Compounds containing N-arylpyrimidine-2-amine derivatives as therapeutic agents

Abstract

The present invention relates generally 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)), which are useful in the treatment of diseases and disorders regulated by HPK1, LRRK2, FLT3, IRAK1, IRAK4, and JAKs, and have the formula (I): JPEG2024535867000480.jpg38170

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority and interest to U.S. Provisional Patent Application No. 63 / 244,775, filed on 16 September 2021, entitled “Compounds Having N-Arylpyrimidine-2-amine Derivatives as Therapeutic Agents,” the disclosure thereof is incorporated herein by reference in its entirety for all purposes.

[0002] (Field of invention) The present invention relates to inhibitors of hematopoietic precursor kinase 1 (HPK1), leucine-rich repeat kinase 2 (LRRK2) protein, FMS-like tyrosine kinase 3 (FLT3) gene, interleukin-1 receptor-related kinase 1 (IRAK1), interleukin-1 receptor-related kinase 4 (IRAK4), and Janus kinase (JAK) (including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2)). The inhibitors described herein may be useful in treating diseases or disorders related to HPK1, LRRK2, FLT3, IRAK1, IRAK4, and JAK, such as cancer, autoimmune diseases, inflammatory diseases, viral infections, male fertility control, benign hyperplasia, sepsis, vascular disorders, atherosclerosis, and neurodegenerative disorders. In particular, the present invention relates to compounds and pharmaceutical compositions that inhibit HPK1, LRRK2, FLT3, IRAK1, IRAK4, and JAK, methods for treating diseases or disorders related to HPK1, LRRK2, FLT3, IRAK1, IRAK4, and JAK, and methods for synthesizing these compounds. [Background technology]

[0003] (Background of the invention) Hematopoietic precursor kinase 1 (HPK1) is a Ste20 serine / threonine kinase restricted to hematopoietic cells. HPK1 kinase activity is induced by activation signals generated by various different cell surface receptors found on hematopoietic cells upon ligand binding. Ligand binding or antibody-mediated crosslinking of T cell receptors (TCRs), B cell antigen receptors (BCRs), transforming growth factor β receptors (TGF-βRs), erythropoietin receptors (EPORs), and Fas can induce HPK1 kinase activity. Each receptor utilizes its own, but sometimes overlapping, signaling mechanisms to activate HPK1. HPK1 acts as a downregulator of T cell and B cell function via the AP-1, NFKB, Erk2, and Fas pathways. For example, HPK1 is involved as a negative regulator of signaling in T cells through phosphorylation and activation of the T cell receptor adapter 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] Therefore, HPK1 is considered a potential target for therapeutic intervention. For example, HPK1 has been reported to be a potential new target for cancer immunotherapy (Sawasdikosol et al., Immunol Res. 2012 Dec;54(1-3):262-5). Specifically, targeted disruption of the HPK1 allele leads to increased Th1 cytokine production in T cells in response to TCR involvement. HPK1(- / -) T cells proliferate more rapidly than haplotype-matched wild-type T cells and are resistant to prostaglandin E2 (PGE(2))-mediated suppression. Most surprisingly, mice that received adoptive transfer of HPK1(- / -) T cells acquired resistance to lung tumor growth. Furthermore, loss of HPK1 from dendritic cells (DCs) gives them superior antigen-presenting ability, allowing HPK1(- / -) DCs to induce a stronger anti-tumor immune response when used as a cancer vaccine.

[0005] Full-length HPK1 can promote the activation of the nuclear factor-kappa light chain enhancer (NF-κB) pathway in activated B cells via the TCR, while the catalytically inactive cleavage product HPK1-C can suppress NF-κB activation upon TCR restimulation, potentially inducing activation-induced cell death (AICD) (Brenner et al., EMBO J. 2005, 24:4279). Summarizing the catalytic and non-catalytic roles of HPK1, blocking HPK1 kinase activity with small molecule inhibitors may promote the activation of B and T cells, resulting in superior antitumor immunity, while simultaneously promoting AICD, potentially contributing to the maintenance of peripheral immune tolerance.

[0006] The invention described in publication US2020 / 0390776A1 generally relates to isofranone compounds (e.g., compounds of formula 1.1) that modulate or inhibit the enzymatic activity of hematopoietic precursor kinase 1 (HPK1). The compounds are described as having HPK1 inhibitory activity and being more selective than IRAK-4. [ka]

[0007] Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transmit cytokine signaling from membrane receptors to STAT transcription factors. Four JAK family members—JAK1, JAK2, JAK3, and TYK2—are described. When cytokines bind to their receptors, JAK family members autophosphorylate and / or transphosphorylate each other, subsequently phosphorylating STAT, which then translocates to the nucleus to regulate transcription. JAK-STAT intracellular signaling acts on a variety of cytokines and endocrine factors, including interferons, most interleukins, as well as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, and PRL. Combining studies of genetic models with small molecule JAK inhibitors has revealed the therapeutic potential of JAK inhibitors (JAKinibs).

[0008] Using TYK2 knockout 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 interferon signaling are TYK2-dependent. However, it has recently been shown that JAK1 is the major driver of IFNa, IL-6, IL-10, and IL-22 signaling, and that TYK2 is involved in type 1 interferon (including IFNa and IFNb), IL-23, and IL-12 signaling. Since IL-12 and IL-23 activity is particularly increased in patients with autoimmune diseases such as psoriasis, systemic lupus erythematosus (SLE), psoriatic arthritis, and inflammatory bowel disease, selective TYK2 inhibition may be particularly advantageous in treating these diseases while evading JAK2-dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling. Furthermore, because TYK2 inhibition is involved in type I interferon signaling (including IFNa and IFNb), it may be particularly useful in treating cytokine storms associated with COVID-19 infection.

[0009] Furthermore, TYK2 gene variants reported in the general human population involve a modification of one amino acid within the kinase domain of TYK2, which inactivates its kinase activity and is associated with a reduced risk of autoimmune and inflammatory diseases.

[0010] Leucine-rich repeat kinase 2 (LRRK2) is a member of the ROCO protein family, all members of which share five conserved domains. In cell culture models, there is evidence that increased LRRK2 kinase activity is associated with neurotoxicity (Smith et al., 2006 Nature Neuroscience 9: 1231-1233), and kinase inhibitors prevent LRRK2-mediated cell death (Lee et al., 2010 Nat. Med. 16: 998-1000).

[0011] Additional evidence links LRRK2 function and dysfunction to the autophagy-lysosomal pathway (Manzoni and Lewis, 2013 Faseb J. 27:3234-3429). The LRRK2 protein impairs chaperone-mediated autophagy and negatively affects the cell's ability to degrade alpha-synuclein (Orenstein et al., 2013 Nature Neurosci. 16 394-406). 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 be useful in treating diseases characterized by defects in cellular protein homeostasis resulting from abnormal 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-synuclein diseases, tauopathies, Alzheimer's disease (Li et al., 2010 Neurodegen. Dis. 7: 265-271), and other neurodegenerative diseases (Nixon 2013 Nat. Med. 19: 983-997).

[0012] Other studies have shown that overexpression of the G2019S mutant of LRRK2 impairs the proliferation and migration of subventricular zone (SVZ) neural progenitor cells in transgenic mouse models (Winner et al., 2011 Neurobiol. Dis. 41: 706-716), and shortens neurite length and branched cell culture models (Dachsel et al., 2010 Parkinsonism & Related Disorders 16: 650-655). Furthermore, drugs that promote the proliferation and migration of SVZ neural progenitor cells have been reported to improve neurological outcomes after ischemic injury in rodent stroke models (Zhang et al., 2010 J. Neurosci. Res. 88: 3275-3281). These findings suggest that compounds that inhibit the abnormal activity of LRRK2 may be useful in therapies designed to stimulate the recovery of CNS function after neurological injuries such as ischemic stroke, traumatic brain injury, and spinal cord injury.

[0013] Mutations in LRRK2 have also been clinically associated with the progression from mild cognitive impairment (MCI) to Alzheimer's disease (WO2007149798). These data suggest that inhibitors of LRRK2 kinase activity may be useful in treating diseases such as Alzheimer's disease, other dementias, and related neurodegenerative diseases.

[0014] Abnormal regulation of normal LRRK2 protein is also observed in some disease tissues and disease models. The normal mechanism of LRRK2 translational regulation by miR-205 is disrupted in some sporadic PD cases, and a significant decrease in miR-205 levels in PD brain samples coincides with an increase in LRRK2 protein levels in those samples (Cho et al., (2013) Hum. Mol. Gen. 22: 608-620). Therefore, LRRK2 inhibitors may be used to treat sporadic PD patients with elevated levels of normal LRRK2 protein. In an experimental model of Parkinson's disease in marmosets, elevated LRRK2 mRNA is observed in correlation with levels of L-Dopa-induced dyskinesia (Hurley, M. J et al., 2007 Eur. J. Neurosci. 26: 171-177). This suggests that LRRK2 inhibitors may be useful in improving such dyskinesia.

[0015] Significant elevations in LRRK2 mRNA levels have been reported in muscle biopsy samples from ALS patients (Shtilbans et al., 2011 Amyotrophic Lateral Sclerosis 12: 250-256), suggesting that elevated LRRK2 kinase activity may be a characteristic feature of ALS. Therefore, this observation indicates that LRRK2 inhibitors may be useful in the treatment of ALS.

[0016] There is also evidence suggesting that LRRK2 kinase activity may play a role in mediating pro-inflammatory responses in microglia (Moehle et al., 2012, J. Neuroscience 32:1602-1611). This observation suggests the potential usefulness of LRRK2 inhibitors in treating abnormal neuroinflammatory mechanisms that contribute to various 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 the differentiation of neuronal progenitor cells in vitro (Milosevic, J. et al., 2009 Mol. Neurodegen. 4: 25). This evidence suggests that LRRK2 inhibitors may be useful for in vitro neuronal progenitor cell production for resulting therapeutic applications in cell-based therapies for CNS diseases.

[0017] A meta-analysis of three genome-wide association scans for Crohn's disease identified numerous disease-associated loci, including one containing the LRRK2 gene (Barrett et al., 2008, Nature Genetics, 40: 955-962). Evidence also emerged that LRRK2 may be an IFN-γ target gene involved in signaling pathways related to the pathogenesis of Crohn's disease (Gardet et al., 2010, J. Immunology, 185: 5577-5585). These findings suggest that LRRK2 inhibitors may be useful in the treatment of Crohn's disease.

[0018] LRRK2 may also play a role as an IFN-γ target gene in the underlying T-cell mechanisms of multiple sclerosis and other immune system diseases such as rheumatoid arthritis. Further potential usefulness of LRRK2 inhibitors stems from the reported finding that B lymphocytes constitute the major population of LRRK2-expressing cells (Maekawa et al. 2010, BBRC 392: 431-435). This suggests that LRRK2 inhibitors may be effective, or could be effective, in treating immune system disorders in which B cell depletion is effective, or could be effective, in conditions such as lymphoma, leukemia, multiple sclerosis (Ray et al., 2011 J. Immunol. 230: 109), rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red blood cell dysplasia, idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis, bullous skin diseases, type 1 diabetes, Sjögren's syndrome, Devick's disease, and inflammatory myopathy (Engel et al., 2011 Pharmacol. Rev. 63: 127-156; Homam et al., 2010 J. Clin. Neuromuscular Disease 12: 91-102).

[0019] The FMS-like tyrosine kinase 3 (FLT3) gene encodes a membrane-bound receptor tyrosine kinase that affects hematopoiesis and causes blood disorders and malignancies. Activation of FLT3 receptor tyrosine kinase is initiated when the FLT3 ligand (FLT3L) binds to the FLT3 receptor, also known as stem cell tyrosine kinase-1 (STK-1) and fetal liver kinase-2 (flk-2), which is expressed in hematopoietic progenitor cells and hematopoietic stem cells.

[0020] FLT3 is one of the most frequently mutated genes in hematological malignancies and is present in approximately 30% of adult acute myeloid leukemia (AML) cases. The presence of internal tandem duplication of FLT3 in AML patients adds important prognostic information to cytogenetic risk groups and response to the first cycle of chemotherapy. FLT3 mutations have been detected in approximately 2% of patients diagnosed with intermediate-risk and high-risk myelodysplastic syndromes (MDS). Similar to MDS, the number of FLT3 mutations in acute promyelocytic leukemia (APL) patients is small. The most common FLT3 mutation is internal tandem duplication (ITD), which causes an in-frame insertion within the near-membrane domain of the FLT3 receptor. FLT3-ITD mutations have been reported in 15–35% of adult AML patients. Internal tandem duplication of FLT3 is associated with leukocytosis in acute promyelocytic leukemia. FLT3-ITD mutations are an independent predictor of poor patient prognosis and are associated with an increased risk of relapse after standard chemotherapy, as well as decreased disease-free and overall survival. The prognostic impact of FLT3 and N-RAS gene mutations in acute myeloid leukemia is as follows: The least frequent are FLT3 point mutations occurring in the activation loop of the FLT3 receptor. The most commonly affected codon is aspartate 835 (D835). Nucleotide substitutions at the D835 residue occur in approximately 5–10% of adult patients with acute myeloid leukemia.

[0021] The FLT3 gene is a highly attractive drug target in adult AML due to the increased frequency of constitutively activated variant FLT3. Several FLT3 inhibitors with varying degrees of potency and selectivity against the target have been investigated and tested, or are currently being investigated, in AML patients.

[0022] Toll-like receptor (TLR) / interleukin-1 receptor (IL-1R) signaling is involved in IRAK4 and IRAK1 phosphorylation, driving downstream events such as NF-κB and interferon signaling in inflammatory responses, and this process has recently been implicated in tumorigenesis. Furthermore, pharmacological inhibition of IRAK1 / 4 has been shown to be effective in targeting MDS and acute lymphoblastic leukemia (ALL), leading to IRAK1 activation through NF-κB-dependent or independent mechanisms.

[0023] Therefore, there is a need for novel compounds that effectively and selectively inhibit hematopoietic precursor kinase 1 (HPK1), leucine-rich repeat kinase 2 (LRRK2) protein, FMS-like tyrosine kinase 3 (FLT3) gene, interleukin-1 receptor-related kinase 1 (IRAK1), interleukin-1 receptor-related kinase 4 (IRAK4), and Janus kinases (JAK), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). This would enable the design of specific therapies and dosages tailored to the disease state. (Summary of the invention)

[0024] A first aspect of the present invention relates to a compound of formula (I): [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, During the ceremony, X is H, a halogen, or OH, where R 4 If is an unsubstituted phenyl and X is H, then R 1 is C(O)OR 6 and; R 1 -CN, -NO2, -C(O)NHR 6 , C(O)N(R 6 )2, -C(O)OR 6 -S(O)2C 1-6Selected from alkyl or monocyclic heteroaryl containing one or more heteroatoms independently selected from N, S, and O, said heteroaryl being -OH, oxo, halogen, C 1-4 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, or optionally substituted with one or more substituents selected from 4-7 member monocyclic heterocycloalkyl, and alkyl or alkoxy is halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 alkyl, -COOH, -CONH2 or optionally further substituted with one or more substituents selected from 4-7 member monocyclic heterocycloalkyl; R 2 is H or C 1-4 alkyl; or R 2 and R 8 together with the atoms to which they are attached and any intervening atoms form a 5-6 member heterocyclyl; R 3 is H; or R 3 and R 8 together with the atoms to which they are attached and any intervening atoms form a 5-6 member cycloalkyl; R 4 is -(CH2) m -aryl, -(CH2) m -heteroaryl, -(CH2) m -cycloalkyl, or heterocyclyl, and said -(CH2) m -aryl, -(CH2) m -heteroaryl, -(CH2) m -cycloalkyl, or heterocyclyl is optionally substituted with one or more R 8 ;<0​​​​​​​​​​​​​2-6 Alkenyl, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2,-CH2C(O)NH2,-CH2C(O)NH(C 1-6 Alkyl), -CH2C(O)N(C 1-6 Independently selected from alkyl)2, -NHC(O)CH3, aryl, heteroaryl; or Two R's 5 These, together with the atoms to which they are bonded and any intervening atoms, form a 6-7 membered heterocyclyl or 5-7 membered heteroaryl, which includes at least one heteroatom selected from N, O, and S; the heterocyclyl or heteroaryl may contain one or more R 7 It is optionally replaced by; Each R 6 H, OH, C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 3-8 Independently selected from cycloalkyl, heterocyclyl, or heteroaryl, alkyl, alkoxy, heteroaryl, or heterocyclyl is one or more R 9 It is optionally replaced by; or Two R's 6 They form 4-8 membered heterocyclines together with the atoms to which they are bonded and any intervening atoms; Each R 7 OH, oxo, halogen, C 1-6 Alkyl, aryl, oxy C 1-6 Alkyl, -CH2OC(O)C 1-6 Alkyl, or independently selected from -CH2OCH2CH2Si(CH3)3; Each R 8 These are halogens, OH, NH2, and C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, or -N(C 1-6 Independently selected from alkyl)2; Each R 9 These are halogens, OH, NH2, and C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-8 Independently selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; and m and n are integers independently selected from 0, 1, 2, 3, 4, 5, and 6.

[0025] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may include excipients, diluents, or surfactants.

[0026] Another aspect of the present invention relates to a method for treating a disease or disorder related to the regulation of hematopoietic precursor kinase 1 (HPK1). The method comprises administering to a patient in need of treatment for a disease or disorder related to the regulation 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.

[0027] Another aspect of the present invention relates to a method for inhibiting hematopoietic precursor kinase 1 (HPK1). The method comprises administering an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient in need.

[0028] Another aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition for use in the manufacture of agents for inhibiting hematopoietic precursor kinase 1 (HPK1).

[0029] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of diseases associated with inhibition of hematopoietic precursor kinase 1 (HPK1).

[0030] Unexpectedly, this application provides compounds that exhibit higher activity, bioavailability, and lower cytotoxicity compared to, for example, the compounds described in US2020 / 0390776A1.

[0031] Another aspect of the present invention relates to a method for treating a disease or disorder related to the modulation of the leucine-rich repeat kinase 2 (LRRK2) protein. The method comprises administering to a patient in need of treatment for a disease or disorder related to the 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.

[0032] Another aspect of the present invention relates to a method for inhibiting the leucine-rich repeat kinase 2 (LRRK2) protein. The method comprises administering an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient in need.

[0033] Another aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition for use in the manufacture of agents for inhibiting the leucine-rich repeat kinase 2 (LRRK2) protein.

[0034] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of diseases associated with inhibition of the leucine-rich repeat kinase 2 (LRRK2) protein.

[0035] Another aspect of the present invention relates to a method for treating a disease or disorder related to the regulation of the FMS-like tyrosine kinase 3 (FLT3) gene. The method comprises administering to a patient in need of treatment for a disease or disorder related to the regulation 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.

[0036] Another aspect of the present invention relates to a method for inhibiting the FMS-like tyrosine kinase 3 (FLT3) gene. The method comprises administering an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient in need.

[0037] Another aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition for use in the manufacture of agents for inhibiting the FMS-like tyrosine kinase 3 (FLT3) gene.

[0038] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of diseases associated with inhibition of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0039] Another aspect of the present invention relates to a method for treating a disease or disorder related to the modulation of interleukin-1 receptor-associated kinase 1 (IRAK1). The method comprises administering to a patient in need of treatment for a disease or disorder related to the 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.

[0040] Another aspect of the present invention relates to a method for inhibiting interleukin-1 receptor-associated kinase 1 (IRAK1). The method comprises administering an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient in need.

[0041] Another aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition for use in the manufacture of agents for inhibiting interleukin-1 receptor-associated kinase 1 (IRAK1).

[0042] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of diseases associated with inhibition of interleukin-1 receptor-related kinase 1 (IRAK1).

[0043] Another aspect of the present invention relates to a method for treating a disease or disorder related to the modulation of interleukin-1 receptor-associated kinase 4 (IRAK4). The method comprises administering to a patient in need of treatment for a disease or disorder related to the 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.

[0044] Another aspect of the present invention relates to a method for inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4). The method comprises administering an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient in need.

[0045] Another aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition for use in the manufacture of agents for inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4).

[0046] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of diseases associated with the inhibition of interleukin-1 receptor-related kinase 4 (IRAK4).

[0047] Another aspect of the present invention relates to a method for treating diseases or disorders related to the 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 treatment for a disease or disorder related to the 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.

[0048] Another aspect of the present invention relates to a method for inhibiting Janus kinases (JAK), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). The method comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient in need.

[0049] Another aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition for use in the manufacture of agents for inhibiting Janus kinases (JAK), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2).

[0050] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of diseases associated with inhibition of Janus kinases (JAK), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2).

[0051] Another aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0052] Another aspect of the present invention relates to a method for treating or preventing a disease or disorder disclosed herein in a subject that requires treatment or prevention of such disease or disorder. The method comprises administering an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient requiring treatment.

[0053] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0054] The present invention further provides a method for treating a disease or disorder related to the regulation of hematopoietic precursor kinase 1 (HPK1), comprising administering to a patient suffering from at least one of the said disease or disorder a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0055] The present invention provides inhibitors of hematopoietic precursor kinase 1 (HPK1), which are therapeutic agents used in the treatment of diseases and disorders.

[0056] The present invention further provides compounds and compositions having improved efficacy and safety profiles compared to known hematopoietic precursor kinase 1 (HPK1) inhibitors. The disclosure also provides agents having novel mechanisms of action against protein tyrosine phosphatase enzymes in the treatment of various types of diseases.

[0057] The present invention further provides a method for treating a disease or disorder related to the regulation of the leucine-rich repeat kinase 2 (LRRK2) protein, comprising administering to a patient suffering from at least one of the diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0058] The present invention provides inhibitors of the leucine-rich repeat kinase 2 (LRRK2) protein, which are therapeutic agents in the treatment of diseases and disorders.

[0059] The present invention further provides compounds and compositions having improved efficacy and safety profiles compared to known leucine-rich repeat kinase 2 (LRRK2) protein inhibitors. The disclosure also provides agents with novel mechanisms of action against LRRK2 in the treatment of various types of diseases.

[0060] The present invention further provides a method for treating a disease or disorder related to the regulation of the FMS-like tyrosine kinase 3 (FLT3) gene, comprising administering to a patient suffering from at least one of the said disease or disorder a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0061] This invention provides an inhibitor of the FMS-like tyrosine kinase 3 (FLT3) gene, which is a therapeutic agent for the treatment of diseases and disorders.

