Compounds having N-arylpyrimidin-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 TO RELATED APPLICATIONS) This application claims priority to and benefit of U.S. Provisional Patent Application No. 63 / 244,775, filed September 16, 2021, entitled "Compounds Having N-Arylpyrimidin-2-amine Derivatives as Therapeutic Agents," the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0002] FIELD OF THE INVENTION The present invention relates to inhibitors of hematopoietic progenitor kinase 1 (HPK1), leucine-rich repeat kinase 2 (LRRK2) protein, FMS-like tyrosine kinase 3 (FLT3) gene, interleukin 1 receptor-associated kinase 1 (IRAK1), interleukin 1 receptor-associated kinase 4 (IRAK4), and Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). The inhibitors described herein may be useful in treating diseases or disorders associated with HPK1, LRRK2, FLT3, IRAK1, IRAK4, and JAKs, 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 of treating diseases or disorders associated with HPK1, LRRK2, FLT3, IRAK1, IRAK4, and JAK, and methods of synthesizing these compounds. [Background technology]

[0003] BACKGROUND OF THE INVENTION Hematopoietic progenitor kinase 1 (HPK1) is a Ste20 serine / threonine kinase restricted to hematopoietic cells. HPK1 kinase activity is induced by activation signals generated by a variety of different cell surface receptors found on hematopoietic cells upon ligand binding. Ligand binding or antibody-mediated crosslinking of the T cell receptor (TCR), B cell antigen receptor (BCR), transforming growth factor β receptor (TGF-βR), erythropoietin receptor (EPOR), and Fas can induce HPK1 kinase activity. Each receptor utilizes unique, but sometimes overlapping, signaling mechanisms to activate HPK1. HPK1 functions as a downregulator of T and B cell function via the AP-1, NFKB, Erk2, and Fas pathways. For example, HPK1 has been implicated as a negative regulator of signal transduction in T cells through phosphorylation and activation of the T cell receptor adaptor protein SLP-76, which subsequently leads to 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, it has been reported that HPK1 could be a novel target for cancer immunotherapy (Sawasdikosol et al., Immunol Res. 2012 Dec;54(1-3):262-5). Specifically, targeted disruption of the HPK1 allele confers increased Th1 cytokine production in T cells in response to TCR engagement. HPK1(- / -) T cells proliferate more rapidly than haplomatched wild-type T cells and are resistant to prostaglandin E2 (PGE(2))-mediated suppression. Most strikingly, mice that received adoptive transfer of HPK1(- / -) T cells acquired resistance to lung tumor growth. Furthermore, loss of HPK1 from dendritic cells (DCs) confers superior antigen-presenting ability, allowing HPK1(- / -) DCs to elicit stronger antitumor immune responses when used as cancer vaccines.

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

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

[0007] Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transduce cytokine signaling from membrane receptors to STAT transcription factors. Four JAK family members, JAK1, JAK2, JAK3, and TYK2, are described. Upon cytokine binding to its receptor, JAK family members autophosphorylate and / or transphosphorylate each other, subsequently phosphorylating STATs, which then translocate to the nucleus and regulate transcription. JAK-STAT intracellular signaling affects a variety of cytokines and endocrine factors, including interferons, most interleukins, as well as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, and PRL. A combination of genetic modeling and small-molecule JAK inhibitor studies has revealed the therapeutic potential of JAK inhibitors (JAKinibs).

[0008] Using TYK2 knockout mice, it was shown that IL-6, IL-10, IL-11, IL-12, 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 dependent on TYK2. However, recent studies have shown that JAK1 is the primary driver of IFNα, IL6, IL10, and IL22 signaling, while TYK2 is involved in type 1 interferon (including IFNα and IFNβ), IL23, and IL12 signaling. Because IL12 and IL23 activity is particularly elevated in patients with autoimmune diseases such as psoriasis, systemic lupus erythematosus (SLE), psoriatic arthritis, and inflammatory bowel disease, selective TYK2 inhibition, while avoiding JAK2-dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling, may be particularly advantageous for the treatment of these diseases. Furthermore, TYK2 inhibition may be particularly useful for treating the cytokine storm associated with COVID-19 infection, as it is involved in type I interferon signaling (including IFNa and IFNb).

