72 (m, 3H), 1.98-1.74 (m, 6H), 1.63-1.44 (m, 2H). [0523] (P54-B). 1H-NMR (400 MHz, DMSO-d6) δ: 7.30-7.14 (m, 5H), 5.79 (s, 1H), 4.78- 4.69 (m, 2H), 3.53-3.39 (m, 2H), 3.30-3.18 (m, 2H), 2.98-2.69 (m, 3H), 1.96-1.74 (m, 6H), 1.62-1.43 (m, 2H). [0524] Preparation 55:

[0525] The compounds were synthesized according to the procedure described in Preparation 43 using 4-methylpiperidine instead of tert-butyl azetidin-3-ylcarbamate. [0526] (P55-A). This isomer was not isolated. [0527] (P55-B).1H-NMR (400 MHz, DMSO-d6) δ 5.75 (s, 1H), 4.58-4.45 (m, 2H), 3.50- 3.37 (m, 2H), 3.29-3.17 (m, 2H), 2.83-2.71 (m, 2H), 1.97-1.78 (m, 4H), 1.69-1.52 (m, 3H), 1.04-0.94 (m, 2H), 0.91 (d, J = 6.2 Hz, 3H). [0528] Preparation 56:

[0529] The compounds were synthesized according to the procedure described in Preparation 43 using N,N-dimethylpiperidin-4-amine instead of tert-butyl azetidin-3- ylcarbamate. [0530] (P56-A).1H-NMR (400 MHz, DMSO-d6) δ 5.55 (s, 1H), 4.47-4.35 (m, 2H), 3.49- 3.25 (m, 5H), 2.88-2.78 (m, 2H), 2.76 (s, 3H), 2.74 (s, 3H), 2.04-1.96 (m, 2H), 1.95-1.82 (m, 4H), 1.58-1.38 (m, 2H). [0531] (P56-B).1H-NMR (400 MHz, DMSO-d6) δ 5.77 (s, 1H), 4.60-4.48 (m, 2H), 3.64- 3.35 (m, 3H), 3.29-3.18 (m, 2H), 2.87-2.73 (m, 2H), 2.16 (s, 6H), 1.97-1.83 (m, 4H), 1.79-1.69 (m, 2H), 1.301.17 (m, 2H). [0532] Preparation 57:

[0533] The compounds were synthesized according to the procedure described in Preparation 43 using N-methylcyclohexanamine instead of tert-butyl azetidin-3-ylcarbamate. [0534] (P57-A). This isomer was not isolated. [0535] (P57-B). 1H-NMR (400 MHz, DMSO-d6) δ 5.74 (s, 1H), 4.48-4.33 (m, 1H), 3.53- 3.38 (m, 2H), 3.29-3.19 (m, 2H), 2.88 (s, 3H), 1.96-1.84 (m, 4H), 1.81-1.73 (m, 2H), 1.64-1.55 (m, 3H), 1.52-1.40 (m, 2H), 1.33-1.22 (m, 2H), 1.18-1.05 (m, 1H). [0536] Preparation 58: tert-butyl (3S)-4-(2-chloro-6-pyrrolidin-1-ylpyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (P58-A) and tert-butyl (3S)-4-(4-chloro-6-pyrrolidin-1- ylpyrimidin-2-yl)-3-methylpiperazine-1-carboxylate (P58-B):

[0537] The compounds were synthesized according to the procedure described in Preparation 43 using tert-butyl (3S)-3-methylpiperazine-1-carboxylate instead of tert-butyl azetidin-3-ylcarbamate. [0538] Preparation 59: tert-butyl 4-(2-chloro-6-pyrrolidin-1-ylpyrimidin-4-yl)-1,4- diazepane-1-carboxylate (P59-A) and tert-butyl 4-(6-chloro-2-pyrrolidin-1-ylpyrimidin-4-yl)- 1,4-diazepane-1-carboxylate (P59-B).

[0539] The compounds were synthesized according to the procedure described in Preparation 43 using pyrrolidine instead of tert-butyl 4-(2,6-dichloropyrimidin-4-yl)-1,4- diazepane-1-carboxylate. [0540] (P59-A) 1H-NMR (400 MHz, CDCl3) δ 5.08 (s, 1H), 3.93 – 3.17 (m, 12H), 2.20 – 1.80 (m, 6H), 1.44 (s, 9H). [0541] (P59-B) 1H-NMR (400 MHz, CDCl3) δ 5.77 (s, 1H), 3.62 (m, 9H), 3.40-33.2 (m, 2H), 1.94 (m, 6H), 1.44 (s, 9H). [0542] Preparation 60: tert-butyl 4-(4-chloro-6-pyrrolidin-1-ylpyrimidin-2-yl)-1,4- diazepane-1-carboxylate

[0543] The compound was synthesized according to the procedure described in Preparation 43 using pyrrolidine instead of tert-butyl 4-(4,6-dichloropyrimidin-2-yl)-1,4-diazepane-1- carboxylate.1H-NMR (400 MHz, CDCl3) δ 5.66 (s, 1H), 3.87 – 3.78 (m, 2H), 3.74 – 3.67 (m, 2H), 3.62 – 3.43 (m, 4H), 3.42 – 3.16 (m, 4H), 2.05 – 1.90 (m, 6H), 1.45 (c, 9H). [0544] Preparation 61: tert-butyl (3aR,6aS)-5-(6-chloro-2-pyrrolidin-1-ylpyrimidin-4- yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0545] A mixture of 4,6-dichloro-2-pyrrolidin-1-ylpyrimidine (See Preparation P33-B) (1g, 4.6 mmol) tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1g, 4.7mmol), NEt3 ( 1.5g, 14.8 mmol), and MeCN (50 mL) was stirred at ambient temperature for 12 h, cooled, and concentrated under reduced pressure. The residue was dissolved in DCM, washed with water, brine, dried over anh. Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica FC eluting with a mixture of Et2O (0 to 5 %) and DCM to afford 1.51g (83%) of the title compound P61. 1H-NMR (400 MHz, CDCl3) δ 5.64 (s, 1H), 3.76-3.58 (m, 4H), 3.57-3.50 (m, 4H), 3.40-3.28 (m, 2H), 3.28-3.16 (m, 2H), 3.02-2.88 (m, 2H), 1.96-1.90 (m, 4H), 1.46 (s, 9H). [0546] Preparation 62:

[0547] The compound was synthesized according to the procedure described in Preparation 61 using tert-butyl (2S)-2-methylpiperazine-1-carboxylate instead tert-butyl (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. [0548] Preparation 63: tert-butyl 4-[(6-chloro-2-pyrrolidin-1-ylpyrimidin-4- yl)amino]piperidine-1-carboxylate

[0549] The compound was synthesized according to the procedure described in Preparation 61 using tert-butyl 4-aminopiperidine-1-carboxylate instead tert-butyl (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. [0550] Preparation 64: tert-butyl 4-(6-chloro-2-pyrrolidin-1-ylpyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate

[0551] The compound was synthesized according to the procedure described in Preparation 61 using tert-butyl 2,5-dimethylpiperazine-1-carboxylate instead tert-butyl (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. [0552] Preparation 65: 2-[(6-chloro-2-pyrrolidin-1-ylpyrimidin-4-yl)amino]-2- phenylethanol

[0553] The compound was synthesized according to the procedure described in Preparation 61 using 2-amino-2-phenylethanol instead tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate. [0554] Preparation 66: 1-(1-methylethyl)-N-(4-piperazin-1-yl-6-pyrrolidin-1-ylpyrimidin- 2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine hydrochloride

[0555] Step A: tert-butyl 4-(2-{[1-(1-methylethyl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-pyrrolidin-1-ylpyrimidin-4-yl)piperazine-1-carboxylate. A mixture of tert-butyl 4-(2-chloro-6-pyrrolidin-1-ylpyrimidin-4-yl)piperazine-1-carboxylate (See Preparation P35- A) (1.6 g, 4.35 mmol), 1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine (See preparation (0.8 g, 4.50 mmol), Pd(dba)2 (0.4 g, 0.44 mmol), X-Phos (0.3 g, 0.65 mmol) and t-BuONa (0.83 g, 8.60 mmol) in dioxane (50 mL) was stirred and heated under reflux for 18 h, cooled, and concentrated under reduced pressure. The residue was subjected to silica CC eluting with a mixture of EtOAc (0 to 25 %) and DCM to afford 1.8 g (82 %) of the title compound. [0556] Step B: 1-(1-methylethyl)-N-(4-piperazin-1-yl-6-pyrrolidin-1-ylpyrimidin-2-yl)- 1H-pyrazolo[4,3-c]pyridin-6-amine hydrochloride. A mixture of the compound obtained at Step (1.8 g, 3.50 mmol) and 3M HCl/Dioxane (8 mL, 2.38 mmol) in DCM (30 mL) was stirred at ambient temperature for 7 h and diluted with anh. Et2O. The formed precipitate was collected by filtration, washed with Et2O, and dried to afford 1.5 g (96%) of the title compound. [0557] Preparation 67: 1-(cyclohexylmethyl)-N-(4-piperazin-1-yl-6-pyrrolidin-1- ylpyrimidin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0558] The compound was synthesized according to the procedure described in Preparation 66 using 1-(cyclohexylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-amine (See Preparation P18) instead of 1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine. [0559] Preparation 68: N-(4-piperazin-1-yl-6-pyrrolidin-1-ylpyrimidin-2-yl)-1-(2,2,2- trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0560] The compound was synthesized according to the procedure described in Preparation 66 using 1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-amine (See Preparation P28) instead of 1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine. [0561] Preparation 69: 1-cyclohexyl-N-(4-piperazin-1-yl-6-pyrrolidin-1-ylpyrimidin-2- yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0562] The compound was synthesized according to the procedure described in Preparation 66 using 1-cyclohexyl-1H-pyrazolo[4,3-c]pyridin-6-amine (See Preparation P19) instead of 1- isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine. [0563] Preparation 70: 1-cyclopentyl-N-(4-piperazin-1-yl-6-pyrrolidin-1-ylpyrimidin-2- yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0564] The compound was synthesized according to the procedure described in Preparation 66 using 1-cyclopentyl-1H-pyrazolo[4,3-c]pyridin-6-amine (see Preparation P22) instead of 1- isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine. [0565] Preparation 71: N-(4-piperazin-1-yl-6-pyrrolidin-1-ylpyrimidin-2-yl)-1- (tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0566] The compound was synthesized according to the procedure described in Preparation 66 using 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine (see Preparation P23) instead of 1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine. [0567] Preparation 72: 1-cyclohex-2-en-1-yl-N-(4-piperazin-1-yl-6-pyrrolidin-1- ylpyrimidin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0568] The compound was synthesized according to the procedure described in Preparation 66 using 1-cyclohex-2-en-1-yl-1H-pyrazolo[4,3-c]pyridin-6-amine (see Preparation P24) instead of 1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine. [0569] Preparation 73: 1-(cyclobutylmethyl)-N-(4-piperazin-1-yl-6-pyrrolidin-1- ylpyrimidin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0570] The compound was synthesized according to the procedure described in Preparation 66 using 1-(cyclobutylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-amine (see Preparation P25) instead of 1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine. [0571] Preparation 74: 1-benzyl-N-(4-piperazin-1-yl-6-pyrrolidin-1-ylpyrimidin-2-yl)- 1H-pyrazolo[4,3-c]pyridin-6-amine