[0062] The present invention further provides compounds and compositions having improved efficacy and safety profiles compared to known FMS-like tyrosine kinase 3 (FLT3) gene inhibitors. The disclosure also provides agents with novel mechanisms of action against FLT3 in the treatment of various types of diseases.

[0063] The present invention further provides a method for treating a disease or disorder related to the modulation of interleukin-1 receptor-associated kinase 1 (IRAK1), comprising administering to a patient suffering from at least one of the said disease or disorder a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0064] The present invention provides an inhibitor of interleukin-1 receptor-related kinase 1 (IRAK1), which is a therapeutic agent for the treatment of diseases and disorders.

[0065] The present invention further provides compounds and compositions having improved efficacy and safety profiles compared to known interleukin-1 receptor-related kinase 1 (IRAK1) inhibitors. The disclosure also provides agents with novel mechanisms of action against IRAK1 in the treatment of various types of diseases.

[0066] The present invention further provides a method for treating a disease or disorder related to the modulation of interleukin-1 receptor-associated kinase 4 (IRAK4), comprising administering to a patient suffering from at least one of the said disease or disorder a compound of formula (I), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0067] The present invention provides an inhibitor of interleukin-1 receptor-related kinase 4 (IRAK4), which is a therapeutic agent for the treatment of diseases and disorders.

[0068] The present invention further provides compounds and compositions having improved efficacy and safety profiles compared to known interleukin-1 receptor-related kinase 4 (IRAK4) inhibitors. The disclosure also provides agents with novel mechanisms of action against IRAK4 in the treatment of various types of diseases.

[0069] The present invention further provides a method for treating a disease or disorder related to the regulation of Janus kinases (JAK), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2), comprising administering a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient suffering from at least one of the said disease or disorder.

[0070] The present invention provides Janus kinase (JAK) inhibitors, including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2), which are therapeutic agents for the treatment of diseases and disorders.

[0071] The present invention further provides compounds and compositions having improved efficacy and safety profiles compared to known Janus kinase (JAK) inhibitors. This disclosure also provides agents with novel mechanisms of action against JAK in the treatment of various types of diseases.

[0072] The present invention further provides a method for treating a disease, disorder, or condition selected from cancer, autoimmune diseases, inflammatory diseases, viral infections, male reproductive capacity control, benign hyperplasia, sepsis, vascular disorders, atherosclerosis, and neurodegenerative disorders, the method comprising administering a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, to a patient suffering from at least one of the aforementioned diseases or disorders.

[0073] In some embodiments, the present disclosure provides compounds that can be obtained by or obtained by methods for preparing the compounds described herein (for example, methods comprising one or more steps described in General Procedure A).

[0074] In some embodiments, the Disclosure provides intermediates described herein that are suitable for use in methods for preparing the compounds described herein (for example, the intermediates are selected from the intermediates described in Example 1).

[0075] In some embodiments, the Disclosure provides a method for preparing the compounds of the Disclosure.

[0076] In some embodiments, the Disclosure provides a method for preparing the compounds of the Disclosure, comprising one or more steps described herein.

[0077] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in which this disclosure pertains. In this specification, singular nouns also include plural nouns unless the context clearly indicates otherwise. Similar or equivalent methods and materials to those described herein may be used in the practice or testing of this disclosure, but suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References made herein are not considered prior art to the inventions described herein. In case of any conflict, this specification, including definitions, shall prevail. Furthermore, materials, methods, and examples are illustrative only and not intended to be limiting. In case of any conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

[0078] Other features and advantages of this disclosure will become apparent from the following detailed description and claims. [Modes for carrying out the invention]

[0079] (Detailed description of the invention) This disclosure relates to compounds and compositions that can inhibit the activity of hematopoietic precursor kinase 1 (HPK1), leucine-rich repeat kinase 2 (LRRK2) protein, FMS-like tyrosine kinase 3 (FLT3) gene, interleukin-1 receptor-related kinase 1 (IRAK1), interleukin-1 receptor-related kinase 4 (IRAK4), and Janus kinases (JAK), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). This disclosure features methods for treating, preventing, or improving diseases or disorders in which HPK1, LRRK2, FLT3, IRAK1, IRAK4, and / or JAK play a role, by administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to a patient in need. The methods of the present invention can be used to treat a variety of diseases, disorders, and symptoms, including cancer, autoimmune diseases, inflammatory diseases, viral infections, male reproductive capacity control, benign hyperplasia, sepsis, vascular disorders, atherosclerosis, and neurodegenerative disorders. In a first aspect of the present invention, a compound of formula (I): [ka] Furthermore, pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof are described, where n, R 1 , R 2 , R 3 , R 4 , R 5 , and X are described herein.

[0080] Details of the present invention are described in the following appendix. Similar or equivalent methods and materials to those described herein may be used in the practice or testing of the present invention, but only exemplary methods and materials are described here. Other features, purposes and advantages of the present invention will become apparent from this specification and the claims. In this specification and the appendix claims, singular forms include plural forms unless the context makes it obvious otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains. All patents and publications cited herein are incorporated herein by reference in their entirety. definition

[0081] In this disclosure, the articles "a" and "an" are used to refer to one or more (i.e., at least one) grammatical objects of the article. For example, "element" means one or more elements.

[0082] In this disclosure, the term "and / or" means either "and" or "or" unless otherwise specified.

[0083] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) bond to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group could be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group could have substituents other than hydrogen. For example, at any point along the chain, it could be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety may contain other functional groups, but does not necessarily have any further functional groups. Preferred substituents used for any substitution of the listed groups are, but are not limited to, halogens, 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 This includes (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 themselves may be optionally substituted. As used herein, “optionally substituted” means substituted or unsubstituted, the meaning of which is set out below.

[0084] As used herein, the term “substituted” means that a particular group or site has one or more suitable substituents, and the substituents may be linked to the particular group or site at one or more positions. For example, an aryl substituted with a cycloalkyl group indicates that the cycloalkyl group is linked to one atom of the aryl group by bonding or by condensation with the aryl group, sharing two or more common atoms.

[0085] In this specification, the term "unsubstituted" means that a particular group does not have substituents.

[0086] Unless otherwise defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. If it contains two aromatic rings (e.g., bicyclic), the aromatic rings of the aryl group can be bonded at one point (e.g., biphenyl) or condensed (e.g., naphthyl). The aryl group can be optionally substituted at any bonding point with one or more substituents, e.g., one to five substituents. Examples of 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. Substituents can be optionally substituted themselves. Furthermore, if the group contains two fused rings, the aryl group as defined herein may have a saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring. Examples of these aryl ring systems include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenantrenyl, indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannerenyl.

[0087] Unless otherwise defined, “heteroaryl” means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, comprising one or more ring heteroatoms selected from N, O, S, P, Se, or B, with the remaining ring atoms being carbon. Heteroaryl as defined herein also means a bicyclic heteroaromatic group in which the heteroatoms are selected from N, O, S, P, Se, or B. Heteroaryl as defined herein also means a tricyclic heteroaromatic group comprising one or more ring heteroatoms selected from N, O, S, P, Se, or B. Aromatic radicals may optionally be independently substituted with one or more substituents described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolinyl, benzopyranil, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, tri Azinyl, imidazo[1,2-b]pyrazolyl, flo[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, chromanil, thiochromanil, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthilidinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthilidinyl, thieno[2,3-b]pyrazinyl, quinazolinyl Lu, 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]pyridinyl, tetrahydropyrrolo[1,2-a]pyridinyl, 3,4-dihydro-2H-1λ 2-Pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridine-2-one, flo[3,2-c]pyridinyl, flo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiadinyl, benzoxazolyl, benzisoxazolyl, flo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthilidinyl, flo[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[ This includes, but is not limited to, [4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazole-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 their derivatives. Furthermore, if the heteroaryl ring system includes two or more fused rings, the heteroaryl group as defined herein may have one or more saturated or partially unsaturated rings fused with a fully unsaturated aromatic ring, for example, a five-membered heteroaromatic ring containing one to three heteroatoms selected from O, S, P, Se, or B, or a six-membered heteroaromatic ring containing one to three nitrogen atoms, where the saturated or partially unsaturated ring contains 0 to 4 heteroatoms selected from N, O, S, P, Se, or B and is optionally substituted with one or more oxos. In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated ring may be further fused with the 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, oxyindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridine-7-onyl, 7,8-di This includes hydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrroridine, pyrazolo[1,5-a]pyrimidine-7(4H)-onlyl, 3,4-dihydropyrazino[1,2-a]indole-1(2H)-onyl, or benzo[c][1,2]oxabolol-1(3H)-olyl.

[0088] "Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0089] "Alkyl" refers to a linear or branched saturated hydrocarbon containing 1 to 12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, iso-pentyl, neo-pentyl, and isohexyl.

[0090] "Alkoxy" refers to a straight-chain or branched saturated hydrocarbon containing 1 to 12 carbon atoms, including a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy groups.

[0091] An "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in its chain. The double bond of the alkenyl group may be unconjugated or conjugated with another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. Alkenyl groups may be unsubstituted or substituted. Alkenyls as defined herein may be straight-chain or branched.

[0092] "Alkynyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon containing 2 to 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. Alkynyl groups can be unsubstituted or substituted.

[0093] The terms "alkylene" or "alkylenyl" refer to a divalent alkyl radical. Any of the monovalent alkyl groups described above may be alkylenes obtained by the extraction of a second hydrogen atom from the alkyl. As defined herein, alkylenes may be C1-C6 alkylenes. Alkylenes may further be C1-C4 alkylenes. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-.

[0094] "Cycloalkyl" refers to a group of 3 to 30 carbon atoms (for example, C3-C3). 12 , C3-C 10This refers to monocyclic or polycyclic (e.g., fused ring, crosslinked ring, or spirocycle) saturated or partially unsaturated hydrocarbon systems having C3-C8. Examples of cycloalkyl groups include 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, octahydropentarenyl, 3a,4,5,6 This includes, but is not limited to, 7,7a-hexahydro-1H-indenyl, 1,2,3,3a-tetrahydropentarenyl, 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 cycloalkyls, only one of the cycloalkyl rings must be non-aromatic.

[0095] Unless otherwise specified, "heterocyclyl," "heterocycle," or "heterocycloalkyl" refers to a saturated or partially unsaturated 3-10 member monocyclic, 7-12 member bicyclic (fused, bridging, or spirocycle) or 11-14 member tricyclic ring system (fused, bridging, or spirocycle) having one or more heteroatoms (such as O, N, S, P, Se, or B) independently selected from the group consisting of nitrogen, oxygen, and sulfur, for example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms.Examples of heterocycloalkyl groups include piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxyranyl, 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'-fl[3,4-b]pyridine]-yl, 3'H-Spiro[cyclohexane-1,1'-fl[3,4-c]pyridine]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexane-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 This includes, but is not limited to, 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-oxazaspiro[3.4]octanyl, 2-oxazaspiro[3.4]octan-6-yl, and others.

[0096] As used herein, the term “haloalkyl” refers to an alkyl group as defined herein, which is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trichloromethyl.

[0097] As used herein, the term “haloalkoxy” refers to an alkoxy group as defined herein, which is substituted with one or more halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, and trichloromethoxy.

[0098] As used herein, the term "cyano" refers to a substituent having a carbon atom bonded to a nitrogen atom by a triple bond, i.e., C≡N.

[0099] As used herein, the term “amine” refers to primary (R-NH2, where R is not H), secondary (R2-NH, where R2 is not H), and tertiary (R3-N, where R is not H) amines. Substitutive amines are intended to mean amines in which at least one hydrogen atom is substituted with a substituent.

[0100] As used herein, the term “amino” means a substituent containing at least one nitrogen atom. Specifically, the terms “amino” include -NH2, -NH(alkyl) or alkylamino, -N(alkyl)2 or dialkylamino, amide-, carbamide-, urea, and sulfamide substituents.

[0101] The term "solvate" refers to various stoichiometric complexes formed by a solute and a solvent. Such solvents for the purposes of this invention are not those that can impede the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are usually called hydrates. Hydrates include compositions containing a stoichiometric amount of water, as well as compositions containing a variable amount of water.

[0102] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. Structural differences can be in their composition (geometric isomers) or their ability to rotate the plane of polarization (stereoisomers). Regarding stereoisomers, the compound of formula (I) may have one or more chiral carbon atoms and can arise as racemates, racemic mixtures, and individual enantiomers or diastereomers.

[0103] The present invention also relates to isotope-labeled compounds of formula I (e.g., 2 H and 14 The intention is to perform deuteration (i.e., labeled with C). 2 H or D) isotopes and carbon-14 (i.e., 14 C) Isotopes are particularly preferred in terms of ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium may result in certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced required dose), and may therefore be preferred in some situations. Isotope-labeled compounds of formula I can generally be prepared by replacing unisotopically labeled reagents with appropriate isotope-labeled reagents, following procedures similar to those disclosed in the following schemes and / or examples.

[0104] This disclosure also includes a pharmaceutical composition comprising an effective amount of the disclosed compound and a pharmaceutically acceptable carrier. Typical "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, butyrate, calcium, calcium edetate, cansylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estrate, esylate, fumarate, fiunarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydravamin, hydrobromide, hydrochloride, hydroxynaphthoate, and iodide. Contains substances, isethionates, lactates, lactobionates, laurates, magnesium, malates, maleates, mandelates, mesylates, methyl bromide, methyl nitrate, methyl sulfate, mucinates, napsylates, nitrates, N-methylglucamine ammonium salts, 3-hydroxy-2-naphthoate, oleates, oxalates, palmitates, pamoates (1,1-methene-bis-2-hydroxy-3-naphthoate, emponate), pantothenates, phosphates / diphosphates, picrates, polygalacturonates, propions, p-toluenesulfonates, salicylates, stearates, basic acetates, succinates, sulfates, sulfosalicylates, suramates, tannates, tartrates, theoclates, tosylates, triethiodides, and valersates.

[0105] "Patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cattle, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus macaque.

[0106] "Effective dose" is the amount effective to treat or prevent a disease or disorder in the subject described herein, when used in conjunction with the compound.

[0107] As used in this disclosure, the term "carrier" encompasses carriers, excipients, and diluents, and means materials, compositions, or vehicles, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials, that are involved in the transport or delivery of a pharmaceutical product from one organ or part of the body to another.

[0108] The term “to treat” in relation to an object refers to improving at least one symptom of the disorder in that object. Treating includes curing, improving, or at least partially improving the disorder.

[0109] In this disclosure, unless otherwise specified, the term “disability” is used to mean the term “disease,” “condition,” or “illness,” and is used interchangeably with the term “disease,” “condition,” or “illness.”

[0110] As used in this disclosure, the terms “administer,” “give administration,” or “give administration” refer to either directly administering the disclosed compound or a pharmaceutically acceptable salt or composition of the disclosed compound to a subject, or administering a prodrug derivative or analogue of the compound or a pharmaceutically acceptable salt or composition of the compound to a subject so that an equivalent amount of the active compound can be formed in the subject’s body.

[0111] As used in this disclosure, the term “prodrug” means a compound that can be converted in vivo into the disclosed compound by metabolic means (e.g., hydrolysis).

[0112] In some embodiments, the present disclosure relates to compounds of formula IA: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer or tautomer thereof, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0113] In some embodiments, the disclosure provides a compound of formula I-A1:

Chemical formula

[0114] In some embodiments, the disclosure provides a compound of formula I-A2:

Chemical formula

[0115] In some embodiments, the disclosure provides a compound of formula I-B1, I-B2, I-B3, I-B3’ or I-B4:

Chemical formula

Chemical formula

[0116] In some embodiments, the disclosure relates to a compound of formula I-B1-a:

Chemical formula

[0117] In some embodiments, the disclosure relates to a compound of formula I-B1-a*:

Chemical formula

[0118] In some embodiments, the disclosure relates to a compound of formula I-B1-b:

Chemical formula

[0119] In some embodiments, this disclosure relates to compounds of formula I-B1-b*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0120] In some embodiments, the present disclosure relates to compounds of formula I-B1-c: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0121] In some embodiments, the present disclosure relates to compounds of formula I-B1-c*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0122] In some embodiments, the present disclosure relates to compounds of formula I-B1-d: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer or tautomer thereof, wherein p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0123] In some embodiments, the present disclosure provides a compound of formula I-B1-d*:

Chemical formula

[0124] In some embodiments, the present disclosure provides a compound of formula I-B2-a:

Chemical formula

[0125] In some embodiments, the present disclosure provides a compound of formula I-B2-a*:

Chemical formula

[0126] In some embodiments, the present disclosure provides a compound of formula I-B2-b:

Chemical formula

[0127] In some embodiments, the present disclosure relates to compounds of formula I-B2-b*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0128] In some embodiments, the present disclosure relates to compounds of formula I-B2-c: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0129] In some embodiments, the present disclosure relates to compounds of formula I-B2-c*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0130] In some embodiments, the present disclosure relates to compounds of formula I-B2-d: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0131] In some embodiments, this disclosure relates to compounds of formula I-B2-d*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0132] In some embodiments, the present disclosure relates to compounds of formula I-B2-e: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0133] In some embodiments, the present disclosure relates to compounds of formula I-B2-e*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0134] In some embodiments, the present disclosure relates to compounds of formula I-B2-f: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0135] In some embodiments, the present disclosure relates to compounds of formula I-B2-f*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0136] In some embodiments, the present disclosure relates to a compound of formula I-B2-g: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0137] In some embodiments, this disclosure relates to compounds of formula I-B2-g*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0138] In some embodiments, the present disclosure relates to compounds of formula I-B2-h: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0139] In some embodiments, this disclosure relates to compounds of formula I-B2-h*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0140] In some embodiments, the present disclosure relates to compounds of formula I-B2-i: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0141] In some embodiments, the present disclosure relates to compounds of formula I-B2-i*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0142] In some embodiments, the present disclosure relates to compounds of formula I-B2-j: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0143] In some embodiments, the present disclosure relates to compounds of formula I-B2-j*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0144] In some embodiments, the present disclosure relates to compounds of formula I-B2-k: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0145] In some embodiments, the present disclosure relates to compounds of formula I-B2-k*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0146] In some embodiments, this disclosure relates to compounds of formula I-B4-G1: [ka] with respect to the compound or its pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer or tautomer, wherein X is selected from NH, O, S; each Y is independently selected from N, CH; R 10 is H, C 1-4 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, or 4- to 7-membered monocyclic heterocycloalkyl, wherein the alkyl or alkoxy is further optionally substituted with one or more substituents selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 alkyl, -COOH, -CONH2 or 4- to 7-membered monocyclic heterocycloalkyl, and p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0147] In some embodiments, the disclosure relates to a compound of formula I-B4-G2:

Chemical formula

[0148] In some embodiments, the disclosure relates to a compound of formula I-B4-I:

Chemical formula

[0149] In some embodiments, the disclosure relates to a compound of formula I-B4-I*:

Chemical formula

[0150] In some embodiments, the disclosure relates to a compound of formula I-B4-I-a:

Chemical formula

[0151] In some embodiments, the present disclosure relates to compounds of formula I-B4-Ia*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0152] In some embodiments, the present disclosure relates to compounds of formula I-B4-Ib: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0153] In some embodiments, the present disclosure relates to compounds of formula I-B4-Ib*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0154] In some embodiments, the present disclosure relates to compounds of formula I-B4-II: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where R 10 H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyls, selected from 4-7 membered monocyclic heterocycloalkyls, alkyl or alkoxy, halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 It is further optionally substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0155] In some embodiments, the present disclosure relates to compounds of formula I-B4-II*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where R 10 H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyls, selected from 4-7 membered monocyclic heterocycloalkyls, alkyl or alkoxy, halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 It is further optionally substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0156] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-a: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0157] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-a*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0158] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-b: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0159] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-b*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0160] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-c: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0161] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-c*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0162] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-d: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0163] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-d*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0164] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-e: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0165] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-e*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0166] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-f: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0167] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-f*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0168] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-g: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0169] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-g*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0170] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-h: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0171] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-h*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0172] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-i: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0173] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-i*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0174] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-j: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0175] In some embodiments, the present disclosure relates to compounds of formula I-B4-II-j*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0176] In some embodiments, the present disclosure relates to the compound of formula I-B4-III: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where R 10 H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyls, selected from 4-7 membered monocyclic heterocycloalkyls, alkyl or alkoxy, halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 It is further optionally substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0177] In some embodiments, the present disclosure relates to compounds of formula I-B4-III*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where R 10 H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyls, selected from 4-7 membered monocyclic heterocycloalkyls, alkyl or alkoxy, halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 It is further optionally substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0178] In some embodiments, the present disclosure relates to compounds of formula I-B4-III-a: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0179] In some embodiments, the present disclosure relates to compounds of formula I-B4-III-a*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0180] In some embodiments, the present disclosure relates to compounds of formula I-B4-III-b: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0181] In some embodiments, the present disclosure relates to compounds of formula I-B4-III-b*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0182] In some embodiments, the present disclosure relates to compounds of formula I-B4-III-c: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0183] In some embodiments, the present disclosure relates to compounds of formula I-B4-III-c*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0184] In some embodiments, the present disclosure relates to compounds of formula I-B4-III-d: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0185] In some embodiments, the present disclosure relates to compounds of formula I-B4-III-d*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0186] In some embodiments, the present disclosure relates to compounds of formula I-B4-III-e: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0187] In some embodiments, the present disclosure relates to compounds of formula I-B4-III-e*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0188] In some embodiments, the present disclosure relates to compounds of formula I-B4-III-f: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0189] In some embodiments, the present disclosure relates to compounds of formula I-B4-III-f*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0190] In some embodiments, the present disclosure relates to a compound of formula I-B4-III-g: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0191] In some embodiments, the present disclosure relates to compounds of formula I-B4-III-g*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0192] In some embodiments, the present disclosure relates to compounds of formula I-B4-III-h: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0193] In some embodiments, the present disclosure relates to compounds of formula I-B4-III-h*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0194] In some embodiments, the present disclosure relates to compounds of formula I-B4-IV: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where R 10 H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyls, selected from 4-7 membered monocyclic heterocycloalkyls, alkyl or alkoxy, halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 It is further optionally substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0195] In some embodiments, the present disclosure relates to compounds of formula I-B4-IV*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where R 10 H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyls, selected from 4-7 membered monocyclic heterocycloalkyls, alkyl or alkoxy, halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 It is further optionally substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0196] In some embodiments, the present disclosure relates to compounds of formula I-B4-IV-a: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0197] In some embodiments, the present disclosure relates to compounds of formula I-B4-IV-a*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0198] In some embodiments, the present disclosure relates to compounds of formula I-B4-V: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where R 10 H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyls, selected from 4-7 membered monocyclic heterocycloalkyls, alkyl or alkoxy, halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 It is further optionally substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0199] In some embodiments, the present disclosure relates to compounds of formula I-B4-V*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where R 10 H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyls, selected from 4-7 membered monocyclic heterocycloalkyls, alkyl or alkoxy, halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 It is further optionally substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0200] In some embodiments, the present disclosure relates to compounds of formula I-B4-Va: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0201] In some embodiments, the present disclosure relates to compounds of formula I-B4-Va*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0202] In some embodiments, the present disclosure relates to compounds of formula I-B4-VI: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where R 10 H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyls, selected from 4-7 membered monocyclic heterocycloalkyls, alkyl or alkoxy, halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 It is further optionally substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0203] In some embodiments, the present disclosure relates to compounds of formula I-B4-VI*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where R 10 H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyls, selected from 4-7 membered monocyclic heterocycloalkyls, alkyl or alkoxy, halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 It is further optionally substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0204] In some embodiments, the present disclosure relates to compounds of formula I-B4-VI-a: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0205] In some embodiments, the present disclosure relates to compounds of formula I-B4-VI-a*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0206] In some embodiments, the present disclosure relates to compounds of formula I-B4-VII: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where R 10 H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyls, selected from 4-7 membered monocyclic heterocycloalkyls, alkyl or alkoxy, halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 It is further optionally substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0207] In some embodiments, the present disclosure relates to compounds of formula I-B4-VII*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where R 10 H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyls, selected from 4-7 membered monocyclic heterocycloalkyls, alkyl or alkoxy, halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 It is further optionally substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0208] In some embodiments, the present disclosure relates to compounds of formula I-B4-VII-a: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0209] In some embodiments, the present disclosure relates to compounds of formula I-B4-VII-a*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0210] In some embodiments, the present disclosure relates to compounds of formula I-B4-VIII: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where R 10 H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyls, selected from 4-7 membered monocyclic heterocycloalkyls, alkyl or alkoxy, halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 It is further optionally substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0211] In some embodiments, the present disclosure relates to compounds of formula I-B4-VIII*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where R 10 H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyls, selected from 4-7 membered monocyclic heterocycloalkyls, alkyl or alkoxy, halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 It is further optionally substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0212] In some embodiments, the present disclosure relates to compounds of formula I-B4-VIII-a: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0213] In some embodiments, the present disclosure relates to compounds of formula I-B4-VIII-a*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0214] In some embodiments, the present disclosure relates to compounds of formula I-B4-VIII-b: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0215] In some embodiments, the present disclosure relates to compounds of formula I-B4-VIII-b*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0216] In some embodiments, the present disclosure relates to compounds of formula I-B4-VIII-c: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0217] In some embodiments, the present disclosure relates to compounds of formula I-B4-VIII-c*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0218] In some embodiments, the present disclosure relates to compounds of formula I-B4-IX: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where R 10 H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyls, selected from 4-7 membered monocyclic heterocycloalkyls, alkyl or alkoxy, halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 It is further optionally substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0219] In some embodiments, the present disclosure relates to compounds of formula I-B4-IX*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where R 10 H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyls, selected from 4-7 membered monocyclic heterocycloalkyls, alkyl or alkoxy, halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 It is further optionally substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0220] In some embodiments, the present disclosure relates to compounds of formula I-B4-IX-a: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0221] In some embodiments, the present disclosure relates to compounds of formula I-B4-IX-a*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0222] In some embodiments, the present disclosure relates to compounds of formula I-B4-IX-b: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0223] In some embodiments, the present disclosure relates to compounds of formula I-B4-IX-b*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0224] In some embodiments, the present disclosure relates to compounds of formula I-B4-X: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where R 10 H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyls, selected from 4-7 membered monocyclic heterocycloalkyls, alkyl or alkoxy, halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 It is further optionally substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0225] In some embodiments, the present disclosure relates to compounds of formula I-B4-X*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where R 10 H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyls, selected from 4-7 membered monocyclic heterocycloalkyls, alkyl or alkoxy, halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 It is further optionally substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0226] In some embodiments, the present disclosure relates to compounds of formula I-B4-Xa: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0227] In some embodiments, the present disclosure relates to compounds of formula I-B4-Xa*: [ka] The term also refers to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers or tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0228] In some embodiments, the present disclosure relates to compounds of formula IC: [ka] The present invention relates to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where ring B is a 6-7 membered heterocyclyl containing at least one heteroatom selected from N, O, and S, w is an integer selected from 0, 1, 2, and 3, and all other variables are as defined herein.

[0229] In some embodiments, the present disclosure relates to compounds of formula IC*: [ka] The present invention relates to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where ring B is a 6-7 membered heterocyclyl containing at least one heteroatom selected from N, O, and S, w is an integer selected from 0, 1, 2, and 3, and all other variables are as defined herein.

[0230] In some embodiments, this disclosure relates to compounds of formula ID: [ka] The present invention relates to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where u is an integer selected from 0 or 1, p is an integer from 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0231] In some embodiments, the present disclosure relates to compounds of formula IE: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where ring D is aryl or heteroaryl; p is an integer from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0232] In some embodiments, the present disclosure relates to compounds of formula IF: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0233] In some embodiments, the compound of the present disclosure is of formula IG. [ka] as well as its pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0234] In some embodiments, the present disclosure relates to compounds of formula IH: [ka] With regard to its pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers, where n is an integer selected from 0, 1, 2, 3, 4, and 5, p is an integer selected from 0, 1, 2, 3, or 4, s is 0 or 1, and all other variables are as defined herein.

[0235] In some embodiments, the present disclosure relates to compounds of formula II-A: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where each R 5a H, halogen, C 1-6 Alkyl, C 1-6The alkoxy is selected independently, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0236] In some embodiments, the present disclosure relates to compounds of formula II-A*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where each R 5a H, halogen, C 1-6 Alkyl, C 1-6 The alkoxy is selected independently, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0237] In some embodiments, the present disclosure relates to the compound of formula II-B: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where each R 5a H, halogen, C 1-6 Alkyl, C 1-6 The alkoxy is selected independently, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0238] In some embodiments, the present disclosure relates to compounds of formula II-B*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where each R 5a H, halogen, C 1-6 Alkyl, C 1-6The alkoxy is selected independently, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0239] In some embodiments, the present disclosure relates to compounds of formula II-C: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where each R 5a H, halogen, C 1-6 Alkyl, C 1-6 The alkoxy is selected independently, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0240] In some embodiments, the present disclosure relates to compounds of formula II-C*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where each R 5a H, halogen, C 1-6 Alkyl, C 1-6 The alkoxy is selected independently, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0241] In some embodiments, the present disclosure relates to compounds of formula II-D: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where each R 5a H, halogen, C 1-6 Alkyl, C 1-6The alkoxy is selected independently, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0242] In some embodiments, the present disclosure relates to compounds of formula II-D*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where each R 5a H, halogen, C 1-6 Alkyl, C 1-6 The alkoxy is selected independently, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0243] In some embodiments, the present disclosure relates to compounds of formula II-E: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where each R 5a H, halogen, C 1-6 Alkyl, C 1-6 The alkoxy is selected independently, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0244] In some embodiments, the present disclosure relates to compounds of formula II-E*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where each R 5a H, halogen, C 1-6 Alkyl, C 1-6The alkoxy is selected independently, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0245] In some embodiments, the present disclosure relates to compounds of formula II-F: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where each R 5a H, halogen, C 1-6 Alkyl, C 1-6 The alkoxy is selected independently, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0246] In some embodiments, the present disclosure relates to compounds of formula II-F*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where each R 5a H, halogen, C 1-6 Alkyl, C 1-6 The alkoxy is selected independently, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0247] In some embodiments, the present disclosure relates to compounds of formula II-G: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where each R 5a H, halogen, C 1-6 Alkyl, C 1-6The alkoxy is selected independently, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0248] In some embodiments, the present disclosure relates to compounds of formula II-G*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where each R 5a H, halogen, C 1-6 Alkyl, C 1-6 The alkoxy is selected independently, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0249] In some embodiments, the present disclosure relates to compounds of formula II-H: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where each R 5a H, halogen, C 1-6 Alkyl, C 1-6 The alkoxy is selected independently, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0250] In some embodiments, the present disclosure relates to compounds of formula II-H*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where each R 5a H, halogen, C 1-6 Alkyl, C 1-6The alkoxy is selected independently, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0251] In some embodiments, the present disclosure relates to compounds of formula II-I: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where each R 5a H, halogen, C 1-6 Alkyl, C 1-6 The alkoxy is selected independently, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0252] In some embodiments, the present disclosure relates to compounds of formula II-I*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where each R 5a H, halogen, C 1-6 Alkyl, C 1-6 The alkoxy is selected independently, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0253] In some embodiments, the present disclosure relates to compounds of formulas II-J-1, II-J-2, II-J-3, and II-J-4: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0254] In some embodiments, the present disclosure relates to compounds of formulas II-J-1*, II-J-2*, II-J-3*, and IJ-4*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0255] In some embodiments, the present disclosure relates to compounds of formula II-K: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0256] In some embodiments, the present disclosure relates to compounds of formula II-K*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0257] In some embodiments, the present disclosure relates to compounds of formulas II-L-1 and II-L-2: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0258] In some embodiments, the present disclosure relates to compounds of formulas II-L-1* and II-L-2*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0259] In some embodiments, the present disclosure relates to compounds of formula II-M-1 and formula II-M-2: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0260] In some embodiments, the present disclosure relates to compounds of formula II-M-1*, formula II-M-2*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0261] In some embodiments, the present disclosure relates to compounds of formula II-N: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0262] In some embodiments, the present disclosure relates to compounds of formula II-N*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0263] In some embodiments, the present disclosure relates to compounds of formula II-O: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0264] In some embodiments, the present disclosure relates to compounds of formula II-O*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0265] In some embodiments, the present disclosure relates to compounds of formula II-P: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where n' is selected from 0 and 1, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0266] In some embodiments, the present disclosure relates to compounds of formula II-P*: [ka] Or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, where n' is selected from 0 and 1, p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0267] In some embodiments, the present disclosure relates to compounds of formula II-R: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0268] In some embodiments, the present disclosure relates to compounds of formula II-R*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0269] In some embodiments, the present disclosure relates to compounds of formula II-S: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0270] In some embodiments, the present disclosure relates to compounds of formula II-S*: [ka] or relating to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof, where p is an integer selected from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

[0271] In some embodiments, X is H, a halogen, or an OH group. In some embodiments, X is a halogen or an OH group. In some embodiments, X is H or a halogen. In some embodiments, X is H or an OH group. In some embodiments, X is H. In some embodiments, X is a halogen. In some embodiments, X is an OH group.

[0272] In some embodiments, R 1 The heteroaryl group is selected from monocyclic heteroaryl groups containing -CN, -NO2, -C(O)NHR6, C(O)N(R6)2, -C(O)OR6, or one or more heteroatoms independently selected from N, S, and O, where the heteroaryl group contains -OH, oxo, halogen, and C 1-4 Alkoxy, C 1-6 Alkyl, C 2- The alkyl or alkoxy atoms are optionally substituted with one or more substituents selected from C6 alkenyls or 4-7 membered monocyclic heterocycloalkyls, where the substituent is halogen, -NH2, -N(C1-C6 alkyl)2, -OH, or -COOC. 1-4It is optionally further substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups.

[0273] In some embodiments, R 1 The following are selected from -CN, -NO2, -C(O)NHR6, C(O)N(R6)2, and -C(O)OR6.

[0274] In some embodiments, R 1 It is a monocyclic heteroaryl containing one or more heteroatoms independently selected from N, S, and O, where the heteroaryl is -OH, oxo, halogen, C 1-4 Alkoxy, C 1-6 Alkyl, C 2- The alkyl or alkoxy atoms are optionally substituted with one or more substituents selected from C6 alkenyls or 4-7 membered monocyclic heterocycloalkyls, where the substituent is halogen, -NH2, -N(C1-C6 alkyl)2, -OH, or -COOC. 1-4 It is optionally further substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups.

[0275] In some embodiments, R 1 is -CN.

[0276] In some embodiments, R 1 It is -NO2.

[0277] In some embodiments, R 1 It is -C(O)NHR6.

[0278] In some embodiments, R 1 It is -C(O)N(R6)2.

[0279] In some embodiments, R 1 It is -C(O)OR6.

[0280] In some embodiments, R 1It is a monocyclic heteroaryl containing one or more heteroatoms independently selected from N, S, and O, where the heteroaryl is -OH, oxo, halogen, C 1-4 Alkoxy, C 1-6 Alkyl, C 2- The alkyl or alkoxy atoms are optionally substituted with one or more substituents selected from C6 alkenyls or 4-7 membered monocyclic heterocycloalkyls, where the substituent is halogen, -NH2, -N(C1-C6 alkyl)2, -OH, or -COOC. 1-4 It is optionally further substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl groups.

[0281] In some embodiments, R 1 The following is selected from the table below. [ka] [ka]

[0282] In some embodiments, R 2 is H or C 1-4 It is alkyl. In some embodiments, R 2 is H. In some embodiments, R 2 is C 1-4 It is alkyl.

[0283] In some embodiments, R 2 and R 8 These, along with the atoms to which they are bonded and any intervening atoms, form a 5-6 membered heterocycline.

[0284] In some embodiments, this disclosure relates to compounds of formula IAA: [ka] The invention relates to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof.

[0285] In some embodiments, this disclosure relates to compounds of formula IAA-1: [ka] The invention relates to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof.

[0286] In some embodiments, this disclosure relates to compounds of formula IAB: [ka] The invention relates to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof.

[0287] In some embodiments, this disclosure relates to compounds of formula IAB-1: [ka] The invention relates to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof.

[0288] In some embodiments, R 3 H is H.

[0289] In some embodiments, R 3 and R 8 These, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 membered cycloalkyl group.

[0290] In some embodiments, the present disclosure relates to compounds of formula IAC: [ka] The invention relates to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof.

[0291] In some embodiments, the present disclosure relates to compounds of formula IAC-1: [ka] The invention relates to pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof.

[0292] In some embodiments, R 4 is, -(CH2) m -Aryl, -(CH2) m -heteroaryl, -(CH2) m - It is a cycloalkyl or heterocyclyl. In some embodiments, R 4 is, -(CH2) m -aryl, or -(CH2) m -It is a heteroaryl. 4 ha-(CH2) m - is an arrow. In another embodiment, R 4 ha-(CH2) m -It is a heteroaryl. 4 is a heterocycline. In other embodiments, R 4 ha-(CH2) m -It is a cycloalkyl. In another embodiment, R 4 It is cyclohexanyl.

[0293] In other embodiments, R 4 is, -(CH2) m -aryl, where the aryl is optionally substituted with one or more halogens, OH, or NH2. In other embodiments, R 4 is, -(CH2) m -A heteroaryl group, where the heteroaryl group is optionally substituted with one or more halogens, OH, or NH2. In other embodiments, R 4 It is a heterocyclyl, which is optionally substituted with one or more halogens, OH groups, or NH2 groups.

[0294] Several embodiments, each R5 is halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, oxy C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-C 2-6 Alkenyl, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2,-CH2C(O)NH2,-CH2C(O)NH(C 1-6 Alkyl), -CH2C(O)N(C 1-6 A molecule is independently selected from alkyl)2, -NHC(O)CH3, aryl, and heteroaryl.

[0295] In some embodiments, R 5 is a halogen. In some embodiments, R 5 is F. In some embodiments, R 5 It is Cl.

[0296] In some embodiments, R 5 is C 1-6 It is alkyl.

[0297] In some embodiments, R 5 It is -CH3.

[0298] In some embodiments, R 5 is C 1-6 It is an alkoxy.

[0299] In some embodiments, R 5 It is -OCH3.

[0300] In some embodiments, R 5 is C 1-6 It is a halogen alkyl.

[0301] In some embodiments, R 5 teeth [ka] That is the case.

[0302] In other embodiments, R 5 is oxy C 1-6 It is alkyl.

[0303] In other embodiments, R 5 teeth [ka] That is the case.

[0304] In some embodiments, R 5 is -S(O)2-C 1-6 It is alkyl.

[0305] In some embodiments, R 5 teeth [ka] That is the case.

[0306] In some embodiments, R 5 teeth [ka] That is the case.

[0307] In some embodiments, R 5 teeth [ka] That is the case.

[0308] In some embodiments, R 5 It is -C(O)NH2.

[0309] In some embodiments, R 5 is -C(O)NH(C 1-6 It is alkyl.

[0310] In some embodiments, R 5 teeth [ka] That is the case.

[0311] In some embodiments, R 5 is -C(O)N(C 1-6 It is alkyl(2).

[0312] In some embodiments, R 5 teeth [ka] That is the case.

[0313] In some embodiments, R 5 It is Ariel.

[0314] In some embodiments, R 5 It is phenyl.

[0315] In other embodiments, at least one R 5 These are halogens or -S(O)2-C1-C6 alkyl groups.

[0316] In other embodiments, at least one R 5 It is a halogen, and another R 5 It is -S(O)2-CH3.

[0317] In other embodiments, at least one R 5 It is methyl, and another R 5 It is -S(O)2-CH3.

[0318] In some embodiments, two R 5 These, together with the atoms to which they are bonded and any intervening atoms, form a 5-7 membered heterocyclyl or 5-7 membered heteroaryl, which includes at least one heteroatom selected from N, O, and S; the heterocyclyl or heteroaryl may contain one or more R 7 It is being replaced by an arbitrary choice.

[0319] In some embodiments, fragments of the compound of formula (I) [ka] The following table is used to select the appropriate option. [ka] [ka]

[0320] In some embodiments, R 6 H, OH, C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 3-8 Independently selected from cycloalkyl, heterocyclyl, or heteroaryl, alkyl, alkoxy, heteroaryl, or heterocyclyl is one or more R 9 It is optionally replaced.

[0321] In some embodiments, R 6 H is H.

[0322] In some embodiments, R 6 It is OH.

[0323] In some embodiments, R 6 is C 1-6 It is alkyl.

[0324] In other embodiments, R 7 is oxo or C 1-6 It is alkyl. In other embodiments, R 7 is oxo. In other embodiments, R 7 is C 1-6 It is alkyl.

[0325] In some embodiments, R 8 is a halogen, OH, or NH2. In some embodiments, R 8is a halogen. In some embodiments, R 8 is OH. In some embodiments, R 8 It is NH2.

[0326] In other embodiments, R 9 These are halogens, OH, NH2, and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-8 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R 9 is a halogen. In some embodiments, R 9 is OH. In some embodiments, R 9 is NH2. In some embodiments, R 9 is C 1-6 It is alkyl. In some embodiments, R 9 is C 1-6 It is an alkoxy. In some embodiments, R 9 is C 1-6 In some embodiments, R 9 is C 2-6 It is an alkenyl. In some embodiments, R 9 is C 2-6 In some embodiments, R 9 is C 1-6 In some embodiments, R 9 is C 3-8 It is cycloalkyl. In some embodiments, R 9 is a heterocycline. In some embodiments, R 9 is an arrow. In some embodiments, R 9 It is either or a heteroaryl compound.

[0327] In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m is 0, 1, 2, 3, 4, or 5. In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. 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.

[0328] In some embodiments, n is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. 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. In some embodiments, n is 6.

[0329] In some embodiments, p is 1, 2, 3, 4, or 5. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

[0330] In some embodiments, t is 1, 2, 3, or 4. In some embodiments, t is 1, 2, or 3. In some embodiments, t is 1 or 2. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4.

[0331] In some embodiments, s is 0 or 1. In some embodiments, s is 0. In some embodiments, s is 1.

[0332] In some embodiments, u is 0 or 1. In some embodiments, u is 0. In some embodiments, u is 1.

[0333] In other embodiments, ring A is a monocyclic heteroaryl ring containing at least one nitrogen atom.

[0334] In some embodiments, ring D is aryl or heteroaryl. In some embodiments, ring D is aryl. In some embodiments, ring D is heteroaryl.