[0009] Furthermore, variants in the TYK2 gene reported in the general human population result in a modification of a single amino acid within the kinase domain of TYK2, abolishing its kinase activity and are 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, and all members of this family share five conserved domains. In cell culture models, evidence suggests that increased LRRK2 kinase activity is associated with neurotoxicity (Smith et al., 2006 Nature Neuroscience 9: 1231-1233), and kinase inhibitor compounds 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). LRRK2 protein impairs chaperone-mediated autophagy and negatively impacts the cell's ability to degrade alpha-synuclein (Orenstein et al., 2013 Nature Neurosci. 16 394-406). In other cellular 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 for treating diseases characterized by defects in cellular proteostasis due to aberrant autophagy / lysosomal degradation pathways, including forms of Parkinson's disease associated with GBA mutations (Swan and Saunders-Pullman 2013 Curr. Neurol. Neurosci Rep. 13: 368), other alpha-synucleinopathies, tauopathies, Alzheimer's disease (Li et al., 2010 Neurodegen. Dis. 7: 265-271), and other neurodegenerative disorders (Nixon 2013 Nat. Med. 19: 983-997).

[0012] Other studies have shown that overexpression of the G2019S mutant form of LRRK2 confers defects in 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 reduces neurite length and branching in 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 recovery of CNS function after neuronal injuries such as ischemic stroke, traumatic brain injury, and spinal cord injury.

[0013] Mutations in LRRK2 have also been identified as 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 the treatment of diseases such as Alzheimer's disease, other dementias, and related neurodegenerative disorders.

[0014] Abnormal regulation of normal LRRK2 protein is also observed in some disease tissues and disease models. The normal mechanism of LRRK2 translational control by miR-205 is disrupted in some sporadic PD cases, and a significant decrease in miR-205 levels in PD brain samples is consistent with increased 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 marmoset model of Parkinson's disease, elevated LRRK2 mRNA is observed in a manner correlated with the level of L-Dopa-induced dyskinesia (Hurley, M. J et al., 2007 Eur. J. Neurosci. 26: 171-177). This suggests that LRRK2 inhibitors may be useful for ameliorating such dyskinesias.

[0015] Significant increases 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 hallmark of ALS. Therefore, this observation indicated that LRRK2 inhibitors may be useful for the treatment of ALS.

[0016] Evidence also suggests that LRRK2 kinase activity may play a role in mediating microglial proinflammatory responses (Moehle et al., 2012, J. Neuroscience 32:1602-1611). This observation suggests the potential utility of LRRK2 inhibitors in treating the 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 generating neural progenitor cells in vitro, for potential therapeutic applications in cell-based treatment of CNS diseases.

[0017] A meta-analysis of three genome-wide association scans for Crohn's disease identified numerous disease-associated loci, including the LRRK2 gene (Barrett et al., 2008, Nature Genetics, 40: 955-962). Evidence also emerged that LRRK2 is an IFN-γ target gene that may be 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 for the treatment of Crohn's disease.

[0018] LRRK2, as an IFN-γ target gene, may also play a role in the T cell mechanisms underlying other immune system diseases such as multiple sclerosis and rheumatoid arthritis. Further potential utility of LRRK2 inhibitors comes 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 in treating diseases of the immune system in which B cell depletion is or could be effective, 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 aplasia, idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis, bullous skin diseases, type 1 diabetes, Sjögren's syndrome, Devic's disease, and inflammatory myopathies (Engel et al., 2011 Pharmacol. Rev. 63: 127-156; Homam et al., 2010 J. Clin. Neuromuscular Disease 12: 91-102).

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

[0020] FLT3 is one of the most frequently mutated genes in hematologic malignancies and is present in approximately 30% of adult acute myeloid leukemia (AML). The presence of FLT3 internal tandem duplications in AML patients adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy. FLT3 mutations have been detected in approximately 2% of patients diagnosed with intermediate-risk and high-risk myelodysplastic syndromes (MDS). Similar to MDS, the number of FLT3 mutations in patients with acute promyelocytic leukemia (APL) is low. The most common FLT3 mutation is an internal tandem duplication (ITD), which causes an in-frame insertion within the juxtamembrane domain of the FLT3 receptor. FLT3-ITD mutations have been reported in 15–35% of adult AML patients. FLT3 internal tandem duplications are 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 reduced disease-free and overall survival. The prognostic impact of FLT3 and N-RAS gene mutations in acute myeloid leukemia (AML) is unclear. FLT3 point mutations occur less frequently in the activation loop of the FLT3 receptor. The most commonly affected codon is aspartic acid 835 (D835). Nucleotide substitutions at the D835 residue occur in approximately 5–10% of adult AML patients.