[0572] The compound was synthesized according to the procedure described in Preparation 66 using 1-benzyl-1H-pyrazolo[4,3-c]pyridin-6-amine (see Preparation P26) instead of 1- isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine. [0573] Preparation 75: N-(4-piperazin-1-yl-6-pyrrolidin-1-ylpyrimidin-2-yl)-1-(pyridin- 3-ylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0574] The compound was synthesized according to the procedure described in Preparation 66 using 1-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-amine (see Preparation P27) instead of 1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine. [0575] Preparation 76: 1-phenyl-N-(4-piperazin-1-yl-6-pyrrolidin-1-ylpyrimidin-2-yl)- 1H-pyrazolo[4,3-c]pyridin-6-amine

[0576] The compound was synthesized according to the procedure described in Preparation 66 using 1-phenyl-1H-pyrazolo[4,3-c]pyridin-6-amine (see Preparation P29) instead of 1- isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine. [0577] Preparation 77: 1-(1-methylethyl)-N-[4-(2-methylpyrrolidin-1-yl)-6-piperazin-1- ylpyrimidin-2-yl]-1H-pyrazolo[4,3-c]pyridin-6-amine

[0578] The compound was synthesized according to the procedure described in Preparation 66 using tert-butyl 4-[2-chloro-6-(2-methylpyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1- carboxylate (see Preparation P36-A) instead of tert-butyl 4-(2-chloro-6-pyrrolidin-1- ylpyrimidin-4-yl)piperazine-1-carboxylate. [0579] Preparation 78: 1-(1-methylethyl)-N-{4-[3-(1-methylethyl)piperazin-1-yl]-6- pyrrolidin-1-ylpyrimidin-2-yl}-1H-pyrazolo[4,3-c]pyridin-6-amine

[0580] The compound was synthesized according to the procedure described in Preparation 66 using tert-butyl 4-(2-chloro-6-pyrrolidin-1-ylpyrimidin-4-yl)-2-(1-methylethyl)piperazine- 1-carboxylate (see Preparation P47-A) instead of tert-butyl 4-(2-chloro-6-pyrrolidin-1- ylpyrimidin-4-yl)piperazine-1-carboxylate. [0581] Preparation 79: 1-(2-{[1-(1-methylethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}- 6-piperazin-1-ylpyrimidin-4-yl)pyrrolidin-3-ol

[0582] The compound was synthesized according to the procedure described in Preparation 66 using tert-butyl 4-[2-chloro-6-(3-hydroxypyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1- carboxylate (see Preparation P37-A) instead of tert-butyl 4-(2-chloro-6-pyrrolidin-1- ylpyrimidin-4-yl)piperazine-1-carboxylate. [0583] Preparation 80: 1-(1-methylethyl)-N-(2-piperazin-1-yl-6-pyrrolidin-1-ylpyrimidin- 4-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0584] The compound was synthesized according to the procedure described in Preparation 66 using tert-butyl 4-(4-chloro-6-pyrrolidin-1-ylpyrimidin-2-yl)piperazine-1-carboxylate instead of tert-butyl 4-(2-chloro-6-pyrrolidin-1-ylpyrimidin-4-yl)piperazine-1-carboxylate. [0585] Preparation 81: 1-(1-methylethyl)-N-(6-piperazin-1-yl-2-pyrrolidin-1-ylpyrimidin- 4-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0586] The compound was synthesized according to the procedure described in Preparation 66 using tert-butyl 4-(6-chloro-2-pyrrolidin-1-ylpyrimidin-4-yl)piperazine-1-carboxylate (see Preparation P35-B) instead of tert-butyl 4-(2-chloro-6-pyrrolidin-1-ylpyrimidin-4- yl)piperazine-1-carboxylate. [0587] Example 1: N-{2-[4-(dimethylamino)piperidin-1-yl]-6-pyrrolidin-1- ylpyrimidin-4-yl}-1-(1-methylethyl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0588] A mixture of 1-(4-chloro-6-pyrrolidin-1-ylpyrimidin-2-yl)-N,N-dimethylpiperidin- 4-amine (150 mg, 0.48 mmol), 1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine (93 mg, 0.53 mmol), Pd(cin)ClIPent (42 mg, 0.048 mmol), 2,6-di-tert-butyl-4-methylphenol (BHT) (137 mg, 0.62 mmol) and t-BuOK (65 mg, 0.58 mmol) in THF (5 ml) was stirred and heated under reflux for 18 h, cooled, and concentrated under reduced pressure. The residue was subjected to silica CC eluting with a mixture of EtOAc (0 to 25 %) and DCM to afford 146 mg (67 %) of the title compound. [0589] This protocol was used for the synthesis of the following compounds: [0590] Example 2: N2-(2-methoxyethyl)-N2-methyl-N4-[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]-6-(pyrrolidin-1-yl)pyrimidine-2,4-diamine

[0591] Example 3: N-[2-(4-methylpiperidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl]- 1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0592] Example 4: N-[2-(3,3-difluoropiperidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-4- yl]-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0593] Example 5: N2-butyl-N2-methyl-N4-[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]-6-(pyrrolidin-1-yl)pyrimidine-2,4-diamine

[0594] Example 6: N2-cyclohexyl-N2-methyl-N4-[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]-6-(pyrrolidin-1-yl)pyrimidine-2,4-diamine

[0595] Example 7: N-[2-(4-phenylpiperidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl]- 1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0596] Example 8: {1-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6- (pyrrolidin-1-yl)pyrimidin-2-yl]piperidin-4-yl}methanol

[0597] Example 9: 2-phenyl-2-{[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-2-(pyrrolidin-1-yl)pyrimidin-4-yl]amino}ethanol

[0598] Example 10: {1-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}- 6-(pyrrolidin-1-yl)pyrimidin-4-yl]piperidin-4-yl}methanol

[0599] Example 11: N-[4-(3,3-difluoropiperidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2- yl]-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0600] Example 12: N4-butyl-N4-methyl-N2-[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]-6-(pyrrolidin-1-yl)pyrimidine-2,4-diamine

[0601] Example 13: N4-(2-methoxyethyl)-N4-methyl-N2-[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]-6-(pyrrolidin-1-yl)pyrimidine-2,4-diamine

[0602] Example 14: N-[4-(4-phenylpiperidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]- 1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0603] Example 15: N-[2-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1- (propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0604] Example 16: N-[6-(piperazin-1-yl)-2-(pyrrolidin-1-yl)pyrimidin-4-yl]-1- (propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0605] Example 17: N2-butyl-N2-methyl-6-(piperazin-1-yl)-N4-[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]pyrimidine-2,4-diamine

[0606] Example 18: N-[2-(4-aminopiperidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl]- 1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0607] Example 19: N-[2-(3-aminoazetidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1- (propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0608] Example 20: 1-(propan-2-yl)-N-{2-[3-(propan-2-yl)piperazin-1-yl]-6- (pyrrolidin-1-yl)pyrimidin-4-yl}-1H-pyrazolo[4,3-c]pyridin-6-amine

[0609] Example 21: N-{2-[(3S)-3-methylpiperazin-1-yl]-6-(pyrrolidin-1-yl)pyrimidin- 4-yl}-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0610] Example 22: N-[2-(1,4-diazepan-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1- (propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0611] Example 23: N-[6-(1,4-diazepan-1-yl)-2-(pyrrolidin-1-yl)pyrimidin-4-yl]-1- (propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0612] Example 24: N-{6-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2- (pyrrolidin-1-yl)pyrimidin-4-yl}-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0613] Example 25: N-[2,6-di(piperazin-1-yl)pyrimidin-4-yl]-1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-amine

[0614] Example 26: N-[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1- (propan-2-yl)-1H-imidazo[4,5-c]pyridin-6-amine

[0615] Example 27: N-[2-(3-aminopyrrolidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-4- yl]-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0616] Example 28: 1-[4-(piperazin-1-yl)-6-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}pyrimidin-2-yl]pyrrolidin-3-ol

[0617] Example 29: N-(piperidin-4-yl)-N'-[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]-2-(pyrrolidin-1-yl)pyrimidine-4,6-diamine

[0618] Example 30: N-[2-(2-methylpyrrolidin-1-yl)-6-(piperazin-1-yl)pyrimidin-4- yl]-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0619] Example 31: N-{2-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6- (pyrrolidin-1-yl)pyrimidin-4-yl}-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0620] Example 32: N-{2-[(2S)-2-methylpiperazin-1-yl]-6-(pyrrolidin-1-yl)pyrimidin- 4-yl}-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0621] Example 33: N-[4-(4-aminopiperidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]- 1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0622] Example 34: 1-[6-(piperazin-1-yl)-2-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}pyrimidin-4-yl]pyrrolidin-3-ol

[0623] Example 35: N-[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1- (propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0624] Example 36: N-[4-(1,4-diazepan-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1- (propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0625] Example 37: N-[4-(3-aminopyrrolidin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2- yl]-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0626] Example 38: N4-(piperidin-4-yl)-N2-[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]-6-(pyrrolidin-1-yl)pyrimidine-2,4-diamine

[0627] Example 39: N-[4-(2-methylpyrrolidin-1-yl)-6-(piperazin-1-yl)pyrimidin-2- yl]-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0628] Example 40: N-{4-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6- (pyrrolidin-1-yl)pyrimidin-2-yl}-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0629] Example 41: 1-cyclopentyl-N-[6-(piperazin-1-yl)-2-(pyrrolidin-1- yl)pyrimidin-4-yl]-1H-pyrazolo[4,3-c]pyridin-6-amine