[0335] Non-limiting exemplary compounds of this disclosure include: 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(3-methyl-4-methylsulfonylanilino)-pyrimidine-5-carbonitrile; 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-pyrimidine-5-carbonitrile; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-oxazol-2-ylpyrimidine-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-1,2,4-triazole-5-yl)pyrimidine-2-yl]-amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-triazole-5-yl)pyrimidine-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]-amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]-amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidine-2-yl]-amino]-2-methyl-benzamide; 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-N-methyl-2-[(1-oxo-3,4-dihydro-2H-isoquinoline-6-yl)amino]pyrimidine-5-carboxamide; Ethyl 2-(4-carbamoyl-3-methyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; 2-[4-(2-hydroxy-1,1-dimethyl-ethyl)anilino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methylpyrimidine-5-carboxamide; 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)-pyrimidine-5-carboxamide; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-oxazol-2-ylpyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-oxazol-2-ylpyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-triazole-5-yl)pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-triazole-5-yl)pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-1,2,4-triazole-5-yl)pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; (2S)-2-[[2-(3-methyl-4-methylsulfonylanilino)-5-nitropyrimidine-4-yl]amino]-2-phenyl-ethanol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-pyrazole-3-yl)pyrimidine-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-oxazol-2-ylpyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-oxazol-2-ylpyrimidine-2-yl]amino]-N,2-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidine-2-yl]-amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-triazole-5-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-triazole-5-yl)pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-1,2,4-triazole-5-yl)pyrimidine-2-yl]-amino]-N,N-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-1,2,4-triazole-5-yl)pyrimidine-2-yl]-amino]-N,2-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-1,2,4-triazole-3-yl)-pyrimidine-2-yl]amino]-2-methyl-benzamide; 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-5-carboxamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]-amino]-N,N-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]-amino]-N,2-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]-amino]-N,N-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]-amino]-N,2-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)-pyrimidine-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-oxadiazole-2-yl)-pyrimidine-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,2,4-oxadiazole-3-yl)-pyrimidine-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidine-2-yl]-amino]-N,N-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidine-2-yl]-amino]-N,2-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidine-2-yl]-amino]-2-methyl-benzamide; 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-pyrimidine-5-carboxylic acid; 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-N-methyl-2-[(2-methyl-1-oxo-3,4-dihydroisoquinoline-6-yl)amino]pyrimidine-5-carboxamide; 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-N-methyl-2-[(2-methyl-3-oxo-1,4-dihydroisoquinoline-7-yl)amino]pyrimidine-5-carboxamide; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[(1-oxo-3,4-dihydro-2H-isoquinoline-6-yl)amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[(2-oxo-3,4-dihydro-1H-quinoline-6-yl)amino]pyrimidine-5-carboxylate; Ethyl 2-[4-(dimethylcarbamoyl)anilino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[3-methyl-4-(methylcarbamoyl)-anilino]pyrimidine-5-carboxylate; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-oxazol-2-ylpyrimidine-2-yl]aminobenzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-1,2,4-triazole-5-yl)-pyrimidine-2-yl]amino]benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-triazole-5-yl)pyrimidine-2-yl]aminobenzamide; Ethyl 2-[4-(2-hydroxy-1,1-dimethyl-ethyl)anilino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidine-2-yl]aminobenzamide; (2S)-2-[[2-(4-methylsulfonylanilino)-5-oxazole-2-ylpyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(4-methylsulfonylanilino)-5-(1H-1,2,4-triazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(4-methylsulfonylanilino)-5-(1H-triazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(4-methylsulfonylanilino)-5-(1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(4-methylsulfonylanilino)-5-(1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(4-methylsulfonylanilino)-5-(1H-tetrazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 4-[[5-Ethoxycarbonyl-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methoxybenzoic acid; 2-[3-fluoro-4-(2-hydroxy-1,1-dimethyl-ethyl)anilino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methylpyrimidine-5-carboxamide; Ethyl 2-(3-methyl-4-methylsulfonyl-anilino)-4-[[(1R)-1-phenylethyl]amino]pyrimidine-5-carboxylate; 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-N-methyl-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxamide; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-pyrazole-3-yl)pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-pyrazole-3-yl)pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(4-methylsulfonylanilino)pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(3-methylsulfonylanilino)pyrimidine-5-carboxylate; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-oxazol-2-ylpyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-oxazol-2-ylpyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-1,2,4-triazole-3-yl)pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-1,2,4-triazole-3-yl)pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-triazole-5-yl)pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-triazole-5-yl)pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-1,2,4-triazole-5-yl)pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-1,2,4-triazole-5-yl)pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carbohydroxamic acid; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,2,4-oxadiazole-3-yl)pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 2-(4-fluoro-3-phenyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methylpyrimidine-5-carboxamide; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,2,4-oxadiazole-3-yl)pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-tetrazole-5-yl)pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-tetrazole-5-yl)pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-pyrazole-3-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-pyrazole-3-yl)pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; Ethyl 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1R)-1-phenylethyl]amino]pyrimidine-5-carboxylate; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-oxazol-2-ylpyrimidine-2-yl]amino]-N,N,2-trimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-1,2,4-triazole-3-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-1,2,4-triazole-3-yl)pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-triazole-5-yl)pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-1,2,4-triazole-5-yl)pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; 2-(3-fluoro-4-methylsulfonylanilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-N-methylpyrimidine-5-carboxamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,2,4-oxadiazole-3-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,2,4-oxadiazole-3-yl)pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; 4-[[5-(3-ethyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methyl-benzamide; 4-[[5-(5-ethyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; N-ethyl-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[(2-methyl-1-oxo-3,4-dihydroisoquinoline-6-yl)amino]pyrimidine-5-carboxamide; 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-5-carbohydroxamic acid; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-2-yl]amino]-2-methyl-benzamide; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[(2-methyl-1-oxo-3,4-dihydroisoquinoline-6-yl)amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[(2-methyl-3-oxo-1,4-dihydroisoquinoline-7-yl)amino]pyrimidine-5-carboxylate; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-pyrazole-3-yl)pyrimidine-2-yl]aminobenzamide; Ethyl 2-[4-(dimethylcarbamoyl)-3-methyl-anilino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-oxazol-2-ylpyrimidine-2-yl]amino]-N-methyl-benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidine-2-yl]aminobenzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-triazole-5-yl)pyrimidine-2-yl]amino]-N-methyl-benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-1,2,4-triazole-5-yl)pyrimidine-2-yl]amino]-N-methyl-benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-1,2,4-triazole-3-yl)pyrimidine-2-yl]aminobenzamide; (2S)-2-[[5-(5-methyl-1H-pyrazole-3-yl)-2-(4-methylsulfonylanilino)-pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-[3-chloro-4-(trifluoromethyl)anilino]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-N-methylpyrimidine-5-carboxamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-N-methyl-benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-N-methyl-benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,2,4-oxadiazole-3-yl)pyrimidine-2-yl]amino]benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidine-2-yl]amino]-N-methyl-benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidine-2-yl]aminobenzamide; (2S)-2-[[2-(3-methyl-4-methylsulfonylanilino)-5-oxazole-2-ylpyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-methyloxazol-2-yl)-2-(4-methylsulfonylanilino)-pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonylanilino)-5-(1H-1,2,4-triazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonylanilino)-5-(1H-triazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(4-methylsulfonylanilino)-5-(5-methyl-1H-1,2,4-triazole-3-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-(1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-(1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-methyl-1,2,4-oxadiazole-5-yl)-2-(4-methylsulfonylanilino)-pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-methyl-1,3,4-oxadiazole-2-yl)-2-(4-methylsulfonylanilino)-pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-methyl-1,2,4-oxadiazole-3-yl)-2-(4-methylsulfonylanilino)-pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonylanilino)-5-(1H-tetrazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(4-methylsulfonylanilino)-5-(1-methyltetrazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; Ethyl 2-[3-fluoro-4-(2-hydroxy-1,1-dimethyl-ethyl)anilino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-oxazole-2-ylpyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(1H-1,2,4-triazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(1H-triazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; N-ethyl-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxamide; 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-N,N-dimethyl-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxamide; 2-[3-chloro-4-(2-hydroxy-1,1-dimethyl-ethyl)anilino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methylpyrimidine-5-carboxamide; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-pyrazole-3-yl)pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-pyrazole-3-yl)pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; Ethyl 2-[(3,3-dioxo-1,3-lambda6-benzoxathiol-6-yl)amino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; Ethyl 2-[(3,3-dioxo-1,3-lambda6-benzoxathiol-5-yl)amino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(1H-tetrazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(2-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; Ethyl 2-(4-ethylsulfonylanilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1R)-2-hydroxy-1-phenylethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-oxazol-2-ylpyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-triazole-5-yl)pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-1,2,4-triazole-5-yl)pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-1,2,4-triazole-3-yl)pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-1,2,4-triazole-3-yl)pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; 6-[[5-(5-ethyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 6-[[5-(5-ethyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 6-[[5-(3-ethyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 6-[[5-(3-ethyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,2,4-oxadiazole-3-yl)pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,2,4-oxadiazole-3-yl)pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; N-ethyl-2-(4-fluoro-3-phenyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxamide; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-tetrazole-5-yl)pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-pyrazole-3-yl)pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; Ethyl 4-[(2-fluoro-1-phenyl-ethyl)amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; Ethyl 2-(4-fluoro-3-phenyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-1,2,4-triazole-3-yl)pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 4-[[5-(5-ethyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[5-(5-ethyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; 4-[[5-(3-ethyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[5-(3-ethyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,2,4-oxadiazole-3-yl)pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; Ethyl 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-5-carboxylate; Ethyl 2-(2-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-N-isopropyl-2-[(2-methyl-1-oxo-3,4-dihydroisoquinoline-6-yl)amino]pyrimidine-5-carboxamide; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-oxazol-2-ylpyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromemen-6-yl)amino]-5-(1H-triazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(1H-1,2,4-triazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; Ethyl 2-[(2-ethyl-1-oxo-3,4-dihydroisoquinoline-6-yl)amino]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-5-carboxylate; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromemen-6-yl)amino]-5-(1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromemen-6-yl)amino]-5-(1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(1H-tetrazol-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; Ethyl 4-[[(1S)-1-cyclohexyl-2-hydroxyethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-oxazol-2-ylpyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-(1H-triazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-(1H-1,2,4-triazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-pyrazole-3-yl)pyrimidine-2-yl]amino]-N-methyl-benzamide; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-(1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-(1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidine-2-yl]amino]-N-methyl-benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-oxazol-2-ylpyrimidine-2-yl]amino]-N,N-dimethylbenzamide; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-(1H-tetrazol-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-1,2,4-triazole-3-yl)pyrimidine-2-yl]amino]-N-methyl-benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-triazole-5-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-1,2,4-triazole-5-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; (2S)-2-[[2-(3-methyl-4-methylsulfonylanilino)-5-(5-methyl-1H-pyrazole-3-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,2,4-oxadiazole-3-yl)pyrimidine-2-yl]amino]-N-methyl-benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-N-methyl-benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-N-methyl-benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 2-Chloro-4-[[5-(3-ethyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]benzamide; 2-Chloro-4-[[5-(5-ethyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidine-2-yl]amino]-N-methyl-benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; (2S)-2-[[2-(3-methyl-4-methylsulfonylanilino)-5-(5-methyloxazol-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonylanilino)-5-(5-methyl-1H-1,2,4-triazole-3-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; Ethyl 2-[4-(dimethylcarbamoyl)-3-methoxy-anilino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; Ethyl 2-[3-chloro-4-(trifluoromethyl)anilino]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-5-carboxylate; (2S)-2-[[5-(3-ethyl-1,2,4-oxadiazole-5-yl)-2-(4-methylsulfonylanilino)-pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-ethyl-1,3,4-oxadiazole-2-yl)-2-(4-methylsulfonylanilino)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonylanilino)-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonylanilino)-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonylanilino)-5-(5-methyl-1,2,4-oxadiazole-3-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonylanilino)-5-(1-methyltetrazol-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-2-yl]amino]benzamide; 4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methylbenzamide; 4-[[5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methyl-benzamide; (2S)-2-[[2-(4-methylsulfonylanilino)-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(5-methyl-1H-pyrazole-3-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; Ethyl 4-[[(1S,2R)-2-hydroxyindan-1-yl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; Ethyl 4-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; Ethyl 4-[[(1R,2S)-2-hydroxyindan-1-yl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; Ethyl 4-[(2S)-2-(hydroxymethyl)-indoline-1-yl]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(5-methyloxazol-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(5-methyl-1H-1,2,4-triazole-3-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; Ethyl 2-[3-chloro-4-(dimethylcarbamoyl)anilino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-N-isopropyl-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxamide; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-pyrazole-3-yl)pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(5-methyl-1,2,4-oxadiazole-3-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(1-methyltetrazol-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; Ethyl 4-[[(1S)-1-benzyl-2-hydroxyethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(4-isopropylsulfonylanilino)pyrimidine-5-carboxylate; Ethyl 2-[3-chloro-4-(2-hydroxy-1,1-dimethyl-ethyl)anilino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-1,2,4-triazole-3-yl)pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-oxazole-2-ylpyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-(1H-triazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-(1H-1,2,4-triazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; Ethyl 4-[[(1S)-1-(hydroxymethyl)-2-(3-pyridyl)ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,2,4-oxadiazole-3-yl)pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 6-[[5-(3-ethyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[5-(3-ethyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; 6-[[5-(5-ethyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[5-(5-ethyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; 2-(4-fluoro-3-phenyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-isopropyl-pyrimidine-5-carboxamide; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-(1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-(1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-(1H-tetrazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; Ethyl 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S,2R)-2-hydroxyindan-1-yl]amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(2-methoxy-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(3-methoxy-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; 2-(3-fluoro-4-methylsulfonylanilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-N-isopropylpyrimidine-5-carboxamide; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; 4-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methyl-benzamide; 4-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methyl-benzamide; 4-[[5-(3-ethyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[5-(5-ethyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromemen-6-yl)amino]-5-(5-methyl-1H-pyrazole-3-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(5-methyloxazol-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromemen-6-yl)amino]-5-(5-methyl-1H-1,2,4-triazole-3-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[(2-isopropyl-1-oxo-3,4-dihydroisoquinoline-6-yl)amino]pyrimidine-5-carboxylate; Ethyl 2-(2-chloro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-5-carboxylate; Ethyl 2-(3-chloro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-5-carboxylate; 2-Hydroxyethyl 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromemen-6-yl)amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromemen-6-yl)amino]-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromemen-6-yl)amino]-5-(5-methyl-1,2,4-oxadiazole-3-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromemen-6-yl)amino]-5-(1-methyltetrazol-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-(5-methyl-1H-pyrazole-3-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-(5-methyloxazol-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-(5-methyl-1H-1,2,4-triazole-3-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-pyrazole-3-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-(5-methyl-1,2,4-oxadiazole-3-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-(1-methyltetrazol-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-1,2,4-triazole-3-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-oxazol-2-ylpyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-triazole-5-yl)pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-1,2,4-triazole-5-yl)pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 2-Chloro-4-[[5-(5-ethyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N-methyl-benzamide; 2-Chloro-4-[[5-(3-ethyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N-methyl-benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,2,4-oxadiazole-3-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]benzamide; 6-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 6-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 6-[[5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 6-[[5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1H-tetrazole-5-yl)pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; (2S)-2-[[5-(5-ethyl-1,3,4-oxadiazole-2-yl)-2-(3-methyl-4-methylsulfonylanilino)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-ethyl-1,2,4-oxadiazole-5-yl)-2-(3-methyl-4-methylsulfonylanilino)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-isopropyl-1,2,4-oxadiazole-5-yl)-2-(4-methylsulfonylanilino)-pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-isopropyl-1,3,4-oxadiazole-2-yl)-2-(4-methylsulfonylanilino)-pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-2-yl]amino]-N-methyl-benzamide; 4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; 4-[[5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; (2S)-2-[[2-(3-methyl-4-methylsulfonylanilino)-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; Ethyl 4-[(3S)-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-yl]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-(5-methyl-1H-pyrazole-3-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-ethyl-1,3,4-oxadiazole-2-yl)-2-(3-fluoro-4-methylsulfonylanilino)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-ethyl-1,2,4-oxadiazole-5-yl)-2-(3-fluoro-4-methylsulfonylanilino)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazole-5-yl]pyrimidine-2-yl]amino]-2-methyl-benzamide; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-(5-methyloxazol-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol;; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-(5-methyl-1H-1,2,4-triazole-3-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-2-yl]amino]-2-methyl-benzamide; [2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-5-yl]pyrrolidine-1-ylmethanone; 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-N-(2-methoxyethyl)-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxamide; 6-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 6-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 6-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 6-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]3,4-dihydro-1H-quinoline-2-one;; 7-[[5-(5-ethyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 7-[[5-(3-ethyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-(5-methyl-1,2,4-oxadiazole-3-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-(1-methyltetrazol-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; Ethyl 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-yl]pyrimidine-5-carboxylate; N-cyclopentyl-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[(2-methyl-1-oxo-3,4-dihydroisoquinoline-6-yl)amino]pyrimidine-5-carboxamide; 2-Chloro-4-[[5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]benzamide; 2-Chloro-4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]benzamide; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 4-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; 4-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; (2S)-2-[[5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]-2-(4-methylsulfonylanilino)-pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-(4-methylsulfonylanilino)-pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-N-(2-methoxyethyl)-pyrimidine-5-carboxamide; 2-(3-fluoro-4-methylsulfonylanilino)-N-(2-hydroxyethyl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-N-methylpyrimidine-5-carboxamide; Ethyl 4-[[(1S)-1-(4-cyclophenyl)-2-hydroxyethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(3-ethyl-1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromemen-6-yl)amino]-5-(5-ethyl-1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromemen-6-yl)amino]-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-pyrazole-3-yl)pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-(3-ethyl-1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-(5-ethyl-1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1H-1,2,4-triazole-3-yl)pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-N-methyl-benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-N-methyl-benzamide; 2-Chloro-4-[[5-(3-ethyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 2-Chloro-4-[[5-(5-ethyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-chlorobenzamide; 4-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-chlorobenzamide; 6-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; 6-[[5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,2,4-oxadiazole-3-yl)pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; (2S)-2-[[5-(5-isopropyl-1,3,4-oxadiazole-2-yl)-2-(3-methyl-4-methylsulfonylanilino)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-isopropyl-1,2,4-oxadiazole-5-yl)-2-(3-methyl-4-methylsulfonylanilino)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-2-(4-methylsulfonylanilino)-pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-2-(4-methylsulfonylanilino)-pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; N-cyclopentyl-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxamide; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazole-5-yl]pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-2-yl]amino]-3,4-dihydro-1H-quinoline-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; N-cyclopentyl-2-(4-fluoro-3-phenyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxamide; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(5-isopropyl-1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(3-isopropyl-1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazole-5-yl]pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazole-5-yl]pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-2-yl]amino]-N,2-dimethylbenzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 6-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; 6-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 7-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-(5-ethyl-1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-(3-ethyl-1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-Chloro-4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N-methyl-benzamide; 2-Chloro-4-[[5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N-methyl-benzamide; 4-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-(3-methyl-4-methylsulfonylanilino)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazole-5-yl]pyrimidine-2-yl]amino]benzamide; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromemen-6-yl)amino]-5-(3-isopropyl-1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromemen-6-yl)amino]-5-(5-isopropyl-1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[(3-isopropyl-2,5-dioxo-3,4-dihydro-1H-1,4-benzodiazepine-7-yl)amino]pyrimidine-5-carboxylate; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-2-yl]amino]benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-2-yl]amino]benzamide; 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)-N-methylsulfonyl-pyrimidine-5-carboxamide; (2S)-2-[[2-(4-methylsulfonylanilino)-5-[3-(trifluoromethyl)-1H-1,2,4-triazole-5-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-[3-chloro-4-(trifluoromethyl)anilino]-N-cyclopentyl-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-5-carboxamide; (2S)-2-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-(3-fluoro-4-methylsulfonylanilino)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]-2-(3-fluoro-4-methylsulfonylanilino)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(4-methylsulfonylanilino)-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(4-methylsulfonylanilino)-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-(3-isopropyl-1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-(5-isopropyl-1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 4-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-chloro-N-methyl-benzamide; 4-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-chloro-N-methyl-benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 7-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 7-[[5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 6-[[5-(5-ethyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[5-(3-ethyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; (2S)-2-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-2-(3-methyl-4-methylsulfonylanilino)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-2-(3-methyl-4-methylsulfonylanilino)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-N-methylsulfonyl-pyrimidine-5-carboxamide; 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)-N-(2,2,2-trifluoroethyl)-pyrimidine-5-carboxamide; Ethyl 4-[[(1S)-1-(hydroxymethyl)-2-(1H-indole-3-yl)ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazole-5-yl]pyrimidine-2-yl]amino]-2-methyl-1,4-dihydro-isoquinoline-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazole-5-yl]pyrimidine-2-yl]amino]-2-methyl-3,4-dihydro-isoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-2-yl]amino]-2-methyl-1,4-dihydro-isoquinoline-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-2-yl]amino]-2-methyl-3,4-dihydro-isoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-2-yl]amino]-2-methyl-1,4-dihydroisoquinoline-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-2-yl]amino]-2-methyl-3,4-dihydroisoquinoline-1-one; 2-(4-fluoro-3-phenyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-(2,2,2-trifluoroethyl)-pyrimidine-5-carboxamide; (2S)-2-[[5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]-2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-[(1,1-dioxo-2H-thioclomen-6-yl)amino]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-2-(3-fluoro-4-methylsulfonylanilino)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-2-(3-fluoro-4-methylsulfonylanilino)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazole-5-yl]pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-2-yl]amino]-N,N,2-trimethyl-benzamide; 7-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 7-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-(5-isopropyl-1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-(3-isopropyl-1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]-2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-Chloro-4-[[5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 2-Chloro-4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazole-5-yl]pyrimidine-2-yl]amino]-N-methyl-benzamide; (2S)-2-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-2-yl]amino]-N-methyl-benzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-2-yl]amino]-N-methyl-benzamide; (2S)-2-[[2-(3-methyl-4-methylsulfonylanilino)-5-[3-(trifluoromethyl)-1H-1,2,4-triazole-5-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonylanilino)-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonylanilino)-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]pyrimidine-4-yl]amino]-2-phenyl-ethanol; 4-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-chloro-N,N-dimethylbenzamide; 4-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-chloro-N,N-dimethylbenzamide; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-[3-(trifluoromethyl)-1H-1,2,4-triazole-5-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazole-5-yl]pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; (2S)-2-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-2-(3-chloro-4-methylsulfonylanilino)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-2-(3-chloro-4-methylsulfonylanilino)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazole-5-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromemen-6-yl)amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromemen-6-yl)amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; 6-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[5-[3-(difluoromethyl)-1,2,4-oxadiazole-5-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazole-5-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazole-5-yl]pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 2-Chloro-4-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-2-yl]amino]-N,N-dimethylbenzamide; 6-[[5-(5-tert-butyl-1,3,4-oxadiazole-2-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[5-(3-tert-butyl-1,2,4-oxadiazole-5-yl)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-[3-(trifluoromethyl)-1H-1,2,4-triazole-5-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonylanilino)-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazole-5-yl]pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; Ethyl 2-(4-carbamoyl-3-chloroanilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-5-carboxylate; Ethyl 2-[3-chloro-4-(methylcarbamoyl)anilino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; Ethyl 6-[5-[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-yl]-1,3,4-oxadiazole-2-yl]hexanoate; Ethyl 6-[5-[2-(3-fluoro-4-methylsulfonylanilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-5-yl]-1,3,4-oxadiazole-2-yl]hexanoate; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-methylsulfonylpyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[(1-oxoisoindorin-5-yl)amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[(1-oxo-2,3,4,5-tetrahydro-2-benzazepin-7-yl)amino]pyrimidine-5-carboxylate; 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[(1-oxo-3,4-dihydro-2H-isoquinoline-6-yl)amino]pyrimidine-5-carbonitrile; Ethyl 4-[[(1R)-2-hydroxy-1-phenylethyl]amino]-2-[(1-oxo-3,4-dihydro-2H-isoquinoline-6-yl)amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-(4-methoxyphenyl)ethyl]amino]-2-[(1-oxo-3,4-dihydro-2H-isoquinoline-6-yl)amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]amino]-2-[(1-oxo-3,4-dihydro-2H-isoquinoline-6-yl)amino]pyrimidine-5-carboxylate; 5-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]isoindorin-1-one; 5-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1,3,4-oxadiazole-2-yl)pyrimidine-2-yl]amino]isoindorin-1-one; Ethyl 2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[(2-oxo-1,3,4,5-tetrahydro-1-benzazepin-8-yl)amino]pyrimidine-5-carboxylate; 6-[[4-[[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; Ethyl 2-[[5-ethoxycarbonyl-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-2-yl]-(1-oxo-2,3,4,5-tetrahydro-2-benzazepine-7-yl)amino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; 2-(3-fluoro-4-methylsulfonylanilino)-9-[(1S)-2-hydroxy-1-phenylethyl]-7H-purine-8-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinoline-1-one; 5-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-3,3-dimethyl-isoindorin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-vinyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-2-(2-trimethylsilylethoxymethyl)-3,4-dihydroisoquinoline-1-one; [6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-1-oxo-3,4-dihydroisoquinoline-2-yl]methyl 2,2-dimethylpropanoate; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-2-yl]amino]-2-(2-trimethylsilylethoxymethyl)-3,4-dihydroisoquinoline-1-one; (2S)-2-[[5-[3-[(dimethylamino)methyl]-1,2,4-oxadiazole-5-yl]-2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]pyrimidine-4-yl]amino]-2-phenyl-ethanol; 6-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-(1-methylpyrazole-4-yl)pyrimidine-2-yl]amino]-3,4-dihydro-2H-isoquinoline-1-one; 5-[[5-[3-[(dimethylamino)methyl]-1,2,4-oxadiazole-5-yl]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]isoindorin-1-one; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromemen-6-yl)amino]-5-[3-(pyrrolidine-1-ylmethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-4-yl]amino]-2-phenyl-ethanol; 5-[[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-5-[3-(pyrrolidine-1-ylmethyl)-1,2,4-oxadiazole-5-yl]pyrimidine-2-yl]amino]isoindorin-1-one or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

[0336] In some embodiments, the compound is: 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-N-methyl-2-[(2-methyl-1-oxo-3,4-dihydroisoquinoline-6-yl)amino]pyrimidine-5-carboxamide; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[(1-oxo-3,4-dihydro-2H-isoquinoline-6-yl)amino]pyrimidine-5-carboxylate; Ethyl 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-5-carboxylate; 2-(3-fluoro-4-methylsulfonylanilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-N-methylpyrimidine-5-carboxamide; 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-N-methyl-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxamide; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[(2-methyl-1-oxo-3,4-dihydroisoquinoline-6-yl)amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; N-ethyl-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxamide; 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)-N-(2,2,2-trifluoroethyl)-pyrimidine-5-carboxamide; N-ethyl-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[(2-methyl-1-oxo-3,4-dihydroisoquinoline-6-yl)amino]pyrimidine-5-carboxamide; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(3-methoxy-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; Ethyl 2-(4-ethylsulfonylanilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-(4-methylsulfonylanilino)pyrimidine-5-carboxylate; (2S)-2-[[2-(3-methyl-4-methylsulfonylanilino)-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-5-carboxamide; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenyl-ethanol; 2-Hydroxyethyl 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; Ethyl 2-[(2-ethyl-1-oxo-3,4-dihydroisoquinoline-6-yl)amino]-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-5-carboxylate; Ethyl 2-[4-(dimethylcarbamoyl)anilino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

[0337] It should be understood that all isomers, including mixtures thereof, are included in the present invention. If a compound contains a double bond, the substituent may be in an E configuration or a Z configuration. If a compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis configuration or a trans configuration. All tautomers are also intended to be included.