[0021] The increasing frequency of constitutively activated mutant FLT3 in adult AML makes the FLT3 gene a highly attractive drug target in this tumor type. Several FLT3 inhibitors with varying degrees of potency and selectivity for their target have been or are currently being investigated and tested in patients with AML.

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

[0023] Therefore, new compounds are needed that effectively and selectively inhibit hematopoietic progenitor kinase 1 (HPK1), leucine-rich repeat kinase 2 (LRRK2) protein, FMS-like tyrosine kinase 3 (FLT3) gene, interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), and Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2), thus enabling the design of specific treatments and dosages tailored to the disease state. (Summary of the Invention)

[0024] A first aspect of the present invention is a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer or tautomer thereof, During the ceremony, X is H, halogen, or OH, with the proviso that R 4 When is unsubstituted phenyl and X is H, R 1 is C(O)OR 6 and; R 1 are -CN, -NO2, and -C(O)NHR 6 , C(O)N(R 6 )2, -C(O)OR 6 , -S(O)2C 1-6alkyl or monocyclic heteroaryl containing one or more heteroatoms independently selected from N, S, and O, wherein said heteroaryl is selected from -OH, oxo, halogen, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 Optionally substituted with one or more substituents selected from alkenyl, or 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 optionally further substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl; R 2 is H or C 1-4 is alkyl; or R 2 and R 8 together with the atom to which they are attached and any intervening atoms, form a 5-6 membered heterocyclyl; R 3 is H; or R 3 and R 8 together with the atom to which they are attached and any intervening atoms, form a 5-6 membered cycloalkyl; R 4 is -(CH2) m -aryl, -(CH2) m -heteroaryl, -(CH2) m -cycloalkyl, or heterocyclyl, wherein said -(CH2) m -aryl, -(CH2) m -heteroaryl, -(CH2) m -cycloalkyl, or heterocyclyl may be one or more R 8 optionally replaced by; Each R 5 is a halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogen alkyl, oxy C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-C2-6 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), -CHC(O)N(C 1-6 alkyl), -NHC(O)CH, aryl, heteroaryl; or The Two R's 5 together with the atom to which they are attached and any intervening atoms form a 6- to 7-membered heterocyclyl or a 5- to 7-membered heteroaryl containing at least one heteroatom selected from N, O, S; the heterocyclyl or heteroaryl may be joined by one or more R 7 optionally substituted with; Each R 6 are H, OH, and C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 3-8 cycloalkyl, heterocyclyl, or heteroaryl, and the alkyl, alkoxy, heteroaryl, or heterocyclyl is selected from one or more R 9 optionally substituted with; or The Two R's 6 together with the atom to which they are attached and any intervening atoms, form a 4- to 8-membered heterocyclyl; Each R 7 OH, oxo, halogen, C 1-6 Alkyl, aryl, oxyC 1-6 Alkyl, -CH2OC(O)C 1-6 alkyl, or —CH2OCH2CH2Si(CH3)3; Each R 8 are halogens, OH, NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, or -N(C 1-6 alkyl)2; Each R 9 are halogens, OH, NH2, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 is 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 comprise an excipient, diluent, or surfactant.

[0026] Another aspect of the present invention relates to a method for treating a disease or disorder associated with the regulation of hematopoietic progenitor kinase 1 (HPK1), comprising administering to a patient in need of treatment for a disease or disorder associated with 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 of inhibiting hematopoietic progenitor kinase 1 (HPK1), comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0028] Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting hematopoietic progenitor 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, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of diseases associated with the inhibition of hematopoietic progenitor kinase 1 (HPK1).

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

[0031] Another aspect of the present invention relates to a method for treating a disease or disorder associated with the regulation of leucine-rich repeat kinase 2 (LRRK2) protein, comprising administering to a patient in need of treatment for a disease or disorder associated with the regulation 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 of inhibiting leucine-rich repeat kinase 2 (LRRK2) protein, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0033] Another aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting 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, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a disease associated with the 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 associated with regulation of the FMS-like tyrosine kinase 3 (FLT3) gene, comprising administering to a patient in need of treatment for a disease or disorder associated with 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, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0037] Another aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, for use in the manufacture of a medicament 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, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of diseases associated with the 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 associated with the modulation of interleukin-1 receptor-associated kinase 1 (IRAK1), comprising administering to a patient in need of treatment for a disease or disorder associated with 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 of inhibiting interleukin-1 receptor-associated kinase 1 (IRAK1), comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

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

[0043] Another aspect of the present invention relates to a method for treating a disease or disorder associated with the modulation of interleukin-1 receptor-associated kinase 4 (IRAK4), comprising administering to a patient in need of treatment for a disease or disorder associated with 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 of inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

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

[0047] Another aspect of the present invention relates to a method of treating a disease or disorder associated with the regulation 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 associated with the regulation 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 of inhibiting Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

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

[0050] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of diseases 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).