[0630] Example 42: 1-(cyclohex-2-en-1-yl)-N-[6-(piperazin-1-yl)-2-(pyrrolidin-1- yl)pyrimidin-4-yl]-1H-pyrazolo[4,3-c]pyridin-6-amine

[0631] Example 43: N-[6-(piperazin-1-yl)-2-(pyrrolidin-1-yl)pyrimidin-4-yl]-1- (tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0632] Example 44: 1-(cyclobutylmethyl)-N-[6-(piperazin-1-yl)-2-(pyrrolidin-1- yl)pyrimidin-4-yl]-1H-pyrazolo[4,3-c]pyridin-6-amine

[0633] Example 45: 1-(cyclohexylmethyl)-N-[4-(piperazin-1-yl)-6-(pyrrolidin-1- yl)pyrimidin-2-yl]-1H-pyrazolo[4,3-c]pyridin-6-amine

[0634] Example 46: 1-cyclopentyl-N-[4-(piperazin-1-yl)-6-(pyrrolidin-1- yl)pyrimidin-2-yl]-1H-pyrazolo[4,3-c]pyridin-6-amine

[0635] Example 47: N-[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1- (tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0636] Example 48: 1-(cyclohex-2-en-1-yl)-N-[4-(piperazin-1-yl)-6-(pyrrolidin-1- yl)pyrimidin-2-yl]-1H-pyrazolo[4,3-c]pyridin-6-amine

[0637] Example 49: 1-(cyclobutylmethyl)-N-[4-(piperazin-1-yl)-6-(pyrrolidin-1- yl)pyrimidin-2-yl]-1H-pyrazolo[4,3-c]pyridin-6-amine

[0638] Example 50: 1-benzyl-N-[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2- yl]-1H-pyrazolo[4,3-c]pyridin-6-amine

[0639] Example 51: 1-cyclohexyl-N-[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin- 2-yl]-1H-pyrazolo[4,3-c]pyridin-6-amine

[0640] Example 52: N-[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1- (pyridin-3-ylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0641] Example 53: 1-phenyl-N-[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2- yl]-1H-pyrazolo[4,3-c]pyridin-6-amine

[0642] Example 54: 3-methyl-6-{[4-(piperazin-1-yl)-6-(pyrrolidin-1-yl)pyrimidin-2- yl]amino}-1-(propan-2-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one

[0643] Example 55: N-(2-methoxyethyl)-4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide

[0644] A mixture of tert-butyl 1-isopropyl-N-(4-piperazin-1-yl-6-pyrrolidin-1- ylpyrimidin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine hydrochloride 8 (1.5 g, 3.40 mmol), 1- isocyanato-2-methoxyethane (0.38 g, 3.74 mmol) and DIPEA (1.5 ml, 8.50 mmol) in DCM (30 ml) was stirred at rt for 0.5 h. The reaction mixture was washed with water; the organic layer was separated, evaporated under pressure. The residue was subjected to silica CC eluting with a mixture of THF and DCM (1:1) to afford 1.38 g (80 %) of the title compound. [0645] This protocol was used for the synthesis of the following compounds: [0646] Example 56: N-(2-methoxyethyl)-4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperazine-1-carboxamide

[0647] Example 57: N-(2-methoxyethyl)-4-[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-2-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide

[0648] Example 58: 1-(2-methoxyethyl)-3-{1-[6-(piperazin-1-yl)-2-{[1-(propan-2-yl)- 1H-pyrazolo[4,3-c]pyridin-6-yl]amino}pyrimidin-4-yl]pyrrolidin-3-yl}urea

[0649] Example 59: 4-[2-{[1-(cyclohexylmethyl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]-N-(2-methoxyethyl)piperazine-1- carboxamide

[0650] Example 60: N-(2-methoxyethyl)-4-[6-(2-methylpyrrolidin-1-yl)-2-{[1- (propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}pyrimidin-4-yl]piperazine-1- carboxamide

[0651] Example 61: N-(2-methoxyethyl)-4-[2-(morpholin-4-yl)-6-{[1-(propan-2-yl)- 1H-pyrazolo[4,3-c]pyridin-6-yl]amino}pyrimidin-4-yl]piperazine-1-carboxamide

[0652] Example 62: N-(2-methoxyethyl)-4-[2-(piperidin-1-yl)-6-{[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]amino}pyrimidin-4-yl]piperazine-1-carboxamide

[0653] Example 63: 4-{2-[(1-cyclohexyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino]-6- (pyrrolidin-1-yl)pyrimidin-4-yl}-N-(2-methoxyethyl)piperazine-1-carboxamide

[0654] Example 64: 4-(2-[butyl(methyl)amino]-6-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}pyrimidin-4-yl)-N-(2-methoxyethyl)piperazine-1-carboxamide

[0655] Example 65: 4-[2-(2,6-dimethylmorpholin-4-yl)-6-{[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]amino}pyrimidin-4-yl]-N-(2-methoxyethyl)piperazine-1- carboxamide

[0656] Example 66: 4-{6-[(1-ethyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino]-2- (pyrrolidin-1-yl)pyrimidin-4-yl}-N-(2-methoxyethyl)piperazine-1-carboxamide

[0657] Example 67: N-(2-methoxyethyl)-4-[6-{[1-(2-methylpropyl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-2-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide

[0658] Example 68: N-(2-methoxyethyl)-4-[2-(pyrrolidin-1-yl)-6-{[1-(2,2,2- trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}pyrimidin-4-yl]piperazine-1- carboxamide

[0659] Example 69: 4-{6-[(1-cyclohexyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino]-2- (pyrrolidin-1-yl)pyrimidin-4-yl}-N-(2-methoxyethyl)piperazine-1-carboxamide

[0660] Example 70: N-(2-methoxyethyl)-2,5-dimethyl-4-[6-{[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]amino}-2-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1- carboxamide

[0661] Example 71: (2S)-N-(2-methoxyethyl)-2-methyl-4-[6-{[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]amino}-2-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1- carboxamide

[0662] Example 72: (2S)-N-(2-methoxyethyl)-2-methyl-4-[4-{[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperazine-1- carboxamide

[0663] Example 73: 1-(2-methoxyethyl)-3-{1-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperidin-4-yl}urea

[0664] Example 74: 1-(2-methoxyethyl)-3-{1-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]piperidin-4-yl}urea

[0665] Example 75: 1-(2-methoxyethyl)-3-{1-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]azetidin-3-yl}urea

[0666] Example 76: 1-(2-methoxyethyl)-3-{1-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]azetidin-3-yl}urea

[0667] Example 77: N-(2-methoxyethyl)-2-(propan-2-yl)-4-[4-{[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperazine-1- carboxamide

[0668] Example 78: N-(2-methoxyethyl)-4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1,4-diazepane-1-carboxamide

[0669] Example 79: N-(2-methoxyethyl)-4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1,4-diazepane-1-carboxamide

[0670] Example 80: N-(2-methoxyethyl)-4-[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-2-(pyrrolidin-1-yl)pyrimidin-4-yl]-1,4-diazepane-1-carboxamide

[0671] Example 81: N-(2-methoxyethyl)-2-(propan-2-yl)-4-[2-{[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1- carboxamide

[0672] Example 82: 4-{6-[(1-cyclopentyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino]-2- (pyrrolidin-1-yl)pyrimidin-4-yl}-N-(2-methoxyethyl)piperazine-1-carboxamide

[0673] Example 83: 4-{2-[(1-cyclopentyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino]-6- (pyrrolidin-1-yl)pyrimidin-4-yl}-N-(2-methoxyethyl)piperazine-1-carboxamide

[0674] Example 84: 4,4'-(6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}pyrimidine-2,4-diyl)bis[N-(2-methoxyethyl)piperazine-1-carboxamide]

[0675] Example 85: 4-[2-(3-hydroxypyrrolidin-1-yl)-6-{[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]amino}pyrimidin-4-yl]-N-(2-methoxyethyl)piperazine-1- carboxamide

[0676] Example 86: 4-[6-(3-hydroxypyrrolidin-1-yl)-2-{[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]amino}pyrimidin-4-yl]-N-(2-methoxyethyl)piperazine-1- carboxamide

[0677] Example 87: 1-(2-methoxyethyl)-3-{1-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]pyrrolidin-3-yl}urea

[0678] Example 88: 1-(2-methoxyethyl)-3-{1-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]pyrrolidin-3-yl}urea

[0679] Example 89: N-(2-methoxyethyl)-4-{[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-2-(pyrrolidin-1-yl)pyrimidin-4-yl]amino}piperidine-1- carboxamide

[0680] Example 90: N-(2-methoxyethyl)-4-[6-(pyrrolidin-1-yl)-2-{[1-(tetrahydro-2H- pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}pyrimidin-4-yl]piperazine-1- carboxamide

[0681] Example 91: 4-[2-{[1-(cyclohex-2-en-1-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]-N-(2-methoxyethyl)piperazine-1- carboxamide

[0682] Example 92: 4-[2-{[1-(cyclobutylmethyl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]-N-(2-methoxyethyl)piperazine-1- carboxamide

[0683] Example 93: N-(2-methoxyethyl)-4-{[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]amino}piperidine-1- carboxamide

[0684] Example 94: 4-{2-[(1-benzyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino]-6- (pyrrolidin-1-yl)pyrimidin-4-yl}-N-(2-methoxyethyl)piperazine-1-carboxamide

[0685] Example 95: (3aR,6aS)-N-(2-methoxyethyl)-5-[2-{[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4- yl]hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

[0686] Example 96: (3aR,6aS)-N-(2-methoxyethyl)-5-[4-{[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2- yl]hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

[0687] Example 97: N-(2-methoxyethyl)-4-[2-{[1-(propan-2-yl)-1H-imidazo[4,5- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide

[0688] Example 98: (3S)-N-(2-methoxyethyl)-3-methyl-4-[4-{[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperazine-1- carboxamide

[0689] Example 99: N-(2-methoxyethyl)-4-[2-{[1-(pyridin-3-ylmethyl)-1H- pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1- carboxamide