[0338] The compounds of the present invention, and their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs, may exist as tautomers (e.g., as amides or iminoethers). All such tautomers are envisioned herein as part of the present invention.

[0339] The compounds of the present invention may contain chiral or asymmetric centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, and mixtures thereof, including racemic mixtures, are intended to form part of the present invention. Furthermore, the present invention encompasses all geometric and positional isomers. For example, if a compound of the present invention incorporates a double bond or a fused ring, both cis and trans forms, as well as mixtures, are included in the scope of the present invention. Each compound disclosed herein includes all enantiomers that conform to the general structure of the compound. The compounds may be in racemic or enantiomerically pure form, or in other stereochemical forms. Assay results may reflect data collected for racemic, enantiomerically pure, or other stereochemical forms.

[0340] Diastereomer mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomer mixture into a diastereomer mixture by reaction with a suitable optically active compound (e.g., a chiral alcohol or chiral auxiliary such as Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers back into their corresponding pure enantiomers (e.g., by hydrolysis). Some of the compounds of the present invention may also be atropisomers (e.g., substituted biaryls) and are considered part of the present invention. Enantiomers can also be separated using a chiral HPLC column.

[0341] The compounds of the present invention may also exist in different tautomers, and all such forms are included within the scope of the present invention. For example, both the keto-enol and imine-enamine forms of the compounds are included in the present invention.

[0342] All stereoisomers of the compound (including salts, solvates, esters, and prodrugs of the compound, as well as salts, solvates, and esters of prodrugs), including geometric isomers, optical isomers, enantiomeric isomers (which may exist even in the absence of a chiral carbon), rotameric forms, atropisomers, and diastereomers, which may exist due to chiral carbons on various substituents, are intended within the scope of the present invention, as are positional isomers (e.g., 4-pyridyl and 3-pyridyl). (For example, if the compound of formula (I) incorporates a double bond or a fused ring, both the cis and trans forms, as well as mixtures, are included in the scope of the present invention. Also, for example, the keto-enol and imine-enamine forms of the compound are all included in the present invention. Individual stereoisomers of the compounds of the present invention may, for example, substantially contain no other isomers, or may be, for example, as a racemate, or mixed with all or other selected stereoisomers. The chiral centers of the present invention may have an S or R configuration as defined by the IUPAC 1974 recommendation. The use of terms such as “salt,” “solvate,” “ester,” and “prodrug” is intended to also apply to salts, solvates, esters, and prodrugs of enantiomers, stereoisomers, rotational isomers, tautomers, positional isomers, racemates, or prodrugs of the compounds of the present invention.)

[0343] The compounds of formula I may also form salts, which are also within the scope of this invention. Unless otherwise specified, references to compounds of formula I herein are understood to include references to their salts.

[0344] This invention relates to a compound that is a modulator of hematopoietic precursor kinase 1 (HPK1).

[0345] In one embodiment, the compound of the present invention is an inhibitor of hematopoietic precursor kinase 1 (HPK1).

[0346] In some embodiments, the compound of formula I is a selective inhibitor of hematopoietic precursor kinase 1 (HPK1).

[0347] This invention relates to a compound that is a modulator of hematopoietic precursor kinase 1 (HPK1).

[0348] In one embodiment, the compound of the present invention is an inhibitor of hematopoietic precursor kinase 1 (HPK1).

[0349] In some embodiments, the compound of formula I is a selective inhibitor of hematopoietic precursor kinase 1 (HPK1).

[0350] This invention relates to a compound that is a modulator of the leucine-rich repeat kinase 2 (LRRK2) protein.

[0351] In one embodiment, the compound of the present invention is an inhibitor of the leucine-rich repeat kinase 2 (LRRK2) protein.

[0352] In some embodiments, the compound of formula I is a selective inhibitor of the leucine-rich repeat kinase 2 (LRRK2) protein.

[0353] This invention relates to a compound that is a modulator of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0354] In one embodiment, the compound of the present invention is an inhibitor of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0355] In some embodiments, the compound of formula I is a selective inhibitor of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0356] This invention relates to a compound that is a modulator of interleukin-1 receptor-related kinase 1 (IRAK1).

[0357] In one embodiment, the compound of the present invention is an inhibitor of interleukin-1 receptor-related kinase 1 (IRAK1).

[0358] In some embodiments, the compound of formula I is a selective inhibitor of interleukin-1 receptor-related kinase 1 (IRAK1).

[0359] This invention relates to a compound that is a modulator of interleukin-1 receptor-related kinase 4 (IRAK4).

[0360] In one embodiment, the compound of the present invention is an inhibitor of interleukin-1 receptor-related kinase 4 (IRAK4).

[0361] In some embodiments, the compound of formula I is a selective inhibitor of interleukin-1 receptor-related kinase 4 (IRAK4).

[0362] The present invention relates to compounds that are modulators of Janus kinases (JAK), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2).

[0363] In one embodiment, the compound of the present invention is an inhibitor of Janus kinase (JAK), comprising Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2).

[0364] In some embodiments, the inhibitors are selective inhibitors of Janus kinase (JAK), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2).

[0365] The present invention relates to the compounds described herein, and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, as well as pharmaceutical compositions comprising one or more of the compounds described herein, or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers. Methods for synthesizing compounds

[0366] The compounds of the present invention can be prepared by various methods, including standard chemistry. A suitable synthesis route is shown in the scheme below.

[0367] Compounds of formula (I) can be prepared by methods known in the art of organic synthesis, as partially defined by the following synthetic scheme. In the scheme described below, it is well understood that protecting groups for sensitive or reactive groups are employed as needed, according to general principles or chemistry. Protecting groups are handled according to standard methods of organic synthesis (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of compound synthesis using methods readily apparent to those skilled in the art. Whether a stereocenter is present in a compound of formula (I) can be recognized by those skilled in the art from the selection process, as well as the reaction conditions and sequence. Thus, the present invention includes both possible stereoisomers (unless specified in synthesis) and includes not only racemic compounds but also individual enantiomers and / or diastereomers. If a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by separation of the final product or any convenient intermediate. The separation of the final product, intermediate, or starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0368] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes. Preparation of compounds

[0369] The compounds of the present invention can be prepared by many methods well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the methods described below, along with synthetic methods known in the art of organic synthesis, or with modifications thereof that will be understood by those skilled in the art. Suitable methods include, but are not limited to, those described below. The compounds of the present invention can be synthesized according to the steps outlined in General Procedure A, which include aggregate intermediates or compounds of different sequences. Starting materials are commercially available or can be prepared by any known procedure in the reported literature or as shown below.

[0370] General Procedure A [ka] Method of use of the disclosed compound

[0371] Another aspect of the present invention relates to a method for treating diseases or disorders related to the regulation of hematopoietic precursor kinase 1 (HPK1). The method comprises administering an effective amount of a composition and compound of formula (I) to a patient who requires treatment for a disease or disorder related to the regulation of HPK1.

[0372] In another embodiment, the present invention relates to a method for inhibiting hematopoietic precursor kinase 1 (HPK1). The method comprises administering an effective amount of the compound of formula (I) to a patient who requires the compound of formula (I).

[0373] Another aspect of the present invention relates to a method for treating, preventing, inhibiting or eliminating a patient disease or disorder associated with the inhibition of hematopoietic precursor kinase 1 (HPK1), the method comprising administering an effective amount of a compound of formula (I) to a patient in need thereof. In one embodiment, the disease may be, but is not limited to, cancer.

[0374] The present invention also relates to the use of HPK1 inhibitors for the preparation of pharmaceuticals used in the treatment, prevention, inhibition or elimination of diseases or conditions mediated by hematopoietic precursor kinase 1 (HPK1), wherein the pharmaceutical comprises a compound of formula (I).

[0375] In another aspect, the present invention relates to a method for producing a pharmaceutical for treating, preventing, inhibiting or eliminating a disease or condition mediated by hematopoietic precursor kinase 1 (HPK1), wherein the pharmaceutical comprises a compound of formula (I).

[0376] Another aspect of the present invention relates to a compound of formula (I) for use in the manufacture of a pharmaceutical for treating diseases associated with the inhibition of hematopoietic precursor kinase 1 (HPK1).

[0377] In another aspect, the present invention relates to the use of a compound of formula (I) in the treatment of diseases associated with the inhibition of hematopoietic precursor kinase 1 (HPK1).

[0378] Another aspect of the present invention relates to a method for treating a disease or disorder related to the regulation of the leucine-rich repeat kinase 2 (LRRK2) protein. The method comprises administering an effective amount of the composition and compounds of formula (I) to a patient in need of treatment for a disease or disorder related to the regulation of LRRK2.

[0379] In another embodiment, the present invention relates to a method for inhibiting the leucine-rich repeat kinase 2 (LRRK2) protein. The method comprises administering an effective amount of the compound of formula (I) to a patient who requires the compound of formula (I).

[0380] Another aspect of the present invention relates to a method for treating, preventing, inhibiting or eliminating a patient's disease or disorder associated with the inhibition of leucine-rich repeat kinase 2 (LRRK2) protein, the method comprising administering an effective amount of a compound of formula (I) to a patient in need thereof.

[0381] The present invention also relates to the use of inhibitors of LRRK2 for the preparation of pharmaceuticals used in the treatment, prevention, inhibition or elimination of diseases or conditions mediated by the leucine-rich repeat kinase 2 (LRRK2) protein, wherein the pharmaceutical comprises a compound of formula (I).

[0382] In another aspect, the present invention relates to a method for producing a pharmaceutical for treating, preventing, inhibiting or eliminating a disease or condition mediated by a leucine-rich repeat kinase 2 (LRRK2) protein, wherein the pharmaceutical comprises a compound of formula (I).

[0383] Another aspect of the present invention relates to a compound of formula (I) for use in the manufacture of a pharmaceutical for treating diseases associated with the inhibition of leucine-rich repeat kinase 2 (LRRK2) protein.

[0384] In another aspect, the present invention relates to the use of a compound of formula (I) in the treatment of diseases associated with the inhibition of leucine-rich repeat kinase 2 (LRRK2) protein.

[0385] In some embodiments, the leucine-rich repeat kinase 2 (LRRK2) protein is a mutant LRRK2 protein.

[0386] Another aspect of the present invention relates to a method for treating a disease or disorder related to the regulation of the FMS-like tyrosine kinase 3 (FLT3) gene. The method comprises administering an effective amount of the composition and compounds of formula (I) to a patient in need of treatment for a disease or disorder related to the regulation of FLT3.

[0387] In another embodiment, the present invention relates to a method for inhibiting the FMS-like tyrosine kinase 3 (FLT3) gene. The method comprises administering an effective amount of the compound of formula (I) to a patient who requires the compound of formula (I).

[0388] Another aspect of the present invention relates to a method for treating, preventing, inhibiting or eliminating a patient's disease or disorder associated with inhibition of the FMS-like tyrosine kinase 3 (FLT3) gene, the method comprising administering an effective amount of a compound of formula (I) to a patient in need thereof.

[0389] The present invention also relates to the use of FLT3 inhibitors for the preparation of pharmaceuticals used in the treatment, prevention, inhibition or elimination of diseases or conditions mediated by the FMS-like tyrosine kinase 3 (FLT3) gene, wherein the pharmaceutical comprises a compound of formula (I).

[0390] In another aspect, the present invention relates to a method for producing a pharmaceutical for treating, preventing, inhibiting or eliminating a disease or condition mediated by the FMS-like tyrosine kinase 3 (FLT3) gene, wherein the pharmaceutical comprises a compound of formula (I).

[0391] Another aspect of the present invention relates to a compound of formula (I) for use in the manufacture of a pharmaceutical for treating diseases associated with inhibition of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0392] In another aspect, the present invention relates to the use of a compound of formula (I) in the treatment of diseases associated with inhibition of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0393] In some embodiments, the FMS-like tyrosine kinase 3 (FLT3) gene is a mutant FLT3 gene.

[0394] Another aspect of the present invention relates to a method for treating a disease or disorder related to the modulation of interleukin-1 receptor-associated kinase 1 (IRAK1). The method comprises administering an effective amount of a composition and compound of formula (I) to a patient who is in need of treatment for a disease or disorder related to the modulation of IRAK1.

[0395] In another embodiment, the present invention relates to a method for inhibiting interleukin-1 receptor-associated kinase 1 (IRAK1). The method comprises administering an effective amount of the compound of formula (I) to a patient who requires the compound of formula (I).

[0396] Another aspect of the present invention relates to a method for treating, preventing, inhibiting or eliminating a patient disease or disorder associated with the inhibition of interleukin-1 receptor-associated kinase 1 (IRAK1), the method comprising administering an effective amount of a compound of formula (I) to a patient in need thereof.

[0397] The present invention also relates to the use of an inhibitor of interleukin-1 receptor-associated kinase 1 (IRAK1) for the preparation of a pharmacopoeia used in the treatment, prevention, inhibition or elimination of a disease or condition mediated by IRAK1, wherein the pharmacopoeia comprises a compound of formula (I).

[0398] In another aspect, the present invention relates to a method for producing a pharmaceutical for treating, preventing, inhibiting or eliminating a disease or condition mediated by interleukin-1 receptor-associated kinase 1 (IRAK1), wherein the pharmaceutical comprises a compound of formula (I).

[0399] Another aspect of the present invention relates to a compound of formula (I) for use in the manufacture of a pharmaceutical for treating diseases associated with the inhibition of interleukin-1 receptor-related kinase 1 (IRAK1).

[0400] In another aspect, the present invention relates to the use of a compound of formula (I) in the treatment of diseases associated with the inhibition of interleukin-1 receptor-related kinase 1 (IRAK1).

[0401] Another aspect of the present invention relates to a method for treating a disease or disorder related to the modulation of interleukin-1 receptor-related kinase 4 (IRAK4). The method comprises administering an effective amount of a composition and compound of formula (I) to a patient who is in need of treatment for a disease or disorder related to the modulation of IRAK4.

[0402] In another embodiment, the present invention relates to a method for inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4). The method comprises administering an effective amount of the compound of formula (I) to a patient who requires the compound of formula (I).

[0403] Another aspect of the present invention relates to a method for treating, preventing, inhibiting or eliminating a patient disease or disorder associated with the inhibition of interleukin-1 receptor-related kinase 4 (IRAK4), the method comprising administering an effective amount of a compound of formula (I) to a patient in need thereof.

[0404] The present invention also relates to the use of IRAK4 inhibitors for the preparation of pharmaceuticals used in the treatment, prevention, inhibition or elimination of diseases or conditions mediated by interleukin-1 receptor-related kinase 4 (IRAK4), wherein the pharmaceutical comprises a compound of formula (I).

[0405] In another aspect, the present invention relates to a method for producing a pharmaceutical for treating, preventing, inhibiting or eliminating a disease or condition mediated by interleukin-1 receptor-related kinase 4 (IRAK4), wherein the pharmaceutical comprises a compound of formula (I).

[0406] Another aspect of the present invention relates to a compound of formula (I) for use in the manufacture of a pharmaceutical for treating diseases associated with the inhibition of interleukin-1 receptor-related kinase 4 (IRAK4).

[0407] In another aspect, the present invention relates to the use of a compound of formula (I) in the treatment of diseases associated with the inhibition of interleukin-1 receptor-related kinase 4 (IRAK4).

[0408] Another aspect of the present invention relates to a method for treating diseases or disorders related to the 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 an effective amount of a composition and compound of formula (I) to a patient who is in need of treatment for a disease or disorder related to the modulation of JAKs.

[0409] In another embodiment, the present invention relates to a method for inhibiting 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 an effective amount of the compound of formula (I) to a patient who requires the compound of formula (I).

[0410] Another aspect of the present invention relates to a method for treating, preventing, inhibiting or eliminating a patient's disease or disorder associated with the inhibition of Janus kinases (JAK), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2), the method comprising administering an effective amount of a compound of formula (I) to a patient in need thereof.

[0411] The present invention also relates to the use of Janus kinase (JAK) inhibitors, including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2), for the preparation of pharmaceuticals used in the treatment, prevention, inhibition, or elimination of diseases or conditions mediated by JAK, wherein the pharmaceuticals comprise compounds of formula (I).

[0412] In another embodiment, the present invention relates to a method for producing a pharmaceutical for treating, preventing, inhibiting or eliminating a disease or condition mediated by Janus kinases (JAK), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2), wherein the pharmaceutical comprises a compound of formula (I).

[0413] Another aspect of the present invention relates to a compound of formula (I) for use in the manufacture of pharmaceuticals for treating diseases associated with inhibition of Janus kinases (JAK), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2).

[0414] Another aspect of the present invention relates to the use of compounds of formula (I) in the treatment of diseases associated with inhibition of Janus kinases (JAK), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2).

[0415] In some embodiments, Janus kinase (JAK) is Janus kinase 1 (JAK1).

[0416] In some embodiments, Janus kinase (JAK) is Janus kinase 2 (JAK2).

[0417] In some embodiments, Janus kinase (JAK) is Janus kinase 3 (JAK3).

[0418] In some embodiments, Janus kinase (JAK) is tyrosine kinase 2 (TYK2).

[0419] Another aspect of the present invention relates to a method for treating cancer. The method comprises administering an effective amount of the compound of formula (I) to a patient who requires the compound of formula (I).

[0420] Another aspect of the present invention relates to a method for treating or preventing cancer. The method comprises administering an effective amount of the compound of formula (I) to a patient who requires the compound of formula (I).

[0421] In one embodiment, the present invention relates to the use of hematopoietic precursor kinase 1 (HPK1) inhibitors for the preparation of pharmaceuticals used for the treatment, prevention, inhibition, or elimination of cancer-related diseases or disorders.

[0422] In some embodiments, the disease, disorder, or symptom is selected from cancer, autoimmune diseases, inflammatory diseases, viral infections, male fertility control, benign hyperplasia, sepsis, vascular disorders, atherosclerosis, and neurodegenerative disorders.

[0423] In some embodiments, the disease, disorder, or symptom is cancer.

[0424] In some embodiments, cancer is selected from bladder cancer, bone cancer, brain tumor, breast cancer, heart 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 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).

[0425] In some embodiments, the disease, disorder, or condition is an autoimmune disease.

[0426] In some embodiments, the disease, disorder, or symptom is an autoimmune disease selected from chronic obstructive pulmonary disease (COPD), asthma, bronchitis, lupus, dermatomyositis, Sjögren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type 1 diabetes and its associated complications, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto's disease and autoimmune thyroiditis), contact dermatitis, as well as eczematous dermatitis, inflammatory bowel disease, interferonopathy, atherosclerosis, and amyotrophic lateral sclerosis.

[0427] In some embodiments, asthma is selected from chronic asthma, severe asthma, endogenous asthma, exogenous asthma, dust asthma, and infantile asthma.

[0428] In some embodiments, severe asthma is selected from late-onset asthma and airway hyperresponsiveness.

[0429] In some embodiments, bronchitis is bronchial asthma.

[0430] In some embodiments, lupus is selected from systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, and lupus nephritis.

[0431] In some embodiments, inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis.

[0432] In some embodiments, the disease, disorder, or condition is an inflammatory immune disorder.

[0433] In some embodiments, the inflammatory disease is selected from rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway diseases, chronic obstructive pulmonary disease (COPD), inflammatory liver disease, inflammatory bowel disease, endotoxin-induced conditions, and related diseases involving cartilage such as joints.

[0434] In some embodiments, the allergic airway disease is selected from asthma and rhinitis.

[0435] In some embodiments, the inflammatory liver disease is selected from primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).

[0436] In some embodiments, inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis.

[0437] In some embodiments, the disease, disorder, or symptom is a viral infection.

[0438] In some embodiments, viral infections are infections caused by viruses 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 hantavirus, Sin Nombre virus, rotavirus, echovirus, foot-and-mouth disease virus, coxsackievirus, West Nile virus, Ebola virus, Ross River virus, human papillomavirus, and coronaviruses.

[0439] In some embodiments, the viral infection is an infection caused by the hepatitis B virus (HBV).

[0440] In some embodiments, the viral infection is infection by human immunodeficiency virus (HIV).

[0441] In some embodiments, the disease, disorder, or symptom is a control of male reproductive capacity.

[0442] In some embodiments, the disease, disorder, or symptom is a benign hyperplasia.

[0443] In some embodiments, the benign hyperplasia is selected from benign hyperplasia of the prostate and benign hyperplasia of the mammary gland.

[0444] In some embodiments, the disease, disorder, or condition is sepsis.

[0445] In some embodiments, the disease, disorder, or symptom is a vascular disorder.

[0446] In some embodiments, the vascular disorder is selected from erythematous pain, peripheral artery disease, renal artery stenosis, Buerger's disease, Raynaud's disease, disseminated intravascular coagulation, and cerebrovascular disease.

[0447] In some embodiments, the disease, disorder, or condition is atherosclerosis.

[0448] In some embodiments, atherosclerosis is selected from myocardial infarction and stroke.

[0449] In some embodiments, the disease, disorder, or condition is a neurodegenerative disorder.

[0450] In some embodiments, neurodegenerative diseases are selected from Alzheimer's disease, vascular dementia, frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Lewy body dementia, collagen disease-dominant senile dementia, Pick's disease (PiD), argyrophilic cereal disease, amyotrophic lateral sclerosis (ALS), other motor neuron diseases, Guam Parkinson's disease-dementia complex, FTDP-17, Ritico-Bodidig disease, multiple sclerosis, traumatic brain injury (TBI), and Parkinson's disease, where the disease, disorder, or symptom is selected from Alzheimer's disease, vascular dementia, frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP

[0451] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, the pharmaceutically acceptable carrier may further comprise an excipient, a diluent, or a surfactant.

[0452] The disclosed compounds of the present invention may be administered in effective amounts to treat or prevent a disorder in a subject, and / or prevent its onset.

[0453] The disclosed compounds may be administered in any mode of administration of the therapeutic agent. These modes include systemic or topical administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical administration.

[0454] Depending on the intended mode of administration, the disclosed compositions may be in solid, semi-solid, or liquid dosage forms, such as injections, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, solutions, or suspensions, and may be in unit doses to conform to conventional pharmaceutical practices. Similarly, they may be administered intravenously (both bolus and infusion), intraperitoneally, subcutaneously, or intramuscularly, and all forms well known to those skilled in the pharmaceutical art may be used.

[0455] Exemplary pharmaceutical compositions include the compounds of the present invention and pharmaceutically acceptable carriers, for example: a) diluents, for example, purified water, triglyceride oils, for example, hydrogenated or partially hydrogenated vegetable oils or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, for example, EPA or DHA, or esters thereof, triglycerides or mixtures, omega-3 fatty acids or their derivatives, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) lubricants, for example, silica, talc, stearic acid, its magnesium or calcium salts, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; also for tablets; c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, Tablets and gelatin capsules containing magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic rubbers such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if desired; d) disintegrants such as starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colorants, flavorings and sweeteners; f) emulsifiers or dispersants such as Tween80, Labrasol, HPMC, DOSS, caproyl909, labrafac, labrafil, peceol, transcutol, capmulMCM, capmulG-12, captex355, gelucire, vitamin ETGPS or other acceptable emulsifiers; and / or; g) agents that enhance the absorption of compounds such as cyclodextrin, hydroxypropyl cyclodextrin, PEG400, PEG200, etc.

[0456] Liquids, particularly injection compositions, can be prepared by means of dissolution, dispersion, etc. For example, the disclosed compounds can be dissolved or mixed in a pharmaceutically acceptable solvent such as water, physiological saline, aqueous dextrose, glycerol, or ethanol to form an injectionable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

[0457] The disclosed compounds can also be formulated as suppositories, which may be prepared from lipid emulsions or suspensions; using polyalkylene glycols such as propylene glycol as a carrier.

[0458] The disclosed compounds may also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer lamellar vesicles, and multilayer vesicles. The liposomes may be formed from a variety of phospholipids, including cholesterol, stearylamine, or phosphatidylcholine. In some embodiments, a film of lipid components is hydrated with an aqueous solution of the drug to form a lipid layer encapsulating the drug, as described in U.S. Patent No. 5,262,564, which is incorporated entirely herein by reference.

[0459] The disclosed compounds may also be delivered by using monoclonal antibodies as individual carriers to which the disclosed compounds are conjugated. The disclosed compounds may also be conjugated to soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl aspanamidophenol, or polyethylene oxide polylysine substituted with palmitoyl residues. Furthermore, the disclosed compounds may be conjugated to a class of biodegradable polymers useful for achieving controlled release of drugs, such as polylactic acid, polyepsilon caprolactone, polyhydroxybutyrate, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels. In embodiments, the disclosed compounds are not covalently bonded to polymers, such as polycarboxylic acid polymers or polyacrylates. Parenteral injection administration is generally used by subcutaneous injection, intramuscular injection or intravenous injection and infusion. Injectable preparations can be prepared in conventional forms, such as liquid solutions or suspensions, or as solid forms suitable for dissolving in liquid before injection.

[0460] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include excipients, diluents, or surfactants. In some embodiments, the pharmaceutical composition may further include additional pharmaceutically active agents. In some embodiments, the additional therapeutic agent is selected from immune checkpoint inhibitors, cell-based therapies, and cytokine therapies.

[0461] In some embodiments, the immune checkpoint antibody is selected from PD-1 antibody, PD-L1 antibody, PD-L2 antibody, CTLA-4 antibody, TIM3 antibody, LAG3 antibody, and TIGIT antibody.

[0462] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0463] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody.

[0464] In some embodiments, cell-based therapies are cancer vaccines.

[0465] In some embodiments, the cancer vaccine is selected from antitumor vaccines or neoantigen-based vaccines.

[0466] Cell-based therapies typically involve removing immune cells from the blood or tumor of a cancer-affected subject. Tumor-specific immune cells are activated, proliferate, and then returned to the cancer-affected subject, where they provide an immune response against the cancer.

[0467] In some embodiments, the immune cells are selected from natural killer cells, lymphokine-activated killer cells, cytotoxic T cells, and dendritic cells.

[0468] In some embodiments, cancer vaccines are based on natural killer cells.

[0469] In some embodiments, cancer vaccines are based on lymphokine-activated killer cells.

[0470] In some embodiments, cancer vaccines are based on cytotoxic T cells.

[0471] In some embodiments, cancer vaccines are based on dendritic cells.

[0472] In some embodiments, cell-based therapies are 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.

[0473] In some embodiments, cytokine therapy is interleukin-2 therapy.

[0474] In some embodiments, the cytokine therapy is interferon-alpha therapy.

[0475] Each composition may be prepared according to a conventional mixing, granulation, or coating method, and the pharmaceutical compositions of the present invention may contain, by weight or volume, about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the disclosed compounds.

[0476] Dosage regimens utilizing the disclosed compounds are selected according to various factors, including the patient's type, breed, age, weight, sex, and medical condition; the severity of the condition being treated; the route of administration; the patient's renal or hepatic function; and the specific disclosed compound to be employed. A physician or veterinarian skilled in the art can easily determine and prescribe the effective dose of the drug necessary for the prevention, treatment, or cessation of the progression of the condition.

[0477] The effective dose of the disclosed compound, when used for the indicated effect, ranges from about 0.5 mg to about 5000 mg of the disclosed compound necessary to treat the symptoms. Compositions for in vivo or in vitro use may contain the disclosed compound in amounts ranging from about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg, or from one amount to another on the dose list. In one embodiment, the composition is in the form of a scoreable tablet. [Examples]

[0478] This disclosure is further illustrated by the following examples and synthesis schemes, which are not intended to limit the scope or spirit of this disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate specific embodiments and are not intended to limit the scope of this disclosure. Furthermore, it should be understood that various other embodiments, modifications, and equivalents may be suggested to those skilled in the art without departing from the spirit of this disclosure and / or the appended claims.

[0479] JPEG0007883791000183.jpg200155

[0480] The purity and identification of all synthesized compounds were confirmed by LC-MS analysis performed on a Shimadzu Analytical 10Avp with a PE SCIEX API 165 mass, Sedex 75 ELSD, and Shimadzu UV (254 and 215) detector. Separation was performed on a C18 column, 100 x 4.6 mm, 5.0 μm, pore size 100 Å, water-acetonitrile + 0.1 TFA, gradient 5–87, 10 minutes.

[0481] Preparative HPLC purification was performed using a Shimadz instrument equipped with an SPD-10Avp detector and an FRC-10A fraction collector. Separation was performed using a YMC-Pack ODS-AQ column, 250×20 mmol, S-10 μm, 12 nm, with a gradient solution A-solution B (A: 1000 mL H2O - 226 μL TFA; B: 1000 mL CH3CN - 226 μL TFA).

[0482] Table 1 shows examples of compounds of formula (I) synthesized within the framework of the present invention, the results of MS analysis, and the ID number of each compound for further reference.

[0483] JPEG0007883791000184.jpg213170JPEG0007883791000185.jpg252170JPEG0007883791000186.jpg219170JPEG0007883791000187.jpg216170JPEG0007883791000188.jpg248170JPEG0007883791000189.jpg234170JPEG0007883791000190.jpg216170JPEG0007883791000191.jpg255170JPEG0007883791000192.jpg234170JPEG0007883791000193.jpg255170JPEG0007883791000194.jpg222170JPEG0007883791000195.jpg252170JPEG0007883791000196.jpg243170JPEG0007883791000197.jpg245170JPEG0007883791000198.jpg210170JPEG0007883791000199.jpg252170JPEG0007883791000200.jpg245170JPEG0007883791000201.jpg252170JPEG0007883791000202.jpg234170JPEG0007883791000203.jpg251170JPEG0007883791000204.jpg234170JPEG0007883791000205.jpg234170JPEG0007883791000206.jpg252170JPEG0007883791000207.jpg243170JPEG0007883791000208.jpg251170JPEG0007883791000209.jpg234170JPEG0007883791000210.jpg216170JPEG0007883791000211.jpg248170JPEG0007883791000212.jpg234170JPEG0007883791000213.jpg216170JPEG0007883791000214.jpg216170JPEG0007883791000215.jpg216170JPEG0007883791000216.jpg252170JPEG0007883791000217.jpg216170JPEG0007883791000218.jpg248170JPEG0007883791000219.jpg216170JPEG0007883791000220.jpg234170JPEG0007883791000221.jpg216170JPEG0007883791000222.jpg245170JPEG0007883791000223.jpg243170JPEG0007883791000224.jpg251170JPEG0007883791000225.jpg251170JPEG0007883791000226.jpg251170JPEG0007883791000227.jpg234170JPEG0007883791000228.jpg243170JPEG0007883791000229.jpg210170JPEG0007883791000230.jpg251170JPEG0007883791000231.jpg234170JPEG0007883791000232.jpg243170JPEG0007883791000233.jpg225170JPEG0007883791000234.jpg216170JPEG0007883791000235.jpg216170JPEG0007883791000236.jpg225170JPEG0007883791000237.jpg234170JPEG0007883791000238.jpg225170JPEG0007883791000239.jpg243170JPEG0007883791000240.jpg243170JPEG0007883791000241.jpg216170JPEG0007883791000242.jpg210170JPEG0007883791000243.jpg216170JPEG0007883791000244.jpg234170JPEG0007883791000245.jpg243170JPEG0007883791000246.jpg255170JPEG0007883791000247.jpg243170JPEG0007883791000248.jpg252170JPEG0007883791000249.jpg234170JPEG0007883791000250.jpg243170JPEG0007883791000251.jpg251170JPEG0007883791000252.jpg251170JPEG0007883791000253.jpg225170JPEG0007883791000254.jpg252170JPEG0007883791000255.jpg255170JPEG0007883791000256.jpg252170JPEG0007883791000257.jpg234170JPEG0007883791000258.jpg227170JPEG0007883791000259.jpg227170JPEG0007883791000260.jpg243170JPEG0007883791000261.jpg251170JPEG0007883791000262.jpg243170JPEG0007883791000263.jpg251170JPEG0007883791000264.jpg251170JPEG0007883791000265.jpg234170JPEG0007883791000266.jpg243170JPEG0007883791000267.jpg234170JPEG0007883791000268.jpg234170JPEG0007883791000269.jpg243170JPEG0007883791000270.jpg216170JPEG0007883791000271.jpg234170JPEG0007883791000272.jpg234170JPEG0007883791000273.jpg251170JPEG0007883791000274.jpg251170JPEG0007883791000275.jpg225170JPEG0007883791000276.jpg225170JPEG0007883791000277.jpg251170JPEG0007883791000278.jpg251170JPEG0007883791000279.jpg225170JPEG0007883791000280.jpg243170JPEG0007883791000281.jpg243170JPEG0007883791000282.jpg245170JPEG0007883791000283.jpg252170JPEG0007883791000284.jpg216170JPEG0007883791000285.jpg251170JPEG0007883791000286.jpg216170JPEG0007883791000287.jpg225170JPEG0007883791000288.jpg243170JPEG0007883791000289.jpg251170JPEG0007883791000290.jpg225170JPEG0007883791000291.jpg251170JPEG0007883791000292.jpg251170JPEG0007883791000293.jpg243170JPEG0007883791000294.jpg243170JPEG0007883791000295.jpg243170JPEG0007883791000296.jpg251170JPEG0007883791000297.jpg234170JPEG0007883791000298.jpg234170JPEG0007883791000299.jpg243170JPEG0007883791000300.jpg243170JPEG0007883791000301.jpg234170JPEG0007883791000302.jpg216170JPEG0007883791000303.jpg251170JPEG0007883791000304.jpg234170JPEG0007883791000305.jpg251170JPEG0007883791000306.jpg251170JPEG0007883791000307.jpg243170JPEG0007883791000308.jpg243170JPEG0007883791000309.jpg255170JPEG0007883791000310.jpg252170JPEG0007883791000311.jpg255170JPEG0007883791000312.jpg255170JPEG0007883791000313.jpg225170JPEG0007883791000314.jpg251170JPEG0007883791000315.jpg245170JPEG0007883791000316.jpg225170JPEG0007883791000317.jpg216170JPEG0007883791000318.jpg243170J PEG0007883791000319.jpg216170JPEG0007883791000320.jpg255170JPEG0007883791000321.jpg255170JPEG0007883 791000322.jpg225170JPEG0007883791000323.jpg216170JPEG0007883791000324.jpg216170JPEG0007883791000325. jpg251170JPEG0007883791000326.jpg251170JPEG0007883791000327.jpg216170JPEG0007883791000328.jpg210170.

[0484] Examples of general synthesis procedures and compound preparation.

[0485] Preparation of monoliths.

[0486] Preparation 1: Ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate [ka] A mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (5.50 g, 24.9 mmol), (S)-2-amino-2-phenylethane-1-ol (3.75 g, 27.3 mmol), and DIPEA (3.52 g, 27.3 mmol) in MeCN (70 mL) was stirred at ambient temperature for 3 hours and concentrated under reduced pressure. The residue was subjected to silica CC elution with a mixed solvent of siRNA and n-hexane (1:2) to obtain the title compound (6.25 g, 78%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.06 (d, J=8.2 Hz, 1H), 8.65 (s, 1H), 7.36-7.24 (m, 5H), 5.25-5.18 (m, 2H), 4.35 (q, J=7.0 Hz, 2H), 3.82-3.70 (m, 2H), 1.34 (t, J=7.0 Hz, 3H).

[0487] Preparation 2: Ethyl 2-chloro-4-{[(1R)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate [ka] The compound was synthesized according to the procedure described in Preparation 1, using (2R)-2-amino-2-phenylethanol instead of (S)-2-amino-2-phenylethane-1-ol. The product was analyzed by LC-MS: [MH] + 324, 322, 323.

[0488] Preparation 3: Ethyl 2-chloro-4-{[(1R)-1-phenylethyl]amino}pyrimidine-5-carboxylate [ka] To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate P3.1 (100 mg, 0.452 mmol) in MeCN (5 mL), (R)-1-phenyl-ethylamine (60 mg, 0.497 mmol) and DIPEA (64 mg, 0.497 mmol) were added at room temperature. After stirring the reaction for 3 hours, the mixture was concentrated to obtain the residue. The residue was purified by silica gel column chromatography (Â:n-hexane = 1:2) to obtain P3 (54 mg, yield 39%). The product was analyzed by LC-MS.

[0489] Preparation 4: Ethyl 2-chloro-4-{[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]aminopyrimidine-5-carboxylate [ka] To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate P4.1 (100 mg, 0.452 mmol) in MeCN (5 mL), (1S,2R)-1-amino-2-indanol (74 mg, 0.497 mmol) and DIPEA (64 mg, 0.497 mmol) were added at room temperature. After stirring the reaction for 3 hours, the mixture was concentrated to obtain the residue. The residue was purified by silica gel column chromatography (siRNA:n-hexane = 1:2) to obtain P4 (112 mg, yield 51%). The product was analyzed by LC-MS.

[0490] Preparation 5: Ethyl 2-chloro-4-{[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]aminopyrimidine-5-carboxylate [ka] The compound was synthesized according to the procedure described in Preparation 1, using (1S,2S)-1-amino-2,3-dihydro-1H-inden-2-ol instead of (S)-2-amino-2-phenylethane-1-ol. The product was analyzed by LC-MS.

[0491] Preparation 6: Ethyl 2-chloro-4-{[(1S)-1-cyclohexyl-2-hydroxyethyl]amino}pyrimidine-5-carboxylate [ka] The compound was synthesized according to the procedure described in Preparation 1, using (2S)-2-amino-2-cyclohexylethanol instead of (S)-2-amino-2-phenylethane-1-ol. The product was analyzed by LC-MS.

[0492] Preparation 7: Ethyl 4-{[(1S)-1-benzyl-2-hydroxyethyl]amino}-2-chloropyrimidine-5-carboxylate [ka] The compound was synthesized according to the procedure described in Preparation 1, using (2S)-2-amino-3-phenylpropane-1-ol instead of (S)-2-amino-2-phenylethane-1-ol. The product was analyzed by LC-MS.

[0493] Preparation 8: Ethyl 2-chloro-4-{[(1S)-1-(4-cyclophenyl)-2-hydroxyethyl]-aminopyrimidine-5-carboxylate [ka] The compound was synthesized according to the procedure described in Preparation 1, using (2S)-2-amino-2-(4-chlorophenyl)ethanol instead of (S)-2-amino-2-phenylethane-1-ol. The product was analyzed by LC-MS.

[0494] Preparation 9: Ethyl 2-chloro-4-[(2-fluoro-1-phenylethyl)amino]pyrimidine-5-carboxylate [ka] The compound was synthesized using 2-fluoro-1-phenylethaneamine instead of (S)-2-amino-2-phenylethane-1-ol, following the procedure described in Preparation 1. The product was analyzed by LC-MS.

[0495] Preparation 10: Ethyl 2-chloro-4-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]aminopyrimidine-5-carboxylate [ka] The compound was synthesized according to the procedure described in Preparation 1, using (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol instead of (S)-2-amino-2-phenylethane-1-ol. The product was analyzed by LC-MS.

[0496] Preparation 11: Ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-(pyridine-3-ylmethyl)ethyl]amino}pyrimidine-5-carboxylate [ka] The compound was synthesized using (2S)-2-amino-3-pyridine-3-ylpropane-1-ol instead of (S)-2-amino-2-phenylethane-1-ol, following the procedure described in Preparation 1. The product was analyzed by LC-MS.

[0497] Preparation 12: Ethyl 2-chloro-4-[3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-yl]pyrimidine-5-carboxylate [ka] To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (100 mg, 0.452 mmol) in MeCN (5 mL), 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (81 mg, 0.497 mmol) and DIPEA (64 mg, 0.497 mmol) were added at room temperature. After stirring the reaction for 3 hours, the mixture was concentrated to obtain the residue. The residue was purified by silica gel column chromatography (Â:n-hexane = 1:2) to obtain 2 (50 mg, 32% yield). The product was analyzed only by LC-MS.

[0498] Preparation 13: Ethyl 2-chloro-4-[(2S)-2-(hydroxymethyl)-2,3-dihydro-1H-indole-1-yl]pyrimidine-5-carboxylate [ka] The compound was synthesized using (2S)-2,3-dihydro-1H-indole-2-ylmethanol instead of (S)-2-amino-2-phenylethane-1-ol, following the procedure described in Preparation 1. The product was analyzed by LC-MS.

[0499] Preparation 14: Ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-(1H-indole-3-ylmethyl)ethyl]aminopyrimidine-5-carboxylate [ka] The compound was synthesized according to the procedure described in Preparation 1, using (2S)-2-amino-3-(1H-indole-3-yl)propan-1-ol instead of (S)-2-amino-2-phenylethane-1-ol. The product was analyzed by LC-MS.

[0500] Preparation 15: (2S)-2-[(2-chloro-5-nitropyrimidine-4-yl)amino]-2-phenyl-ethanol [ka] To a solution of 5-nitro-2,4-dichloropyrimidine (P15.1, 1.0 g, 5.15 mmol) in MeCN (10 mL), (S)-2-amino-2-phenylethane-1-ol (0.77 g, 5.67 mmol) and DIPEA (0.73 g, 5.67 mmol) were added at room temperature. After stirring the reaction for 3 hours, the mixture was concentrated to obtain the residue. The residue was purified by silica gel column chromatography (DCM:Et2O=4:1) to obtain P15 (1.1 g, yield 73%). 1 H NMR (400 MHz, DMSO-d6): δ 9.15 (d, J=7.8 Hz, 1H), 9.05 (s, 1H), 7.43-7.41 (m, 2H), 7.34 (t, J=7.8 Hz, 2H), 7.29-7.25 (m, 1H), 5.38-5.33 (m, 1H), 5.29-5.16 (m, 1H), 3.88-3.80 (m, 4H).