[0690] Example 100: N-(2-methoxyethyl)-4-{2-[(1-phenyl-1H-pyrazolo[4,3-c]pyridin- 6-yl)amino]-6-(pyrrolidin-1-yl)pyrimidin-4-yl}piperazine-1-carboxamide

[0691] Example 101: 4-{6-[(1-cyclohexyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino]-2- (pyrrolidin-1-yl)pyrimidin-4-yl}-N-(3-methoxypropyl)piperazine-1-carboxamide

[0692] Example 102: N-(3-methoxypropyl)-4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide

[0693] Example 103: N-(2-phenylethyl)-4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperazine-1-carboxamide

[0694] Example 104: N-(2-phenylethyl)-4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide

[0695] Example 105: N-(3-methylbutyl)-4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperazine-1-carboxamide

[0696] Example 106: N-(3-methylbutyl)-4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide

[0697] Example 107: N-(3-ethoxypropyl)-4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide

[0698] Example 108: N-tert-butyl-4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin- 6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide

[0699] Example 109: N-benzyl-4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine-1-carboxamide

[0700] Example 110: 4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}- 6-(pyrrolidin-1-yl)pyrimidin-4-yl]-N-(tetrahydrofuran-2-ylmethyl)piperazine-1- carboxamide

[0701] A mixture of tert-butyl 1-isopropyl-N-(4-piperazin-1-yl-6-pyrrolidin-1- ylpyrimidin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine hydrochloride 8 (0.1 g, 0.22 mmol), methoxyacetyl chloride (0.024 g, 0.22 mmol) and DIPEA (0.96 ml, 0.55 mmol) in DCM (3 ml) was stirred at rt for 0.5 h. The reaction mixture was washed with water; the organic layer was separated, evaporated under pressure. The residue was subjected to silica CC eluting with a mixture of Et2O and DCM (1:1) to afford 0.053 g (50 %) of the title compound. [0702] This protocol was used for the synthesis of the following compounds: [0703] Example 111: 2-methoxy-1-{4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazin-1-yl}ethanone

[0704] Example 112: 2-methoxy-1-{4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperazin-1-yl}ethanone

[0705] Example 113: 2-methoxy-1-{4-[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-2-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazin-1-yl}ethanone

[0706] Example 114: 2-methoxy-N-{1-[6-(piperazin-1-yl)-2-{[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]amino}pyrimidin-4-yl]pyrrolidin-3-yl}acetamide

[0707] Example 115: 1-{4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperazin-1-yl}pent-4-yn-1-one

[0708] Example 116: 1-{4-[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-2-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazin-1-yl}pent-4-yn-1-one

[0709] Example 117: 1-{4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazin-1-yl}pent-4-yn-1-one

[0710] Example 118: N-{1-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperidin-4-yl}pent-4-ynamide

[0711] Example 119: N-{1-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]piperidin-4-yl}pent-4-ynamide

[0712] Example 120: N-{1-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]azetidin-3-yl}pent-4-ynamide

[0713] Example 121: N-{1-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]azetidin-3-yl}pent-4-ynamide

[0714] Example 122: 1-{4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1,4-diazepan-1-yl}pent-4-yn-1-one

[0715] Example 123: 1-{4-[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-2-(pyrrolidin-1-yl)pyrimidin-4-yl]-1,4-diazepan-1-yl}pent-4-yn-1-one

[0716] Example 124: 1-{4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]-1,4-diazepan-1-yl}pent-4-yn-1-one

[0717] Example 125: 1-[(3aR,6aS)-5-[6-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin- 6-yl]amino}-2-(pyrrolidin-1-yl)pyrimidin-4-yl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl]pent-4-yn-1-one

[0718] Example 126: 3-[1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl]-1-{4-[4-{[1- (propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2- yl]piperazin-1-yl}propan-1-one

[0719] Example 127: 3-[1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl]-1-{4-[6-{[1- (propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}-2-(pyrrolidin-1-yl)pyrimidin-4- yl]piperazin-1-yl}propan-1-one

[0720] Example 128: ethyl 7-(4-{2-[(1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6- yl)amino]-6-pyrrolidin-1-ylpyrimidin-4-yl}piperazin-1-yl)-7-oxoheptanoate

[0721] Example 129: ethyl 7-(4-{4-[(1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6- yl)amino]-6-pyrrolidin-1-ylpyrimidin-2-yl}piperazin-1-yl)-7-oxoheptanoate

[0722] Example 130: cyclohexyl{4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperazin-1-yl}methanone

[0723] Example 131: (4-ethylphenyl){4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperazin-1-yl}methanone

[0724] Example 132: (3,4-dimethylphenyl){4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperazin-1-yl}methanone

[0725] Example 133: {4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}- 6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperazin-1-yl}(thiophen-2-yl)methanone

[0726] Example 134: 2-ethyl-1-{4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6- yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperazin-1-yl}butan-1-one

[0727] Example 135: 2-(1H-indol-3-yl)-1-{4-[4-{[1-(propan-2-yl)-1H-pyrazolo[4,3- c]pyridin-6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-2-yl]piperazin-1-yl}ethanone

[0728] Example 136: N-(2-oxo-2-{4-[2-{[1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin- 6-yl]amino}-6-(pyrrolidin-1-yl)pyrimidin-4-yl]piperazin-1-yl}ethyl)acetamide

[0729] Example 137: N-{2-[4-(cyclopropylsulfonyl)piperazin-1-yl]-6-(pyrrolidin-1- yl)pyrimidin-4-yl}-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0730] Example 138: N-[2-{4-[4-(dimethylamino)benzyl]piperazin-1-yl}-6- (pyrrolidin-1-yl)pyrimidin-4-yl]-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0731] Example 139: N-{2-[4-(cyclohexylmethyl)piperazin-1-yl]-6-(pyrrolidin-1- yl)pyrimidin-4-yl}-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0732] Example 140: tert-butyl 4-[2-(2,6-dimethylmorpholin-4-yl)-6-{[1-(propan-2- yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]amino}pyrimidin-4-yl]piperazine-1-carboxylate

[0733] Example 141: tert-butyl 4-[2-(morpholin-4-yl)-6-{[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]amino}pyrimidin-4-yl]piperazine-1-carboxylate

[0734] Example 142: tert-butyl 4-[2-(piperidin-1-yl)-6-{[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]amino}pyrimidin-4-yl]piperazine-1-carboxylate

[0735] Example 143: tert-butyl 4-(2-[butyl(methyl)amino]-6-{[1-(propan-2-yl)-1H- pyrazolo[4,3-c]pyridin-6-yl]amino}pyrimidin-4-yl)piperazine-1-carboxylate

[0736] General Scheme A

[0737] Preparation 82: Synthesis of ethyl (S)-2-chloro-4-((2-hydroxy-1- phenylethyl)amino)pyrimidine- 5-carboxylate (2)

[0738] To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (1, 20 g, 91 mmol) in ACN (250 mL) was added (S)-2-amino-2-phenylethan-1-ol (25 g, 18 mmol) and DIPEA (30 mL) at room temperature. After the reaction was stirred for 3 h, the mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography (EtOAc : n- hexane = 1 : 2) to give 2 (22 g, 75% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 9.14 (d, J = 7.6 Hz, 1H), 8.69 (s, 1H), 7.39–7.36 (m, 4H), 7.34–7.31 (m, 1H), 5.50–5.46 (m, 1H), 4.38 (q, J = 7.2 Hz, 2H), 4.00–3.98 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H). [0739] Preparation 83: Synthesis of ethyl (S)-4-((2-hydroxy-1-phenylethyl)amino)-2-((1- isopropyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxylate (4)

[0740] To a solution of 2 (1.1 g, 3.4 mmol) in dioxane (25 mL, degassed) was added 1- isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine (3, 500 mg, 2.84 mmol), potassium phosphate (1.81 g, 8.52 mmol), Xantphos (164 mg, 0.280 mmol), and tris(dibenzylideneacetone)dipalladium(0) (129 mg, 0.140 mmol) at room temperature under argon atmosphere. After the solution was stirred at 100 °C for overnight, the mixture was cooled and filtered through a pad of celite. The filtrate was then concentrated. The residue was purified by silica gel column chromatography (DCM : EtOAc = 1 : 1) to give 4 (188 mg, 12 % yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H), 8.95 (d, J = 8.4 Hz, 1H), 8.80 (s, 1H), 8.69 (s, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 7.39–7.32 (m, 2H), 7.26–7.23 (m, 1H), 5.52–5.48 (m, 1H), 5.18 (t, J = 4.8 Hz, 1H), 4.69 (m, 1H), 4.29 (q, J = 7.2 Hz, 2H), 3.88 (t, J = 4.8 Hz, 2H), 1.46 (d, J = 6.8 Hz, 3H), 1.39 (d, J = 6.8 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H). [0741] Preparation 84: Synthesis of (S)-4-((2-hydroxy-1-phenylethyl)amino)-2-((1- isopropyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxylic acid (5)

[0742] To a solution of 4 (300 mg, 0.650 mmol) in THF (8 mL) was added water (8 mL) and lithium hydroxide (200 mg, 8.30 mmol) at room temperature. After it was stirred for overnight, the mixture was concentrated and purified with C18 column chromatography (5– 100% MeOH in water containing 1% TFA) to give 5 (300 mg, quantitative yield) as a white solid.¹H NMR (400 MHz, MeOD-d₄): δ 8.96 (s, 1H), 8.77 (s, 1H), 8.33 (s, 1H), 7.43–7.35 (m, 4H), 7.30–7.29 (m, 1H), 7.25 (s, 1H), 5.51–5.49 (m, 1H), 4.01–3.90 (m, 2H), 1.56 (m, 6H). [0743] Preparation 85: Synthesis of (S)-2-((2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6- yl)amino)-5-(1,3,4- oxadiazol-2-yl)pyrimidin-4-yl)amino)-2-phenylethan-1-ol (Example 153)

[0744] To a solution of 5 (200 mg, 0.460 mmol) in DCM (10 mL) was added (N- isocyanoimino)triphenylphosphorane (280 mg, 0.920 mmol) at room temperature. After the reaction was stirred at room temperature for 6 h, the mixture was concentrated and then purified by preparative TLC (DCM : EtOAc = 1 : 1) to give 153 (10 mg, 5% yield) as a white solid.¹H NMR (400 MHz, CDCl₃): δ 8.88 (d, J = 8.4 Hz, 1H), 8.75–8.71 (m, 3H), 8.38–8.35 (m, 2H), 8.02 (s, 1H), 7.48–7.26 (m, 5H), 5.73–5.71 (m, 1H), 4.82 (septet, J = 6.8 Hz, 1H), 4.16–4.08 (m, 2H), 2.84 (br s, 1H), 1.62 (d, J = 6.8 Hz, 3H), 1.57 (d, J = 6.8 Hz, 3H); LCMS (ESI) m/z calcd for C23H₂3N9O2457.20; found, 458.48 [M + H]⁺; HPLC purity: 100 %, tR = 16.961 min. [0745] Preparation 86: Synthesis of (S)-2-((5-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)-2-((1- isopropyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidin-4-yl)amino)-2-phenylethan-1-ol (Example 159)

[0746] To a solution of 4 (30 mg, 0.065 mmol) in ethanol (2 mL, degassed) was added N- hydroxy-2,2-dimethylpropanimidamide (30 mg, 0.26 mmol), sodium ethoxide solution (0.12 mL, 21% in EtOH), and molecular sieve (10 mg) at room temperature under argon atmosphere. After the solution was strirred at reflux for overnight, the mixture was concentrated and purified by C18 reverse phase column (5–100% MeOH in water) to give 159 (28 mg, 84 % yield) as a white solid. ¹H NMR (400 MHz, CDCl3): δ 9.33 (d, J = 7.6 Hz, 1H), 8.98 (br s, 1H), 8.92 (s, 1H), 8.77 (s, 1H), 8.4 (s, 1H), 8.02 (s, 1H), 7.48–7.40 (m ,4H), 7.36–7.35 (m, 1H), 5.60–5.58 (m, 1H), 4.85 (septet, d, J = 6.8 Hz, 1H), 4.16–4.06 (m, 2H), 1.62 (d, J = 6.8 Hz, 3H), 1.58 (d, J = 6.8 Hz, 3H), 1.43 (s, 9H); LCMS (ESI) m/z calcd for C27H31N9O2513.26; found, 514.3 [M + H] ⁺; HPLC purity: 98.7 %, t_R = 25.921 min. [0747] Preparation 87: Synthesis of (S)-2-((5-(3-ethyl-1,2,4-oxadiazol-5-yl)-2-((1- isopropyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidin-4-yl)amino)-2-phenylethan-1-ol (Example 161)

[0748] To a solution of 4 (36.8 mg, 0.0870 mmol) in ethanol (2.5 mL, degassed) was added N-hydroxypropionamidine (28.1 mg, 0.35 mmol), sodium ethoxide solution (0.147 mL, 21% in EtOH), and molecular sieve (10 mg) at room temperature under argon atmosphere. After refluxed overnight, the mixture was concentrated and purified by silica gel column chromatography (2% MeOH in DCM containing 0.1% NH4OH(aq)) to give 161 (14 mg, 44% yield) as a white solid.¹H NMR (400 MHz, CDCl₃): δ 9.17 (d, J = 7.6 Hz, 1H), 8.90 (s, 1H), 8.75 (s, 1H), 8.39 (s, 1H), 8.01 (s, 1H), 7.47–7.37 (m, 4H), 7.36–7.34 (m, 1H), 5.65–5.63 (br m, 1H), 4.81 (septet, J = 6.8 Hz, 1H), 4.17–4.07 (m, 2H), 2.80 (q, J = 7.6 Hz, 2H), 1.60 (d, J = 6.8 Hz, 3H), 1.57 (d, J = 6.8 Hz, 3H), 1.37 (t, J = 7.6 Hz, 3H); LCMS (ESI) m/z calcd for C₂₅H₂₇N₉O₂485.23; found, 486.3 [M + H]⁺; HPLC purity: 97.6 %, t_R = 22.453 min. [0749] Preparation 88: Synthesis of (S)-N-cyclopentyl-4-((2-hydroxy-1- phenylethyl)amino)-2-((1-isopropyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5- carboxamide (Example 148) H

5 [0750] To a solution of 5 (30 mg, 0.069 mmol) in DMF (2 mL) was added cyclopentanamine (12 mg, 0.14 mmol), HATU (32 mg, 0.084 mmol), and DIPEA (18 mg, 0.138 mmol) at room temperature. After the solution was stirred at room temperature for overnight, the mixture was directly purified by C18 reverse phase column (5–100% MeOH in water) to give 148 (30 mg, 87% yield) as a white solid.¹H NMR (400 MHz, CDCl₃): δ 9.60 (d, J = 8.4 Hz, 1H), 8.72 (s, 1H), 8.36 (s, 1H), 8.32 (s, 1H), 8.13 (br s, 1H), 8.02 (s, 1H), 7.44– 7.37 (m, 4H), 7.33–7.29 (m, 1H), 5.92 (br s, 1H), 5.58–5.53 (m, 1H), 4.81 (septet, J = 6.8 Hz, 1H), 4.39–4.30 (m, 1H), 4.07–3.98 (m, 2H), 2.11–2.03 (m, 2H), 1.75–1.44 (m, 12H); LCMS (ESI) m/z calcd for C₂₇H₃₂N₈O₂500.26; found, 501.3 [M + H]⁺; HPLC purity: 99.3 %, t_R = 19.267 min. [0751] Preparation 89: Synthesis of (S)-N-benzyl-4-((2-hydroxy-1-phenylethyl)amino)-2- ((1-isopropyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxamide (Example

5 [0752] To a solution of 5 (30 mg, 0.069 mmol) in DMF (2 mL) was added phenylmethanamine (12 mg, 0.11 mmol), HATU (32 mg, 0.084 mmol), and DIPEA (18 mg, 0.138 mmol) at room temperature. After the solution was stirred at room temperature for overnight, the mixture was purified by C18 reverse phase column (5–100% MeOH in water) to give 149 (32 mg, 88% yield) as a white solid.¹H NMR (400 MHz, CDCl₃): δ 9.59 (d, J = 8.0 Hz, 1H), 8.95 (br s, 1H), 8.56 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 7.95 (s, 1H), 7.52–7.27 (m, 10H), 6.52 (br t, 1H), 5.62–5.56 (m, 1H), 4.73 (septet, J = 6.8 Hz, 1H), 4.59–4.54 (m, 2H), 4.03 (br s, 2H), 2.96 (br s, 1H), 1.56 (d, J = 6.8 Hz, 3H), 1.51 (d, J = 6.8 Hz, 3H); LCMS (ESI) m/z calcd for C29H30N8O2522.25; found, 523.3 [M + H]⁺; HPLC purity: 99.5 %, tR = 19.784 min. [0753] Preparation 90: Synthesis of (S)-4-((2-hydroxy-1-phenylethyl)amino)-N-isobutyl- 2-((1-isopropyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxamide (Example 150)

[0754] To a solution of 5 (30 mg, 0.069 mmol) in DMF (2 mL) was added 2-methylpropan- 1-amine (18 mg, 0.25 mmol), HATU (32 mg, 0.084 mmol), and DIPEA (18 mg, 0.14 mmol) at room temperature. After the solution was stirred for overnight, the mixture was purified by C18 reverse phase column (5–100% MeOH in water) to give 150 (22 mg, 65% yield) as a white solid.¹H NMR (400 MHz, CDCl3): δ 9.56 (d, J = 7.6 Hz, 1H), 8.72 (s, 1H), 8.37–8.34 (m, 3H), 8.01 (s, 1H), 7.43–7.36 (m, 4H), 7.32–7.28 (m, 1H), 6.12 (br s, 1H), 5.58–5.54 (m, 1H), 4.82– 4.76 (m, 1H), 4.05–4.02 (m, 2H), 3.25–3.21 (m, 2H), 1.91 (septet, J = 6.4 Hz, 1H), 1.59 (d, J = 6.8 Hz, 3H), 1.59 (d, J = 6.4 Hz, 3H), 0.97 (d, J = 6.4 Hz, 6H); LCMS (ESI) m/z calcd for C₂₆H₃₂N₈O₂488.26; found, 489.3 [M + H]⁺; HPLC purity: 99.9 %, t_R = 19.086 min. [0755] Preparation 91: Synthesis of (S)-4-((2-hydroxy-1-phenylethyl)amino)-N-isopropyl- 2-((1-isopropyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxamide (Example 144)

[0756] To a solution of 5 (20 mg, 0.046 mmol) in DMF (2 mL) was added 2-methylpropan- 1-amine (15 mg, 0.25 mmol), HATU (21 mg, 0.055 mmol), and DIPEA (12 mg, 0.092 mmol) at room temperature. After the solution was stirred for overnight, the mixture was purified by C18 reverse phase column (5–100% MeOH in water) to give 144 (22 mg, 100% yield) as a white solid.¹H NMR (400 MHz, CDCl₃): δ 9.60 (d, J = 7.6 Hz, 1H), 8.72 (s, 1H), 8.49 (br s, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 8.00 (s, 1H), 7.44–7.36 (m, 4H), 7.32–7.28 (m, 1H), 5.88 (br s, 1H), 5.60–5.55 (m, 1H), 4.80 (septet, J = 6.8 Hz, 1H), 4.28–4.19 (m, 1H), 4.08–3.99 (m, 2H), 1.59 (d, J = 6.4 Hz, 3H), 1.54 (d, J = 6.8 Hz, 3H), 1.26 (d, J = 6.4 Hz, 6H); LCMS (ESI) m/z calcd for C₂₅H₃₀N₈O₂474.25; found, 475.3 [M + H]⁺; HPLC purity: 99.1 %, t_R = 17.741 min. [0757] Preparation 92: Synthesis of ethyl 2-chloro-4-((1- (hydroxymethyl)cyclopropyl)amino)pyrimidine- 5-carboxylate (6)

[0758] To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (1, 1 g, 4.5 mmol) in ACN (10 mL) was added (1-aminocyclopropyl)methanol (430 mg, 4.94 mmol) and DIPEA (2 mL) at room temperature. After the reaction was stirred for 3 h, the mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography (EtOAc : n- hexane = 1 : 3) to give 6 (760 mg, 62% yield) as a white solid.¹H NMR (400 MHz, CDCl3): δ 8.74 (br s, 1H), 8.70 (s, 1H), 4.35 (q, J = 7.2 Hz, 2H), 3.83 (t, J = 5.2 Hz, 1H), 3.71 (d, J = 5.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H), 1.05–1.05 (m, 2H), 0.93–0.90 (m, 2H). [0759] Preparation 93: Synthesis of ethyl 4-((1-(hydroxymethyl)cyclopropyl)amino)-2-((1- isopropyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxylate (Example 151)