[0501] Preparation of esters by substitution of a second chlorine atom.

[0502] Preparation 16: Ethyl 4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-{[3-methyl-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate [ka] A mixture of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]aminopyrimidine-5-carboxylate (see Preparation 1) (0.70 g, 2.17 mmol), 4-sulfonylmethyl-3-methylaniline (0.44 g, 2.39 mmol), dioxane (3 mL), and p-TsOH hydrate (0.45 g, 2.39 mmol) was heated at 110°C for 30 minutes under microwave irradiation, diluted with SiO2 (10 mL), washed with 10% aqueous NaHCO3 solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to silica CC elution with a mixture of SiO2 and n-hexane (1:1) to obtain 0.78 g (76%) of the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.12 (s, 1H), 9.01 (d, J = 8.2 Hz, 1H), 8.64 (s, 1H), 7.72-7.64 (m, 2H), 7.38-7.21 (m, 5H), 5.23-5.19 (m, 2H), 4.33 (q, J = 7.0 Hz, 2H), 3.88-3.68 (m, 2H), 3.14(s, 3H), 2.54 (s, 3H), 1.34 (t, J=7.0 Hz, 3H).

[0503] Preparation 17: Ethyl 4-{[(1R)-2-hydroxy-1-phenylethyl]amino}-2-{[3-methyl-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate (Compound 169). The compound was synthesized according to the procedure described in Preparation 16, using ethyl 2-chloro-4-{[(1R)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate instead of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (see Preparation 2). The product was analyzed by LC-MS.

[0504] Preparation 18: Ethyl 2-{[3-methyl-4-(methylsulfonyl)phenyl]amino}-4-{[(1R)-1-phenylethyl]amino}pyrimidine-5-carboxylate (Compound 64). The compound was synthesized according to the procedure described in Preparation 16, using ethyl 2-chloro-4-{[(1R)-1-phenylethyl]amino}pyrimidine-5-carboxylate instead of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (see Preparation 3). The product was analyzed by LC-MS.

[0505] Preparation 19: Ethyl 4-{[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-2-{[3-methyl-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate (Compound 260). The compound was synthesized according to the procedure described in Preparation 16, using (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol instead of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (see Preparation 4). The product was analyzed by LC-MS.

[0506] Preparation 20: Ethyl 4-{[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-2-{[3-methyl-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate (Compound 261). The compound was synthesized according to the procedure described in Preparation 16, using (1S,2S)-1-amino-2,3-dihydro-1H-inden-2-ol instead of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (see Preparation 5). The product was analyzed by LC-MS.

[0507] Preparation 21: Ethyl 4-{[(1S)-1-cyclohexyl-2-hydroxyethyl]amino}-2-{[3-methyl-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate (Compound 222). The compound was synthesized according to the procedure described in Preparation 16, using (2S)-2-amino-2-cyclohexylethanol instead of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (see Preparation 6). The product was analyzed by LC-MS.

[0508] Preparation 22: Ethyl 4-{[(1S)-1-benzyl-2-hydroxyethyl]amino}-2-{[3-methyl-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate (Compound 273). The compound was synthesized according to the procedure described in Preparation 16, using ethyl 4-{[(1S)-1-benzyl-2-hydroxyethyl]amino}-2-chloropyrimidine-5-carboxylate instead of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (see Preparation 7). The product was analyzed by LC-MS.

[0509] Preparation 23: Ethyl 4-{[(1S)-1-(4-cyclophenyl)-2-hydroxyethyl]amino}-2-{[3-methyl-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate (Compound 403). The compound was synthesized according to the procedure described in Preparation 16, using ethyl 2-chloro-4-{[(1S)-1-(4-chlorophenyl)-2-hydroxyethyl]amino}pyrimidine-5-carboxylate instead of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (see Preparation 8). The product was analyzed by LC-MS.

[0510] Preparation 24: Ethyl 4-[(2-fluoro-1-phenylethyl)amino]-2-{[3-methyl-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate (Compound 194). The compound was synthesized according to the procedure described in Preparation 16, using ethyl 2-chloro-4-[(2-fluoro-1-phenylethyl)amino]pyrimidine-5-carboxylate instead of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (see Preparation 9). The product was analyzed by LC-MS.

[0511] Preparation 25: Ethyl 4-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-2-{[3-methyl-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate (Compound 262). The compound was synthesized according to the procedure described in Preparation 16, using ethyl 2-chloro-4-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidine-5-carboxylate instead of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (see Preparation 10). The product was analyzed by LC-MS.

[0512] Preparation 26: Ethyl 4-{[(1S)-2-hydroxy-1-(pyridine-3-ylmethyl)ethyl]amino}-2-{[3-methyl-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate (Compound 281). The compound was synthesized according to the procedure described in Preparation 16, using ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-(pyridine-3-ylmethyl)ethyl]amino}pyrimidine-5-carboxylate instead of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-(pyridine-3-ylmethyl)ethyl]amino}pyrimidine-5-carboxylate (see Preparation 11). The product was analyzed by LC-MS.

[0513] Preparation 27: Ethyl 4-[(2S)-2-(hydroxymethyl)-2,3-dihydro-1H-indole-1-yl]-2-{[3-methyl-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate (Compound 263). The compound was synthesized according to the procedure described in Preparation 16, using ethyl 2-chloro-4-[(2S)-2-(hydroxymethyl)-2,3-dihydro-1H-indole-1-yl]pyrimidine-5-carboxylate instead of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (see Preparation 13). The product was analyzed by LC-MS.

[0514] Preparation 28: Ethyl 4-{[(1S)-2-hydroxy-1-(1H-indole-3-ylmethyl)ethyl]amino}-2-{[3-methyl-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate (Compound 491). The compound was synthesized according to the procedure described in Preparation 16, using ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-(1H-indole-3-ylmethyl)ethyl]amino}pyrimidine-5-carboxylate instead of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (see Preparation 14). The product was analyzed by LC-MS.

[0515] Preparation 29: Ethyl 2-{[3-fluoro-4-(methylsulfonyl)phenyl]amino}-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (Compound 210) [ka] To a solution of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]aminopyrimidine-5-carboxylate (Preparation 1; 1.0 g, 0.0031 mol) in dioxane (20 ml), 3-fluoro-4-(methylsulfonyl)aniline (0.59 g, 0.0031 mol) and TsOH (0.59 g, 0.0031 mmol) were added. The reaction mixture was stirred at 100°C for 30 minutes under microwave irradiation, cooled to room temperature, and concentrated under vacuum. The residue was dissolved in ELISA (20 ml), washed with aqueous NaHCO3 (5%), and dried over sodium sulfate. The organic layer was evaporated under vacuum, and the crude product was purified by column chromatography (elution with DCM / Et2O) to obtain compound 210 as a solid. The yield was 1.4 g, 95%. 1 H-NMR (400 MHz, dmso-d6) δ: 10.38 (br s, 1H), 9.08 (d, J = 7.2 Hz, 1H), 8.67 (s, 1H), 7.83-7.74 (m, 1H), 7.65 (t, J = 8.2 Hz, 1H), 7.49 (d, J = 9.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 7.33 (t, J = 6.1 Hz, 1H), 5.27-5.17 (m, 2H), 4.32 (q, J = 7.6 Hz, 2H), 3.91-3.80 (m, 1H), 3.76-3.66 (m, 1H), 3.26 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).

[0516] Preparation 30: Ethyl 2-{[3-fluoro-4-(methylsulfonyl)phenyl]amino}-4-{[(1R)-1-phenylethyl]amino}pyrimidine-5-carboxylate-compound 97 [ka] To a solution of P3 (54 mg, 0.177 mmol) and 4-sulfonylmethyl-3-fluoroaniline (34 mg, 0.177 mmol) in dioxane (3 ml) in a vial, TsOH-H2O (34 mg, 0.177 mmol) was added. The tube was capped and irradiated at 110°C for 30 minutes. The reaction mixture was diluted with HCl (10 ml), washed with 10% NaHCO3 solution and brine, dried under Na2SO4, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (HCl:n-hexane = 1:1) to obtain compound 97 (29 mg, yield 36%). 1 H NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 8.68-8.67 (m, 2H), 7.86 (d, J=13.8 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.55 (dd, J1=8.9 Hz, J2=1.5 Hz, 1H), 7.42-7.40 (m, 2H), 7.36 (t, J=8.0 Hz, 2H), 7.26-7.23 (m, 1H), 5.35-5.28 (m, 1H), 4.30 (q, J=7.0 Hz, 2H), 3.25 (s, 3H), 1.57 (d, J=7.0 Hz, 3H), 1.32 (t, J=7.0 Hz, 3H).

[0517] Preparation 31: Ethyl 4-{[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-2-{[3-fluoro-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate-compound 298 [ka] To a solution of P4 (112 mg, 0.335 mmol) and 4-sulfonylmethyl-3-fluoroaniline (64 mg, 0.335 mmol) in dioxane (3 ml) in a vial, TsOH-H2O (64 mg, 0.335 mmol) was added. The vial was capped and irradiated at 110°C for 30 minutes. The reaction mixture was diluted with HCl (10 ml), washed with 10% NaHCO3 solution and brine, dried under Na2SO4, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (HCl:n-hexane = 1:1) to obtain compound 298 (75 mg, yield 46%). 1 H NMR (400 MHz, DMSO-d6): δ 10.48 (s, 1H), 8.98 (d, J=8.0 Hz, 1H), 8.72 (s, 1H), 8.03 (d, J=13.6 Hz, 1H), 7.71-7.63 (m, 2H), 7.31-7.30 (m, 1H), 7.25-7.21 (m, 2H), 7.16 (d, J=7.0 Hz, 1H), 5.65-5.62 (m, 1H), 4.61 (t, J=4.8 Hz, 1H), 4.26 (q, J=7.0 Hz, 2H), 3.83-3.80 (m, 1H), 3.22-3.16 (m, 4H), 2.90 (d, J=16.4 Hz, 1H), 1.30 (t, J=7.0 Hz, 3H).

[0518] Preparation 32: Ethyl 4-{[(1S)-1-benzyl-2-hydroxyethyl]amino}-2-{[3-fluoro-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate [ka] The compounds were synthesized according to the procedure described in Preparation 16, using ethyl 4-{[(1S)-1-benzyl-2-hydroxyethyl]amino}chloropyrimidine-5-carboxylate (see Preparation 7) instead of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate and 3-fluoro-4-(methylsulfonyl)aniline instead of 3-methyl-4-(methylsulfonyl)aniline. LCMS: [MH + 489.

[0519] Preparation 33: Ethyl 4-[(2-fluoro-1-phenylethyl)amino]-2-{[3-fluoro-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate [ka] The compounds were synthesized according to the procedure described in Preparation 16, using ethyl 2-chloro-4-[(2-fluoro-1-phenylethyl)amino]pyrimidine-5-carboxylate instead of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (see Preparation 9) and 3-fluoro-4-(methylsulfonyl)aniline instead of 3-methyl-4-(methylsulfonyl)aniline. LCMS: [MH + 477.

[0520] Preparation 34: Ethyl 4-{[(1S)-2-hydroxy-1-(pyridine-3-ylmethyl)ethyl]amino}-2-{[3-fluoro-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate [ka] The compounds were synthesized according to the procedure described in Preparation 16, using ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-(pyridine-3-ylmethyl)ethyl]amino}pyrimidine-5-carboxylate instead of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-(pyridine-3-ylmethyl)ethyl]amino}pyrimidine-5-carboxylate (see Preparation 11) and 3-fluoro-4-(methylsulfonyl)aniline instead of 3-methyl-4-(methylsulfonyl)aniline. LCMS: [MH + 490.

[0521] Preparation 35: Ethyl 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-yl]pyrimidine-5-carboxylate-compound 388 [ka] To a solution of P12 (50 mg, 0.144 mmol) and 4-sulfonylmethyl-3-fluoroaniline (27 mg, 0.144 mmol) in dioxane (3 ml) in a vial, TsOH-H2O (27 mg, 0.144 mmol) was added. The vial was capped and irradiated at 110°C for 30 minutes. The reaction mixture was diluted with HCl (10 ml), washed with 10% NaHCO3 solution and brine, dried under Na2SO4, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (HCl:n-hexane = 1:1) to obtain compound 388 (12 mg, yield 17%). 1H NMR (400 MHz, DMSO-d6): δ 10.83 (s, 1H), 8.87 (s, 1H), 7.96 (d, J=13.1 Hz, 1H), 7.83 (t, J=8.4 Hz, 1H), 7.73 (dd, J1=8.7 Hz, J2=1.6 Hz, 1H), 7.32-7.28 (m, 4H), 4.88-4.84 (m, 1H), 4.73-4.68 (m, 1H), 4.47-4.38 (m, 2H), 4.25 (q, J=7.0 Hz, 2H), 4.12-4.08 (m, 1H), 3.25 (m, 1H), 3.28 (s, 3H), 3.21-3.19 (m, 2H), 1.28 (t, J=7.0 Hz, 3H).

[0522] Preparation 36: Ethyl 4-[(2S)-2-(hydroxymethyl)-2,3-dihydro-1H-indole-1-yl]-2-{[3-fluoro-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate [ka] The compounds were synthesized according to the procedure described in Preparation 16, using ethyl 2-chloro-4-[(2S)-2-(hydroxymethyl)-2,3-dihydro-1H-indole-1-yl]pyrimidine-5-carboxylate instead of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (see Preparation 13) and 3-fluoro-4-(methylsulfonyl)aniline instead of 3-methyl-4-(methylsulfonyl)aniline. LCMS: [MH + 487.

[0523] Preparation 37: Ethyl 4-{[(1S)-2-hydroxy-1-(1H-indole-3-ylmethyl)ethyl]amino}-2-{[3-fluoro-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate [ka] The compounds were synthesized according to the procedure described in Preparation 16, using ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-(1H-indole-3-ylmethyl)ethyl]amino}pyrimidine-5 carboxylate instead of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-(1H-indole-3-ylmethyl)ethyl]amino}pyrimidine-5 carboxylate (see Preparation 14) and 3-fluoro-4-(methylsulfonyl)aniline instead of 3-methyl-4-(methylsulfonyl)aniline. LCMS: [MH + 528.

[0524] Preparation 38: Ethyl 4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-[(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)amino]pyrimidine-5-carboxylate (compound 45) [ka]

[0525] Synthesis of P38.2. To a solution of compound P38.1 (1.50 g, 6.63 mmol) in DMF (50 ml), 60% NaH (0.290 g, 7.30 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then SEMCl (1.21 g) was added, followed by SEMCl (1.21 g, 7.30 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was poured into water (200 ml), extracted with Et2O (2 × 30 ml), the organic layer was washed with water, dried under Na2SO4, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (DCM:Et2O = 10:1) to obtain P38.2 (0.710 g, yield 30%). 1 H NMR (400 MHz, DMSO-d6): δ 7.97 (d, J=8.2 Hz, 1H), 7.59-7.55 (m, 2H), 4.89 (s, 2H), 3.46 (t, J=6.4 Hz, 2H), 3.50 (t, J=7.9 Hz, 2H), 2.98 (t, J=6.4 Hz, 2H), 0.87 (t, J=7.8 Hz, 2H), 0.00 (s, 9H).

[0526] Synthesis of P38.3. A mixture of P38.2 (0.710 g, 1.99 mmol) and 1,1-diphenylmethanymine (0.360 g, 2.00 mmol) in dioxane (20 ml) was mixed with NaOtBu (0.380 g, 4.00 mmol), and the solution was passed through an argon stream. Pd2(dba)3 (91.5 mg, 0.100 mmol) and BINAP (124.0 mg, 0.200 mmol) were added, and the mixture was refluxed under argon for 16 hours. The mixture was then diluted with water (20 ml) and SiO2 (100 ml), the organic layer was separated, and the aqueous layer was extracted with SiO2 (50 ml). The combined organic layers were washed with water, dried under Na2SO4, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (DCM:Et2O=10:1) to obtain P38.3 (0.34g, yield 34%) and P38.4 (0.290g, yield 46%). 1 H NMR (400 MHz, DMSO-d6): δ 7.66-7.62 (m, 3H), 7.57-7.53 (m, 1H), 7.50-7.45 (m, 2H), 7.34-7.32 (m, 3H), 7.18-7.16 (m, 2H), 6.66-6.65 (m, 1H), 6.61 (dd, J1=8.3 Hz, J2=2.6 Hz, 1H), 4.84 (s, 2H), 3.49-3.45 (m, 4H), 2.81 (t, J=6.4 Hz, 2H), 0.85 (t, J=7.9 Hz, 2H), 0.00 (s, 9H).

[0527] Synthesis of P38.4. Compound P38.3 (0.310 g, 0.200 mmol) and hydroxylamine hydrochloride (0.100 g, 1.40 mmol) were dissolved in MeOH (5 ml), to which NaOAc (0.172 g, 2.0 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was then diluted with 1% NaOH solution and extracted with DCM (2 × 10 ml). The combined organic layer was washed with water, dried under Na2SO4, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (DCM:siRNA = 2:1) to obtain P38.4 (0.120 g, yield 60%). 1 H NMR (400 MHz, DMSO-d6): δ 7.56 (d, J=8.4 Hz, 1H), 6.45 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 6.32 (d, J=1.8 Hz, 1H), 5.74 (br, 2H), 4.83 (s, 2H), 3.49-3.44 (m, 4H), 2.77 (t, J=6.6 Hz, 2H), 0.86 (t, J=7.9 Hz, 2H), 0.00 (s, 9H).

[0528] Synthesis of P38.5. A mixture of compound P38.4 (0.400 g, 1.37 mmol) and ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]aminopyrimidine-5-carboxylate (0.440 g, 1.37 mmol, Preparation 1) in dioxane (10 ml) in a vial was mixed with Cs2CO3 (0.890 g, 2.74 mmol), and an argon stream was passed through the solution. Pd(OAc)2 (31 mg, 0.14 mmol) and BINAP (169 mg, 0.28 mmol) were added, the vial was capped, and the mixture was irradiated at 100°C for 1 hour. The mixture was then diluted with water (20 ml) and SiO2 (10 ml), the organic layer was separated, and the aqueous layer was extracted with SiO2 (10 ml). The combined organic layers were washed with water, dried under Na2SO4, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (DCM:Â=2:1) ​​to obtain P38.5 (0.550 g, 70% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 8.99 (d, J=7.5 Hz, 1H), 8.63 (s, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.54-7.52 (m, 2H), 7.37-7.31 (m, 4H), 7.24-7.20 (m, 1H), 5.29-5.24 (m, 1H), 5.15 (t, J=4.8 Hz, 1H), 4.88 (s, 2H), 4.31 (q, J=6.7 Hz, 2H), 3.87-3.82 (m, 1H), 3.75-3.72 (m, 1H), 3.56-3.49 (m, 4H), 2.94-2.84 (m, 2H), 1.34 (t, J=7.1 Hz, 3H), 0.88 (t, J=7.5 Hz, 2H), 0.00 (s, 9H).

[0529] Synthesis of compound 45. To a solution of compound P38.5 (100 mg, 0.17 mmol) in DCM (1 ml), TFA (0.2 ml) was added, and the mixture was stirred at room temperature for 16 hours. The solution was then diluted with 10% NaHCO3 solution, the organic layer was separated, washed with water, dried under Na2SO4, and concentrated to obtain the residue. The residue was purified by HPLC to obtain compound 45 (5 mg, yield 6%). 1 H NMR (400 MHz, DMSO-d6): δ 9.96 (s, 1H), 9.00 (d, J=7.5 Hz, 1H), 8.62 (s, 1H), 7.70-7.62 (m, 2H), 7.52-7.50 (m, 2H), 7.37-7.31 (m, 4H), 7.24-7.21 (m, 1H), 5.29-5.24 (m, 1H), 5.15 (t, J=4.9 Hz, 1H), 4.30 (q, J=7.0 Hz, 2H), 3.86-3.70 (m, 2H), 2.88-2.76 (m, 2H), 1.97-1.64 (m, 2H), 1.33 (t, J=7.0 Hz, 3H).

[0530] Preparation 39: Ethyl 2-[(6-fluorobiphenyl-3-yl)amino]-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (compound 195) [ka]

[0531] Synthesis of P39.2. A mixture of 2-fluoro-5-nitro-bromobenzene P39.1 (2.00 g, 9.09 mmol) and boronic acid (1.66 g, 13.60 mmol) in dioxane (20 ml) was mixed with a solution of K2CO3 (2.50 g, 18.18 mmol) in water (5 ml), and the solution was passed through with an argon stream. Tetrakis (0.50 g, 0.45 mmol) was added, and the mixture was refluxed under argon for 48 hours. The mixture was then diluted with water (20 ml) and HCl (100 ml), the organic layer was separated, and the aqueous layer was extracted with HCl (50 ml). The combined organic layers were washed with water and brine, dried under Na2SO4, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (HCl:n-hexane = 1:10) to obtain P39.2 (1.57 g, yield 77%) as a pale orange solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.35-8.29 (m, 2H), 7.66-7.61 (m, 3H), 7.56-7.47 (m, 3H).

[0532] Synthesis of P39.3. To a solution of P39.2 (1.52 g, 7.00 mmol) in EtOH (20 ml) in an autoclave, 10% Pd / C (0.15 g) was added, and the mixture was stirred at room temperature under H2 (5 bar) for 16 hours. The mixture was then filtered through a Celite pad, and the filtrate was concentrated to obtain P39.3 (1.05 g, yield 80%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.46-7.34 (m, 5H), 6.97-6.91 (m, 1H), 6.66-6.63 (m, 1H), 6.56-6.53 (m, 1H), 5.02 (br., 2H).

[0533] Synthesis of compound 195. TsOH·H2O (0.413 g, 2.175 mmol) was added to a solution of P39.3 (0.406 g, 2.175 mmol) and chloropyrimidine (0.700 g, 2.175 mmol) in dioxane (3 ml) in a vial. The vial was capped and irradiated at 110°C for 30 minutes. The reaction mixture was diluted with HCl (10 ml), washed with 10% NaHCO3 solution and brine, dried under Na2SO4, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (HCl:n-hexane = 1:1) to obtain compound 195 (0.720 g, yield 71%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.84 (br., 1H), 8.97-8.95 (m, 1H), 8.60 (s, 1H), 7.80-7.78 (m, 1H), 7.57-7.43 (m, 6H), 7.25-7.12 (m, 6H), 5.19-5.13 (m, 2H), 4.29 (q, J=7.0 Hz, 2H), 3.80-3.77 (m, 1H), 3.64-3.60 (m, 1H), 1.33 (t, J=7.0 Hz, 3H).

[0534] Preparation 40: Ethyl 2-{[3-chloro-4-(trifluoromethyl)phenyl]amino}-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (compound 248) [ka] The compound was synthesized using 3-chloro-4-(trifluoromethyl)aniline instead of 4-sulfonylmethyl-3-methylaniline, following the procedure described in Preparation 16. 1H NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 9.06 (d, J=7.30 Hz, 1H), 8.66 (s, 1H), 7.99 (s, 1H), 7.70-7.62 (m, 2H), 7.40-7.20 (m, 5H), 5.25-5.22 (m, 2H), 4.31 (q, J=7.2 Hz, 2H), 3.88-3.69 (m, 2H), 1.34 (t, J=7.2 Hz, 3H).

[0535] Preparation 41: Ethyl 4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-[(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)amino]pyrimidine-5-carboxylate (compound 122) [ka]

[0536] Synthesis of P41.2. A mixture of 6-bromo-3,4-dihydroisoquinoline-1(2H)-one P41.1 (1.00 g, 4.42 mmol) in DMF (20 ml) was mixed with 60% NaH (0.230 g, 5.75 mmol), and the mixture was stirred at room temperature for 30 minutes. Then, MeI (0.82 g, 5.75 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was poured into a cold 10% citric acid solution (100 ml) and extracted with siRNA (2 × 20 ml). The organic layer was washed with water, a 10% NaHCO3 solution, and brine, dried under Na2SO4, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (siRNA:n-hexane = 1:1) to obtain P41.2 (0.65 g, yield 61%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6): 7.76 (d, J=8.1 Hz, 1H), 7.54-7.51 (m, 2H), 3.53 (t, J=6.7 Hz, 2H), 3.00-2.97 (m, 5H).

[0537] Synthesis of P41.3. To a solution of P41.2 (570.0 mg, 2.37 mmol) in dioxane (5 mL, degassed), 1,1-diphenylmethaneimine (470.0 mg, 2.61 mmol), NaOtBu (460.0 mg, 4.74 mmol), BINAP (147.0 mg, 0.237 mmol), and Pd2(dba)3 (109.0 mg, 0.118 mmol) were added at room temperature under an argon atmosphere. The solution was stirred overnight at 100°C, then the mixture was cooled, diluted with 10% HCl (10 ml), and stirred at room temperature for 2 hours. The solution was then filtered through a Celite pad, and the filtrate was concentrated. The residue was dissolved in water (10 ml) and extracted with Et2O (2 × 5 ml). The aqueous layer was neutralized to pH 8 with a 10% Na2CO3 solution and extracted with DCM (3 × 10 ml). The organic layer was washed with water, dried under Na2SO4, and concentrated to obtain the residue. The residue was recrystallized from Et2O to obtain P41.3 (345 mg, yield 86%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6): 7.52 (d, J=8.6 Hz, 1H), 6.43 (d, J=6.4 Hz, 1H), 6.31 (s, 1H), 5.64 (br., 2H), 3.41 (t, J=6.6 Hz, 2H), 2.93 (s, 3H), 2.77 (t, J=6.5 Hz, 2H).

[0538] Synthesis of compound 122. TsOH-H2O (215 mg, 1.13 mmol) was added to a solution of P41.3 (200 mg, 1.13 mmol) and ethyl 2-chloro-4-{[(1R)-2-hydroxy-1-phenylethyl]aminopyrimidine-5-carboxylate (27 mg, 1.13 mmol) in dioxane (3 ml) in a vial. The vial was capped and irradiated at 110°C for 30 minutes. The reaction mixture was diluted with RINKAN (10 ml), washed with 10% NaHCO3 solution and brine, dried under Na2SO4, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain compound 122 (290 mg, yield 55%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): 9.97 (s, 1H), 9.00 (d, J=7.2 Hz, 1H), 8.63 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.52-7.50 (m, 2H), 7.37-7.31 (m, 4H), 7.24-7.21 (m, 1H), 5.28-5.24 (m, 1H), 5.17-5.14 (m, 1H), 4.31 (q, J=7.0 Hz, 2H), 3.87-3.70 (m, 2H), 3.52-3.48 (m, 2H), 2.99 (s, 3H), 2.93-2.84 (m, 2H), 1.33 (t, J=7.0 Hz, 3H).

[0539] Preparation 42: Ethyl 2-{[3-fluoro-4-(1-hydroxy-2-methylpropan-2-yl)phenyl]amino}-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate [ka] The compound was synthesized using 2-(4-amino-2-fluorophenyl)-2-methylpropan-1-ol instead of 4-sulfonylmethyl-3-methylaniline, following the procedure described in Preparation 16. LCMS: [MH + 469.

[0540] Preparation 43: Ethyl 2-{[3-chloro-4-(1-hydroxy-2-methylpropan-2-yl)phenyl]amino}-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate [ka] The compound was synthesized using 2-(4-amino-2-chlorophenyl)-2-methylpropan-1-ol instead of 4-sulfonylmethyl-3-methylaniline, following the procedure described in Preparation 16. LCMS: [MH + 485.

[0541] Preparation 44: Ethyl 4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-[(2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl)amino]pyrimidine-5-carboxylate-compound 123. The compound was synthesized according to the procedure described in Preparation 16, using 7-amino-2-methyl-1,4-dihydroisoquinoline-3(2H)-one instead of 4-sulfonylmethyl-3-methylaniline.

[0542] Preparation 45: Ethyl 2-{[4-(1-hydroxy-2-methylpropan-2-yl)phenyl]amino}-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate-compound 52. The compound was synthesized according to the procedure described in Preparation 16, using 2-(4-aminophenyl)-2-methylpropan-1-ol instead of 4-sulfonylmethyl-3-methylaniline.

[0543] Preparation 46: Ethyl 2-{[2-chloro-4-(methylsulfonyl)phenyl]amino}-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate-compound 317. The compound was synthesized according to the procedure described in Preparation 16, using 2-chloro-4-(methylsulfonyl)aniline instead of 4-sulfonylmethyl-3-methylaniline.

[0544] Preparation 47: Ethyl 2-{[2-fluoro-4-(methylsulfonyl)phenyl]amino}-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate-compound 211. The compound was synthesized according to the procedure described in Preparation 16, using 2-fluoro-4-(methylsulfonyl)aniline instead of 4-sulfonylmethyl-3-methylaniline.

[0545] Preparation 48: Ethyl 4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate-compound 299. The compound was synthesized according to the procedure described in Preparation 16, using 2-methoxy-4-(methylsulfonyl)aniline instead of 4-sulfonylmethyl-3-methylaniline.

[0546] Preparation 49: Ethyl 4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-{[2-methyl-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate-compound 167. The compound was synthesized according to the procedure described in Preparation 16, using 2-methyl-4-(methylsulfonyl)aniline instead of 4-sulfonylmethyl-3-methylaniline.

[0547] Preparation 50: Ethyl 2-{[3-chloro-4-(methylsulfonyl)phenyl]amino}-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate-compound 318. The compound was synthesized according to the procedure described in Preparation 16, using 3-chloro-4-(methylsulfonyl)aniline instead of 4-sulfonylmethyl-3-methylaniline.

[0548] Preparation 51: 4-[[5-ethoxycarbonyl-4-[[(1S)-2-hydroxy-1-phenylethyl]amino]pyrimidine-2-yl]amino]-2-methoxybenzoic acid compound 62. [ka] Compound 62 was synthesized using P1 (100 mg, 0.31 mmol) and 4-amino-2-methoxybenzoic acid according to the procedure described in Preparation 16. Yield: 80 mg, 57%. 1H-NMR (400 MHz, dmso-d6) δ: 12.12 (br. S, 1H), 9.94 (s, 1H), 8.98 (d, J = 7.8 Hz, 1H), 8.64 (s, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.44-7.29 (m, 6H), 7.27-7.17 (m, 1H), 5.39-5.26 (m, 1H), 5.22-5.05 (m, 1H), 4.31 (q, J = 6.9 Hz, 2H), 3.92-3.81 (m, 1H), 3.79-3.67 (m, 4H), 1.34 (t, J = 6.8 Hz, 3H).

[0549] Preparation 52: Ethyl 4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-{[4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate-compound 68 [ka] The compound was synthesized using 4-(methylsulfonyl)aniline instead of 4-sulfonylmethyl-3-methylaniline, following the procedure described in Preparation 16. 1 H NMR (400 MHz, DMSO-d6): 10.21 (s, 1H), 9.02 (d, J=6.8 Hz, 1H), 8.65 (s, 1H), 7.70-7.71 (m, 4H), 7.41-7.33 (m, 4H), 7.26-7.22 (m, 1H), 5.25-5.05 (m, 2H), 4.32 (q, J=7.0 Hz, 2H), 3.86-3.68 (m, 2H), 3.15 (s, 3H), 1.34 (t, J=7.0 Hz, 3H).

[0550] Preparation 53: Ethyl 2-{[4-(ethylsulfonyl)phenyl]amino}-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate-compound 168. The compound was synthesized according to the procedure described in Preparation 16, using 4-(ethylsulfonyl)aniline instead of 4-sulfonylmethyl-3-methylaniline.

[0551] Preparation 54: Ethyl 4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-{[4-(propane-2-ylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate-compound 274. The compound was synthesized according to the procedure described in Preparation 16, using 4-[(1-methylethyl)sulfonyl]aniline instead of 4-sulfonylmethyl-3-methylaniline.

[0552] Preparation 55: Ethyl 2-[(3,3-dioxide-1,3-benzoxathiol-5-yl)amino]-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate-compound 164. The compound was synthesized according to the procedure described in Preparation 16, using 1,3-benzoxathiol-5-amine 3,3-dioxide instead of 4-sulfonylmethyl-3-methylaniline.

[0553] Preparation 56: Ethyl 2-[(2-ethyl-1-oxo-3,4-dihydroisoquinoline-6-yl)amino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate-compound 218. [ka]

[0554] Synthesis of P56.2. A mixture of 6-bromo-3,4-dihydroisoquinoline-1(2H)-one P56.1 (0.500 g, 1.88 mmol) in DMF (20 ml) was mixed with 60% NaH (0.112 g, 2.82 mmol), and the mixture was stirred at room temperature for 30 minutes. Then, EtI (0.44 g, 2.82 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was poured into a cold 10% citric acid solution (100 ml) and extracted with RINKAN (2 × 20 ml). The organic layer was washed with water, a 10% NaHCO3 solution, and brine, dried under Na2SO4, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (RINKAN:n-hexane = 1:1) to obtain P56.2 (0.48 g, yield 85%). 1 H NMR (400 MHz, DMSO-d6): δ 7.76 (d, J=8.1 Hz, 1H), 7.54-7.51 (m, 2H), 3.54-3.46 (m, 4H), 2.96 (t, J=6.5 Hz, 2H), 1.10 (t, J=7.2 Hz, 3H).

[0555] Synthesis of P56.3. To a solution of P56.2 (480.0 mg, 1.89 mmol) in dioxane (5 mL, degassed), 1,1-diphenylmethaneimine (376.0 mg, 2.08 mmol), NaOtBu (362.0 mg, 3.78 mmol), BINAP (125.0 mg, 0.189 mmol), and Pd2(dba)3 (86.0 mg, 0.098 mmol) were added under an argon atmosphere at room temperature. The solution was stirred overnight at 100°C, then the mixture was cooled, diluted with 10% HCl (10 ml), and stirred at room temperature for 2 hours. The solution was then filtered through a Celite pad, and the filtrate was concentrated. The residue was dissolved in water (10 ml) and extracted with Et2O (2 × 5 ml). The aqueous layer was neutralized to pH 8 with a 10% Na2CO3 solution and extracted with DCM (3 × 10 ml). The organic layer was washed with water, dried under Na2SO4, and concentrated to obtain the residue. The residue was recrystallized from Et2O to obtain P56.3 (150 mg, yield 42%). 1H NMR (400 MHz, DMSO-d6): δ 7.52 (d, J=8.3 Hz, 1H), 6.43 (dd, J1=8.4 Hz, J2=2.3 Hz, 1H), 6.31 (s, 1H), 5.62 (br, 2H), 3.45-3.38 (m, 4H), 2.75 (t, J=6.6 Hz, 2H), 1.05 (t, J=7.1 Hz, 3H).

[0556] Synthesis of compound 218. TsOH-H2O (150 mg, 0.79 mmol) was added to a solution of P56.3 (150 mg, 0.79 mmol) and ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]aminopyrimidine-5-carboxylate (Preparation 1, 254 mg, 0.79 mmol) in dioxane (3 ml) in a vial. The vial was capped and irradiated at 110°C for 30 minutes. The reaction mixture was diluted with RINKAN (10 ml), washed with 10% NaHCO3 solution and brine, dried under Na2SO4, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain compound 218 (135 mg, yield 36%). 1 H NMR (400 MHz, DMSO-d6): δ 9.96 (s, 1H), 8.98 (d, J=7.3 Hz, 1H), 8.62 (s, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.52-7.49 (m, 2H), 7.38-7.31 (m, 4H), 7.25-7.21 (m, 1H), 5.29-5.25 (m, 1H), 5.14 (t, J=4.6 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.87-3.81 (m, 1H), 3.75-3.71 (m, 1H), 3.52-3.41 (m, 4H), 2.94-2.82 (m, 2H), 1.33 (t, J=7.1 Hz, 3H), 1.10 (t, J=7.0 Hz, 3H).

[0557] Preparation 57: Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[(2-isopropyl-1-oxo-3,4-dihydroisoquinoline-6-yl)amino]pyrimidine-5-carboxylate-compound 316. [ka]

[0558] Synthesis of P57.2. A solution of 6-bromo-3,4-dihydroisoquinoline-1(2H)-one P57.1 (0.500 g, 1.88 mmol) in DMF (20 ml) was mixed with 60% NaH (0.112 g, 2.82 mmol), and the mixture was stirred at room temperature for 30 minutes. Then, i-PrBr (0.347 g, 2.82 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was poured into a cold 10% citric acid solution (100 ml) and extracted with RINKAN (2 × 20 ml). The organic layer was washed with water, a 10% NaHCO3 solution, and brine, dried under Na2SO4, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (RINKAN:n-hexane = 1:1) to obtain P57.2 (0.34 g, yield 72%). 1 H NMR (400 MHz, DMSO-d6): δ 7.77 (d, J=7.9 Hz, 1H), 7.54-7.5...

Claims

1. Compound of formula (I): 【Chemistry 1-1】 or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer, or tautomer thereof. [In the formula, X is a halogen or OH, R １ teeth, 【Chemistry 1-2】 [Chemistry 1-3] Selected from, R ２ is H or C １－４ Alkyl; or R ２ and R ８ They, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 membered heterocycline; R ３ is H; or R ３ and R ８ Together with the atoms to which they are bonded and any intervening atoms, they form a 5-6 membered cycloalkyl group; R ４ is -(CH ２ ) ｍ -aryl, wherein the aryl is optionally substituted with one or more R ８ ; Each R ５ is halogen, C １－６ Alkyl 、 C １－６ Alkoxy, C １－６ Halogenated alkyl, oxy C １－６ Alkyl, -S(O) ２ -C １－６ Alkyl, -S(O) ２ -C ２－６ Alkenyl, -C(O)NH ２ , -C(O)NH(C １－６ Alkyl), -C(O)N(C １－６ Alkyl) ２ ien-CH ２ C(O)NH ２ ien-CH ２ C(O)NH(C １－６ Alkyl), -CH ２ C(O)N(C １－６ Alkyl) ２ , -NHC(O)CH ３ , independently selected from aryl and heteroaryl; or Two R's ５ These, together with the atoms to which they are bonded and any intervening atoms, form a 6-7 membered heterocycline or a 5-7 membered heteroaryl, comprising at least one heteroatom selected from N, O, and S; the cycloalkyl or heterocycline comprises one or more R ７ It is optionally replaced by; Each R ７ OH, halogen, C １－６ Alkyl, aryl, oxy C １－６ Alkyl, -CH ２ OC(O)C １－６ Alkyl, or -CH ２ OCH ２ CH ２ Si(CH ３ ) ３ Selected independently of; Each R ８ Halogen, OH, NH ２ , C １－６ Alkyl, -OC １－６ Alkyl, -NHC １－６ Alkyl, -N(C) １－６ Alkyl) ２ Selected independently of; Each R ９ Halogen, OH, NH ２ , C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－８ Independently selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; and m and n are integers independently selected from 0, 1, 2, 3, 4, 5, and 6. Here, Aryls are cyclic aromatic hydrocarbon groups in which one to three aromatic rings are condensed or bonded to each other by single bonds; A heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, Se, or B, with the remaining ring atoms being C; A heterocyclyl is a saturated or partially unsaturated 3-10 membered monoring, 7-12 membered diring (fused, bridging, or spiroring), or 11-14 membered tricyclic ring system (fused, bridging, or spiroring) having one or more heteroatoms independently selected from O, N, S, P, Se, or B.

2. The compound in question is one of formula I-A: 【Chemistry 2】 The compound described in claim 1, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer, or tautomer thereof. [wherein p is an integer selected from 0, 1, 2, 3, 4, or 5.]

3. The compound in question is of formula I-A1: 【Transformation 3】 The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer, or tautomer thereof. [wherein p is an integer selected from 0, 1, 2, 3, 4, and 5.]

4. The compound is of formula I-B1, I-B3, or I-B3': 【Chemistry 4-1】 【Chemistry 4-2】 The compound described in claim 1, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer, or tautomer thereof.

5. The compound in question is one of the compounds of formula I-C: 【Transformation 5】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer, and tautomer thereof. [wherein ring B is a 6-7 membered heterocycline containing at least one heteroatom selected from N, O, and S, and w is an integer selected from 0, 1, 2, and 3.]

6. The aforementioned compound is one of the following: 【Transformation 6】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer, and tautomer thereof. [wherein u is an integer selected from 0 or 1, and p is an integer from 1, 2, 3, 4, and 5.]

7. The aforementioned compound is one of the following: 【Transformation 7】 The compound according to claim 6, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer, and tautomer thereof. [wherein p is an integer selected from 0, 1, 2, 3, 4, and 5.]

8. The compound in question is one of the following types: 【Transformation 8】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer, or tautomer thereof. [wherein n is an integer selected from 0, 1, 2, 3, 4, and 5; p is an integer selected from 1, 2, 3, 4, and 5; s is 0 or 1.]

9. The aforementioned base 【Chemistry 9-1】 The compound according to claim 1, wherein the group is selected from the following groups. 【Chemistry 9-2】 【Chemistry 9-3】 【Chemistry 9-4】

10. Compounds selected from the following group: 【Chemistry 10-1】 【Chemistry 10-2】 【Chemistry 10-3】 [Chemistry 10-4] [Transformation 10-5] 【Chemistry 10-6】 【Chemistry 10-7】 [Transformation 10-8] 【Chemistry 10-9】 【Chemistry 10-10】 【Chemistry 10-11】 [Chemistry 10-12] [Chemistry 10-13] [Chemistry 10-14] [Chemistry 10-15] [Chemistry 10-16] 【Chemistry 10-17】 [Chemistry 10-18] [Chemistry 10-19] [Chemistry 10-20] [Chemistry 10-21] [Chemistry 10-22] [Chemistry 10-23] [Chemistry 10-24] [Chemistry 10-25] [Chemistry 10-26] [Chemistry 10-27] [Chemistry 10-28] [Chemistry 10-29] [Chemistry 10-30] 【Chemistry 10-31】 【Chemistry 10-32】 【Chemistry 10-33】 【Chemistry 10-34】 [Chemistry 10-35] 【Chemistry 10-36】 【Chemistry 10-37】 [Chemistry 10-38] [Chemistry 10-39] [Chemistry 10-40] 【Chemistry 10-41】 【Chemistry 10-42】 【Chemistry 10-43】 [Chemistry 10-44] [Chemistry 10-45] [Chemistry 10-46] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

11. A compound according to claim 1, selected from the group consisting of the following: Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[(1-oxo-3,4-dihydro-2H-isoquinoline-6-yl)amino]pyrimidine-5-carboxylate; Ethyl 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-[(2-methyl-1-oxo-3,4-dihydroisoquinoline-6-yl)amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(3-methoxy-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; Ethyl 2-(4-ethylsulfonylanilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(4-methylsulfonylanilino)pyrimidine-5-carboxylate; (2S)-2-[[2-(3-methyl-4-methylsulfonylanilino)-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenylethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(1,3,4-oxadiazole-2-yl)pyrimidine-4-yl]amino]-2-phenylethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonylanilino)-5-(3-methyl-1,2,4-oxadiazole-5-yl)pyrimidine-4-yl]amino]-2-phenylethanol; 2-Hydroxyethyl 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; Ethyl 2-[(2-ethyl-1-oxo-3,4-dihydroisoquinoline-6-yl)amino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; Ethyl 2-[4-(dimethylcarbamoyl)anilino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition according to claim 12, further comprising an additional pharmaceutically active agent.

14. Use of a compound according to any one of claims 1 to 11 in the preparation of a pharmaceutical for inhibiting hematopoietic precursor kinase 1 (HPK1), wherein the compound is administered to a subject.

15. Use of a compound according to any one of claims 1 to 11 in the preparation of a pharmaceutical for treating a disease or disorder related to the inhibition of hematopoietic precursor kinase 1 (HPK1), wherein the compound is administered to a subject.

16. Use of a compound according to any one of claims 1 to 11 in the preparation of a pharmaceutical for the treatment of a disease, disorder, or symptom, wherein the compound is administered to a subject in need of treatment.

17. The use according to claim 16, wherein the disease, disorder, or symptom is selected from cancer, autoimmune disease, inflammatory disease, viral infection, male reproductive capacity control, benign hyperplasia, sepsis, vascular disorder, atherosclerosis, and neurodegenerative disorder.

18. The use according to claim 17, wherein the disease, disorder, or symptom is a cancer selected from bladder cancer, bone cancer, brain tumor, breast cancer, heart 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 carcinoma, thymic cancer, lung cancer, ovarian cancer, prostate cancer, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

19. The use according to claim 14, wherein the subject is a mammal.

20. The use according to claim 19, wherein the subject is a human being.

Images