6 [0760] To a solution of 6 (380 mg, 1.40 mmol) in dioxane (5 mL, degassed) was added 1- isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine (3, 200 mg, 1.13 mmol), cesium carbonate (650 mg, 1.99 mmol), Xantphos (65 mg, 0.11 mmol), and tris(dibenzylideneacetone)dipalladium(0) (50 mg, 0.050 mmol) at room temperature under argon atmosphere. After the solution was stirred at 100 °C for overnight, the mixture was cooled and filtered through a pad of celite. The filtrate was then concentrated. The residue was purified by silica gel column chromatography (DCM : EtOAc = 2 : 1) to give 151 (100 mg, 17 % yield) as a white solid.¹H NMR (400 MHz, CDCl3): δ 8.79–8.76 (m, 3H), 8.39 (s, 1H), 8.34 (br s, 1H), 8.04 (s, 1H), 4.86 (septet, J = 6.8 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 3.79 (br s, 2H), 1.60 (d, J = 6.8 Hz, 6H), 1.38 (t, J = 7.2 Hz, 3H), 1.04–1.00 (m, 4H); LCMS (ESI) m/z calcd for C20H₂5N7O3411.20; found, 412.2 [M + H]⁺; HPLC purity: 95.83 %, t_R = 17.078 min. [0761] Preparation 94: Synthesis of ethyl 2-chloro-4-((1- (hydroxymethyl)cyclobutyl)amino)pyrimidine- 5-carboxylate (9)

[0762] To a solution of 1 (1.00 g, 4.56 mmol) in ACN (10 mL) was added (1- aminocyclobutyl)methanol (500 mg, 4.95 mmol) and DIPEA (2.0 mL) at room temperature. After the reaction was stirred for 3 h, the mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 3) to give 9 (840 mg, 65% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.68 (br s, 2H), 4.36 (q, J = 7.2 Hz, 2H), 3.92 (d, J = 5.6 Hz, 2H), 3.50–3.45 (m, 1H), 2.42–2.36 (m, 2H), 2.25–2.17 (m, 2H), 2.04–1.88 (m, 2H), 1.39 (t, J = 7.2 Hz, 3H). [0763] Preparation 95: Synthesis of ethyl 4-((1-(hydroxymethyl)cyclobutyl)amino)-2-((1- isopropyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxylate (Example 174)

⁹ [0764] To a solution of 9 (200 mg, 0.700 mmol) in dioxane (5.0 mL, degassed) was added 1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine (3, 120 mg, 0.700 mmol), potassium phosphate (445 mg, 2.1 mmol), Xantphos (40 mg, 0.067 mmol), and tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.030 mmol) at room temperature under argon atmosphere. After the solution was stirred at 100 °C for overnight, the mixture was cooled and filtered through a pad of celite. The filtrate was then concentrated. The residue was purified by silica gel column chromatography (DCM : EtOAc = 2 : 1) to give 174 (23 mg, 7 % yield) as a white solid. ¹H NMR (400 MHz, CDCl3): δ 8.79 (s, 1H), 8.73 (s, 1H), 8.65 (br s, 1H), 8.29 (br s, 1H), 8.04 (s, 1H), 7.96 (br s, 1H), 4.88 (septet, J = 6.8 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 3.98 (s, 2H), 2.45–2.38 (m, 2H), 2.30–2.22 (m, 2H), 2.04–1.89 (m, 2H), 1.61 (d, J = 6.8 Hz, 6H), 1.39 (t, J = 7.2 Hz, 3H); LCMS (ESI) m/z calcd for C21H₂7N7O3425.22; found, 426.26 [M + H]⁺; HPLC purity: 92.56 %, t_R = 18.747 min. [0765] Preparation 96: Synthesis of ethyl 2-chloro-4-((1-hydroxy-2-methylpropan-2- yl)amino)pyrimidine- 5-carboxylate (11)

[0766] To a solution of 1 (1.00 g, 4.56 mmol) in ACN (10 mL) was added 2-amino-2- methylpropan-1-ol (440 mg, 4.94 mmol) and DIPEA (2.0 mL) at room temperature. After the reaction was stirred for 3 h, the mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 3) to give 10 (1.09 g, 65% yield) as a white solid.¹H NMR (400 MHz, CDCl3): δ 8.68–8.67 (m, 2H), 4.35 (q, J = 7.2 Hz, 2H), 4.13 (t, J = 6.0 Hz, 1H), 3.73 (d, J = 6.0 Hz, 2H), 1.44 (s, 6H), 1.38 (t, J = 7.2 Hz, 3H). [0767] Preparation 97: Synthesis of ethyl 4-((1-hydroxy-2-methylpropan-2-yl)amino)-2- ((1-isopropyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxylate (Example 152)

[0768] To a solution of 10 (200 mg, 0.7 mmol) in dioxane (5 mL, degassed) was added 1- isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine (3, 100 mg, 0.58 mmol), potassium phosphate (300 mg, 1.4 mmol), Xantphos (40 mg, 0.067 mmol), and tris(dibenzylideneacetone)dipalladium(0) (30 mg, 0.03 mmol) at room temperature under argon atmosphere. After the solution was stirred at 100 °C for overnight, the mixture was cooled and filtered through a pad of celite. The filtrate was then concentrated. The residue was purified by silica gel column chromatography (DCM : EtOAc = 2 : 1) to give 152 (19 mg, 6 % yield) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.77 (s, 1H), 8.72 (s, 1H), 8.66 (br s, 1H), 8.31 (s, 1H), 8.08 (br s, 1H), 8.03 (s, 1H), 4.87 (septet, J = 6.8 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 3.83 (s, 2H), 1.60 (d, J = 6.8 Hz, 6H), 1.51 (s, 6H), 1.38 (t, J = 7.2 Hz, 3H); LCMS (ESI) m/z calcd for C20H₂7N7O3413.22; found, 415.27 [M + H]⁺; HPLC purity: 95.29 %, tR = 18.045 min. [0769] Preparation 98: Synthesis of 4-((1-(hydroxymethyl)cyclopropyl)amino)-2-((1- isopropyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxylic acid (11)

[0770] To a solution of 151 (130 mg, 0.32 mmol) in THF (6.0 mL) was added water (6.0 mL) and lithium hydroxide (90 mg, 3.7 mmol) at room temperature. After it was stirred for overnight, the mixture was concentrated and purified by C18 reverse phase column chromatography (5–100% MeOH in water containing 1% TFA) to give 11 (180 mg, quantitative yield) as a white solid. ¹H NMR (400 MHz, MeOD-d₄): δ 9.07 (s, 1H), 8.76 (s, 1H), 8.40 (s, 1H), 7.35 (s, 1H), 4.90–4.88 (overlapped with solvent H₂O peak, 2H), 3.81 (s, 2H), 1.59 (d, J = 6.4 Hz, 6H), 1.05–0.99 (m, 4H). [0771] Preparation 99: Synthesis of (1-((2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6- yl)amino)-5-(1,3,4- oxadiazol-2-yl)pyrimidin-4-yl)amino)cyclopropyl)methanol (Example 166)

[0772] To a solution of 11 (180 mg, 0.470 mmol) in DCM (10 mL) was added (N- isocyanoimino)triphenylphosphorane (260 mg, 0.850 mmol) at room temperature. After the reaction was stirred at room temperature for 6 h, the mixture was concentrated and then purified by preparative TLC (DCM : EtOAc = 1 : 1) to give 166 (3 mg, 1.5% yield) as a white solid.¹H NMR (400 MHz, CDCl₃): δ 8.76 (s, 1H), 8.74 (br s, 1H), 8.71 (s, 1H), 8.41 (s, 2H), 8.17 (br s, 1H), 8.05 (s, 1H), 4.88 (septet, J = 6.4 Hz, 1H), 3.84 (s, 2H), 1.62 (d, J = 6.4 Hz, 6H), 1.10– 1.09 (m, 4H); LCMS (ESI) m/z calcd for C19H₂1N9O2407.18; found, 408.22 [M + H]⁺; HPLC purity: 98.7 %, t_R = 13.446 min. [0773] Examples 144–176 were prepared according to the steps of General Procedure A and Preparations 85–99 in the suitable combination, using suitable starting materials and reagents. [0774] Example 144: (S)-4-((2-hydroxy-1-phenylethyl)amino)-N-isopropyl-2-((1- isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxamide

[0775] Example 148: (S)-N-cyclopentyl-4-((2-hydroxy-1-phenylethyl)amino)-2-((1- isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxamide

[0776] Example 149: (S)-N-benzyl-4-((2-hydroxy-1-phenylethyl)amino)-2-((1- isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxamide

[0777] Example 150: (S)-4-((2-hydroxy-1-phenylethyl)amino)-N-isobutyl-2-((1- isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxamide

[0778] Example 151: ethyl 4-((1-(hydroxymethyl)cyclopropyl)amino)-2-((1- isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxylate

[0779] Example 152: ethyl 4-((1-hydroxy-2-methylpropan-2-yl)amino)-2-((1- isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxylate

[0780] Example 153: (S)-2-((2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)- 5-(1,3,4-oxadiazol-2-yl)pyrimidin-4-yl)amino)-2-phenylethan-1-ol

[0781] Example 159: (S)-2-((5-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)-2-((1-isopropyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidin-4-yl)amino)-2-phenylethan-1-ol

[0782] Example 161: (S)-2-((5-(3-ethyl-1,2,4-oxadiazol-5-yl)-2-((1-isopropyl-1H- pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidin-4-yl)amino)-2-phenylethan-1-ol

[0783] Example 166: (1-((2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-5- (1,3,4-oxadiazol-2-yl)pyrimidin-4-yl)amino)cyclopropyl)methanol

[0784] Example 174: ethyl 4-((1-(hydroxymethyl)cyclobutyl)amino)-2-((1-isopropyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxylate

[0785] Table 1: Exemplary compounds of the present disclosure, as well as molecular weight (MW, amu), retention time (RT, min), mass spectrometry (MS) calculated (calc’d) and experimental (exp’tal) masses, and percent purity (%).

Biological Assays [0786] Exhibit A. Primary Assay used to determine potency of HPK1 enzymatic activity inhibition. [0787] Compound activity was determined using recombinant HPK1 protein and MBP Substrate (both Promega, Cat# V6398) in an in vitro enzymatic reaction. The enzymatic assay used to determine activity was a Luminescence assay using a Microplate Reader ClarioStar Plus. The enzymatic reaction was carried out in assay buffer (40mM TRIS-HCl pH 7.4-7.6, 20mM MgCl2, 0.05mM DTT, 0.1mg/ml BSA). The compounds were dispensed on a 384 well Diamond Well Plate (Axigen, Cat# P-384-120SQ-C-S) using the Biomek FX liquid handling system at 100x solutions of compounds in DMSO. 2x HPK1-MBP mix (final concentration 0.64ng/µl of HPK1 and 45ng/µl of MBP) was prepared in 1x Assay buffer and 5.5µl of mixture per well was added into 384w white Reaction plate with NBS (Corning, Cat#4513). 5.5µl of MBP substrate w/o HPK1 in 1x buffer was used for negative control. Plates were centrifuged for 1 min at 100g. Next step the Compounds were added to Reaction plate using Biomek station via following steps: 1µl of 100x compounds (in DMSO) were mixed thoroughly with 49ul of 2x 10uM ATP in Assay Buffer, then 5.5µl of this mixture was added to Reaction plate with 5.5µl of HPK1-MBP mix. Plates were centrifuged for 1 min at 100g and incubated for 1 hour at room temperature. Next 3µL of ADP-Glo reagent (Promega, ADP-Glo™ Kinase Assay, Cat# V9102) per well was added. Plates were incubated for 30 minutes at room temperature. Then 6µL of Kinase detection reagent (Promega, ADP-Glo™ Kinase Assay, Cat# V9102) per well was added and the Luminescence was measured using Microplate Reader. The % inhibition was then used to calculate the IC50 values. The IC50 values are shown in Table A1, wherein “A” corresponds to IC₅₀ < 10.0 nm, “B” corresponds to 10.0 nm ≤ IC₅₀ < 25.0 nm, “C” corresponds to 25.0 nm ≤ IC50 < 50.0 nm, “D” corresponds to 50.0 nm ≤ IC50 < 100.0 nm, and “E” corresponds to 100.0 nm ≤ IC₅₀ < 500.0 nm, and “F” corresponds to 500.0 nm ≤ IC₅₀. [0788] Table A1. Primary HPK1 inhibition

789] Exhibit B. IL-2 Release Jurkat Assay 790] Jurkat cells (ATCC, USA) (100,000 cells/well in a 96 well flat-bottom plate (Greiner,655061) were cultured in RPMI 1640 supplemented with 10% FBS at 37oC, 5% CO2 in humidified cell culture incubator for 0.5-1 hours. Then 10 μL/well 15x compound (or DMSO)as added in duplicates. Cells were incubated with compound in a humidified ll culture incubator for 0.5-1 hours. After the incubation, 10 μL/well of 15x human anti-CD3IT3a antibody (BioLegend) together with 10 μL/well of 15x human anti-CD28 antibodynvitrogen) were added to stimulate Jurkat cells for 24 hours. Additionally, Jurkat cells withMSO were incubated in the absence of anti-CD3 to evaluate its activation effect. After 24 hours stimulation, supernatants were collected and IL-2 levels in supernatants were assessed using IL- ELISA kit (Vector-Best, Russia). The IL-2 concentrations are shown in Table B1, wherein “A” rresponds to IL-2 < 5.0 pg/mL, “B” corresponds to 5.0 pg/mL ≤ IL-2 < 10.0 pg/mL, “C” rresponds to 10.0 pg/mL ≤ IL-2 < 20.0 pg/mL, and “D” corresponds to 20.0 pg/mL ≤ IL-2. 791] Table B1. IL-2 data from the Jurkat functional assay at 0.5 μM of tested compounds

792] Exhibit C. Cytokines Release hPBMC Assay 793] Donor human PBMCs, 120,000 cells/well in a 96 well flat-bottom plate (Greiner,655061), were cultured in RPMI 1640 supplemented with 10% FBS at 37oC, 5% CO2 in aumidified cell culture incubator for 0.5-1 hours. After the incubation, 10 μL/well 15x compound r DMSO) in duplicates were added together with 20 μL/well of 7.5x anti-CD3 HIT3a activatornvitrogen) to stimulate the PBMCs for 24 hours. Additionally, PBMCs with DMSO werecubated in the absence of anti-CD3 to evaluate its activation effect. After 24 hours of stimulation, pernatants were collected and ΙFΝγ and IL-2 in supernatants were assessed using correspondingLISA kits (Vector-Best, Russia). The IL-2 concentrations are shown in Table C1, wherein “A” rresponds to IL-2 < 25.0 pg/mL, “B” corresponds to 25.0 pg/mL ≤ IL-2 < 50.0 pg/mL, “C” rresponds to 50.0 pg/mL ≤ IL-2 < 100.0 pg/mL, “D” corresponds to 100.0 pg/mL ≤ IL-2 < 250.0g/mL, and “E” corresponds to 250.0 pg/mL ≤ IL-2 < 500.0 pg/mL, and “F” corresponds to 500.0g/mL ≤ IL-2. The ΙFΝγ concentrations are shown in Table C1, wherein “A” corresponds to ΙFΝγ 25.0 pg/mL, “B” corresponds to 25.0 pg/mL ≤ ΙFΝγ < 50.0 pg/mL, “C” corresponds to 50.0g/mL ≤ ΙFΝγ < 100.0 pg/mL, “D” corresponds to 100.0 pg/mL ≤ ΙFΝγ < 250.0 pg/mL, and “E” rresponds to 250.0 pg/mL ≤ ΙFΝγ < 500.0 pg/mL, and “F” corresponds to 500.0 pg/mL ≤ ΙFΝγ. 794] Table C1. Cytokine data from the hPBMC functional assay at 1.5 μM of tested mpounds

Equivalents 795] Those skilled in the art will recognize, or be able to ascertain, using no more thanutine experimentation, numerous equivalents to the specific embodiments described specificallyrein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

hat is claimed is: A compound of Formula (I):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof,herein: X₁ is selected from N and CR_6a; X₂ is selected from N and CR_6b; X3 is selected from N and CR6c; R₁ is selected from C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₁₀ cycloalkyl, aryl, to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, yl, heterocyclyl, and heteroaryl are optionally substituted with one or more R7; R2 and R₃ are each independently selected from hydrogen, halo, –OH, –CN, –NO2,mino, alkylamino, dialkylamino, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl,1–C6 alkoxy, and C₁–C₆ haloalkoxy; each R₄ is independently selected from hydrogen, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆kynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10- embered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, yl, heterocyclyl, and heteroaryl are optionally substituted with one or more R8; or, each R₄, together with the nitrogen atom to which they are attached, come together to rm 3- to 10-membered heterocyclyl or heteroaryl, wherein the heterocyclyl or heteroaryl may rther comprise one or more atom selected from N, O, and S, wherein the heterocyclyl or teroaryl are optionally substituted with one or more R8; R₅ is selected from hydrogen, halo, –OH, –CN, –NO₂, –N(R₉)₂, C₁–C₆ alkyl, C₂–C₆kenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, yl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, kynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more10; each of R_6a, R_6b, and R_6c are independently selected from hydrogen, halo, –OH, –CN, –O2, amino, alkylamino, dialkylamino, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ loalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, –C(O)NR₁₅R₁₅, –C(O)OR₁₅, –NR₁₅C(O)R₁₅, –C(O)R₁₅, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl, wherein thekyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally bstituted with one or more halo, –OH, –CN, –NO2, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-membered terocyclyl, and heteroaryl; each R7 is independently selected from halo, –OH, –CN, –NO2, amino, alkylamino,alkylamino, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-embered heterocyclyl, and heteroaryl; each R8 is independently selected from halo, –OH, –CN, –NO2, amino, alkylamino,alkylamino, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ loalkoxy, –C(O)R₁₂, –C(O)NR_NR₁₂, –C(O)OR₁₂, –NR_NC(O)R₁₂, –NR_NC(O)NR_NR₁₂, –C(O)R₁₂, –OC(O)OR₁₂, –S(O)₂R₁₂, –S(O)₂NR_NR₁₂, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-embered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, terocyclyl, and heteroaryl are optionally substituted with one or more R₁₃; each R₉ is independently selected from hydrogen, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆kynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-embered heterocyclyl, and heteroaryl, wherein the cycloalkyl, aryl, heterocyclyl, and teroaryl are optionally substituted with one or more halo, –OH, –CN, –NO₂, amino,kylamino, dialkylamino, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆koxy, C₁–C₆ haloalkoxy, –C(O)R11, –C(O)NHR11, –C(O)OR11, –NRNC(O)R11, –NRNC(O)R11,NR_NC(O)NR_NR₁₁, –OC(O)R₁₁, and –OC(O)OR₁₁; each R10 is independently selected from halo, –OH, –CN, –NO2, –N(R9)2, C₁–C₆ alkyl,2–C6 alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, and C₁–C₆ haloalkoxy; each R₁₁ is independently selected from hydrogen, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆kynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, and C₁–C₆ haloalkoxy; each R₁₂ is independently selected from C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C1–6 haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, and 3- to 10-membered terocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl, and teroaryl are optionally substituted with one or more halo, –OH, –CN, –NO2, C₁–C₆ alkyl, C2–6 alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, –C(O)R₁₄, –(O)NR_NR_14, –C(O)OR₁₄, –NR_NC(O)R₁₄, –OC(O)R₁₄, C₃–C₁₀ cycloalkyl, aryl, and 3- to 10-embered heterocyclyl; each R₁₃ is independently selected from halo, –OH, –CN, –NO2, C₁–C₆ alkyl, C₂–C₆kenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl,yl, 3- to 10-membered heterocyclyl, and heteroaryl; each R₁₄ is independently selected from C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C1–6 haloalkyl, C₁–C₆ alkoxy, and C₁–C₆ haloalkoxy; each R₁₅ is independently selected from hydrogen, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆kynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-embered heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,yl, heterocyclyl, and heteroaryl are optionally substituted with one or more halo, –OH, –CN, –O₂, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ loalkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and heteroaryl; each R_N is independently selected from hydrogen, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆kynyl, C₃–C₁₀ cycloalkyl, and aryl; wherein, when R1 is phenyl or pyridinyl, then R5 is –N(R9)2, wherein at least one R9 is notydrogen; and wherein, (1) when R₅ is hydrogen, each R₄, together with the nitrogen atom to which theye attached, come together to form piperazinyl; or (2) when R5 is hydrogen and X3 is CR6c, R6c not hydrogen. The compound of claim 1, wherein the compound is of Formula I-A:

or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof. The compound of claim 1, wherein the compound is of Formula I-B-1, I-B-2, or I-B-3:

or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof. The compound of claim 1, wherein the compound is of Formula I-B-3a, I-B-3b, or I-B-:

or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein₄ and X₅ are independently selected from N and CR₁₆, wherein each R₁₆ is selected fromydrogen, halo, –OH, –CN, –NO₂, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₁–C₆ haloalkyl,1–C6 alkoxy, C₁–C₆ haloalkoxy, C₃–C₁₀ cycloalkyl, aryl, 3- to 10-membered heterocyclyl, and teroaryl, and wherein at least one of X₄ and X₅ is CR₁₆. The compound of claim 1, wherein the compound is of Formula I-C:

or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof. The compound of claim 1, wherein the compound is of Formula I-D:

or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein is an integer selected from 0, 1, 2, 3, 4, 5, and 6. The compound of claim 1, wherein the compound is of Formula I-D-1:

or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof. The compound of claim 1, wherein the compound is of Formula I-E:

or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof. The compound of claim 1, wherein the compound is of Formula I-F:

or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein is an integer selected from 0, 1, 2, 3, 4, and 5, and o is an integer selected from 0, 1, 2, 3, or 4. 0. The compound of claim 1, wherein the compound is of Formula I-F-1, I-F-2, I-F-3, or I- 4:

or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein is an integer selected from 0, 1, 2, 3, 4, and 5, and o is an integer selected from 0, 1, 2, 3, or 4. 1. The compound of claim 1, wherein the compound is of Formula I-G:

or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein and q are each an integer independently selected from 1, 2, and 3, and o is an integer selectedom 0, 1, 2, 3, 4, or 5. 2. The compound of claim 1, wherein the compound is of Formula I-G-1, I-G-2, I-G-3, or I--4:

or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein is an integer selected from 0, 1,

2, 3, 4, or 5.

3. A compound selected from:

a pharmaceutically acceptable salt, isomer, solvate, prodrug, or tautomer thereof.

4. The compound of claim 13, wherein the compound is selected from:

5. The compound of claim 13, wherein the compound is (S)-4-((2-hydroxy-1-henylethyl)amino)-N-isopropyl-2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-)amino)pyrimidine-5-carboxamide or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer thereof. 6. The compound of claim 13, wherein the compound is (S)-N-cyclopentyl-4-((2-hydroxy- phenylethyl)amino)-2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5- rboxamide or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof. 7. The compound of claim 13, wherein the compound is (S)-N-benzyl-4-((2-hydroxy-1-henylethyl)amino)-2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5- rboxamide or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof. 8. The compound of claim 13, wherein the compound is (S)-4-((2-hydroxy-1-henylethyl)amino)-N-isobutyl-2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-)amino)pyrimidine-5-carboxamide or a pharmaceutically acceptable salt, stereoisomer, solvate, tautomer thereof. 9. The compound of claim 13, wherein the compound is (S)-2-((2-((1-isopropyl-1H-yrazolo[4,3-c]pyridin-6-yl)amino)-5-(1,3,4-oxadiazol-2-yl)pyrimidin-4-yl)amino)-2-henylethan-1-ol or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomerereof. 0. A pharmaceutical composition comprising the compound or pharmaceutically acceptable lt, prodrug, solvate, hydrate, isomer, or tautomer thereof of any one of claims 1–19, and aharmaceutically acceptable carrier. 1. The pharmaceutical composition of claim 20, further comprising an additionalharmaceutically active agent.

2. A method of inhibiting a hematopoietic progenitor kinase 1 (HPK1), comprising ministering to a subject in need of a treatment for cancer a compound of any one of claims 1–9 or a pharmaceutical composition of any one of claims 20 or 21. 3. A method of treating a disease or disorder associated with the inhibition of hematopoietic ogenitor kinase 1 (HPK1), comprising administering to a subject in need of a treatment for ncer a compound of any one of claims 1–19 or a pharmaceutical composition of any one ofaims 20 or 21. 4. A method of inhibiting a leucine rich repeat kinase 2 (LRRK2) protein, comprising ministering to a subject in need of a treatment for cancer a compound of any one of claims 1–9 or a pharmaceutical composition of any one of claims 20 or 21. 5. A method of treating a disease or disorder associated with the inhibition of leucine richpeat kinase 2 (LRRK2) protein, comprising administering to a subject in need of a treatment r cancer a compound of any one of claims 1–19 or a pharmaceutical composition of any one ofaims 20 or 21.

6. A method of inhibiting an FMS-like tyrosine kinase 3 (FLT3) gene, comprising ministering to a subject in need of a treatment for cancer a compound of any one of claims 1–9 or a pharmaceutical composition of any one of claims 20 or 21.

7. A method of treating a disease or disorder associated with the inhibition of FMS-likerosine kinase 3 (FLT3) gene, comprising administering to a subject in need of a treatment for ncer a compound of any one of claims 1–19 or a pharmaceutical composition of any one ofaims 20 or 21.

8. A method of inhibiting an interleukin-1 receptor-associated kinase 1 (IRAK1), mprising administering to a subject in need of a treatment for cancer a compound of any one claims 1–19 or a pharmaceutical composition of any one of claims 20 or 21.

9. A method of treating a disease or disorder associated with the inhibition of interleukin-1ceptor-associated kinase 1 (IRAK1), comprising administering to a subject in need of aeatment for cancer a compound of any one of claims 1–19 or a pharmaceutical composition of y one of claims 20 or 21. 0. A method of inhibiting an interleukin-1 receptor-associated kinase 4 (IRAK4), mprising administering to a subject in need of a treatment for cancer a compound of any one claims 1–19 or a pharmaceutical composition of any one of claims 20 or 21. 1. A method of treating a disease or disorder associated with the inhibition of interleukin-1ceptor-associated kinase 4 (IRAK4), comprising administering to a subject in need of aeatment for cancer a compound of any one of claims 1–19 or a pharmaceutical composition of y one of claims 20 or 21. 2. A method of inhibiting a Janus kinase (JAK), comprising administering to a subject in ed of a treatment for cancer a compound of any one of claims 1–19 or a pharmaceutical mposition of any one of claims 20 or 21. 3. A method of treating a disease or disorder associated with the inhibition of Janus kinaseAK), comprising administering to a subject in need of a treatment for cancer a compound of y one of claims 1–19 or a pharmaceutical composition of any one of claims 20 or 21. 4. The method of claim 32, wherein the Janus kinase (JAK) is selected from Janus kinase 1AK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). 5. A method of treating a disease, disorder, or condition, comprising administering to a bject in need of a treatment a compound of any one of claims 1–19 or a pharmaceutical mposition of any one of claims 20 or 21.

6. The method of claim 35, wherein the disease, disorder, or condition is selected from ncer, an autoimmune disease, an inflammatory disease, a viral infection, male infertility, a nign hyperplasia, sepsis, a vascular disorder, an atherosclerotic disease, and a urodegenerative disorder. 7. The method of claim 36, wherein the disease, disorder, or condition is cancer selected om bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, lon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal ncer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, mphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell ncer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer, prostate cancer, arginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphomaDLBCL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). 8. The method of claim 36 wherein the disease, disorder, or condition is an autoimmune sease selected from chronic obstructive pulmonary disease (COPD), asthma, bronchitis, lupus, rmatomyositis, Sjogren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I abetes mellitus and complications associated therewith, atopic eczema (atopic dermatitis), yroiditis (Hashimoto’s and autoimmune thyroiditis), contact dermatitis and further eczematous rmatitis, inflammatory bowel disease, interferonopathy, atherosclerosis, and amyotrophic teral sclerosis. 9. The method of claim 36, wherein the disease, disorder, or condition is an inflammatory sease selected from rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, oriatic arthritis, ankylosing spondylitis, allergic airway disease, chronic obstructive pulmonary sease (COPD), inflammatory liver disease, inflammatory bowel disease, endotoxin-driven sease state, and related diseases involving cartilage, such as that of the joints. 0. The method of claim 36, wherein the disease, disorder, or condition is a viral infection is infection caused by a virus selected from human adenovirus, human cytomegalovirus, aposi’s sarcoma-associated herpesvirus, hepatitis A virus (HAV), hepatitis B virus (HBV), patitis C virus (HCV), Epstein-Barr virus, human immunodeficiency virus (HIV), HPS- sociated hantaviruses, Sin Nombre virus, rotavirus, echovirus, foot-and-mouth disease virus, xsackievirus, West Nile virus, Ebola virus, Ross River virus, human papillomavirus, and ronavirus. 1. The method of claim 40, wherein the viral infection is an infection caused by hepatitis B rus (HBV). 2. The method of claim 40, wherein the viral infection is an infection caused by humanmmunodeficiency virus (HIV). 3. The method of claim 36, wherein the disease, disorder, or condition is male infertility. 4. The method of claim 36, wherein the disease, disorder, or condition is a benignyperplasia selected from benign hyperplasia of the prostate gland and benign hyperplasia of the ammary gland. 5. The method of claim 36, wherein the disease, disorder, or condition is sepsis. 6. The method of claim 36, wherein the disease, disorder, or condition is a vascular disorder lected from erythromelalgia, peripheral artery disease, renal artery stenosis, Buerger’s disease, aynaud’s disease, disseminated intravascular coagulation, and cerebrovascular disease. 7. The method of claim 36, wherein the disease, disorder, or condition is an atherosclerotic sorder selected from myocardial infarction and stroke. 8. The method of claim 36, wherein the disease, disorder, or condition is a urodegenerative disorder selected from Alzheimer's disease, vascular disease dementia, ontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear lsy (PSP), Lewy body dementia, tangle-predominant senile dementia, Pick's disease (PiD),gyrophilic grain disease, amyotrophic lateral sclerosis (ALS), other motor neuron diseases,uam parkinsonism-dementia complex, FTDP-17, Lytico-Bodig disease, multiple sclerosis,aumatic brain injury (TBI), and Parkinson's disease. 9. The method of any one of claims 22–48, wherein the subject is a mammal. 0. The method of claim 49, wherein the subject is a human.