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

[0052] Another aspect of the present invention relates to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0053] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, 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 associated with the regulation of hematopoietic progenitor kinase 1 (HPK1), comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

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

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

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

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

[0059] The present invention further provides compounds and compositions with improved efficacy and safety profiles compared to known leucine-rich repeat kinase 2 (LRRK2) protein inhibitors. The present 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 associated with regulation of the FMS-like tyrosine kinase 3 (FLT3) gene, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0061] The present invention provides inhibitors of the FMS-like tyrosine kinase 3 (FLT3) gene that are therapeutic agents in the treatment of diseases and disorders.

[0062] The present invention further provides compounds and compositions with improved efficacy and safety profiles compared to known FMS-like tyrosine kinase 3 (FLT3) gene inhibitors. The present 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 associated with the regulation of interleukin-1 receptor-associated kinase 1 (IRAK1), comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0064] The present invention provides inhibitors of interleukin-1 receptor-associated kinase 1 (IRAK1) that are therapeutic agents in the treatment of diseases and disorders.

[0065] The present invention further provides compounds and compositions with improved efficacy and safety profiles compared to known interleukin-1 receptor-associated kinase 1 (IRAK1) inhibitors. The present 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 associated with the regulation of interleukin-1 receptor-associated kinase 4 (IRAK4), comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0067] The present invention provides inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4) that are therapeutic agents in the treatment of diseases and disorders.

[0068] The present invention further provides compounds and compositions with improved efficacy and safety profiles compared to known interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors. The present 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 methods for treating diseases or disorders associated with the regulation of Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2), comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

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

[0071] The present invention further provides compounds and compositions with improved efficacy and safety profiles compared to known Janus kinase (JAK) inhibitors. The present 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 of treating a disease, disorder, or condition selected from cancer, an autoimmune disease, an inflammatory disease, a viral infection, male fertility control, benign hyperplasia, sepsis, a vascular disorder, atherosclerosis, and a neurodegenerative disorder, 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 said diseases or disorders.

[0073] In some aspects, the disclosure provides compounds obtainable by or obtained by a method for preparing a compound described herein (e.g., a method comprising one or more steps described in General Procedure A).

[0074] In some aspects, the present disclosure provides intermediates described herein that are suitable for use in methods for preparing compounds described herein (e.g., the intermediate is selected from the intermediates described in Example 1).

[0075] In some aspects, the disclosure provides methods of preparing the compounds of the disclosure.

[0076] In some aspects, the present disclosure provides methods of preparing the compounds of the present disclosure, comprising one or more steps described herein.

[0077] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the singular also includes the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. No reference cited herein is admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and not intended to be limiting. In the event of a conflict between the chemical structure and name of a compound disclosed herein, the chemical structure will control.

[0078] Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

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

[0080] Details of the present invention are described in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are described herein. Other features, objects, and advantages of the present invention will become apparent from the specification and claims. In this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited herein are incorporated herein by reference in their entirety. definition

[0081] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

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

[0083] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but need not) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents other than hydrogen. For example, at any point along the chain, it can be bonded to a halogen atom, a hydroxyl group, or other substituents described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to include other functional groups, but does not necessarily have any additional functional groups. Suitable substituents for use in any substitution of the described groups include, but are not limited to, halogen, oxo, —OH, —CN, —COOH, —CHCN, —O—(C-C)alkyl, (C-C)alkyl, (C-C)alkoxy, (C-C)haloalkyl, (C-C)haloalkoxy, —O—(C-C)alkenyl, —O—(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, —OH, —OP(O )(OH), —OC(O)(C-C)alkyl, —C(O)(C-C)alkyl, —OC(O)O(C-C)alkyl, —NH, —NH((C-C)alkyl), —N((C-C)alkyl), —NHC(O)(C-C)alkyl, —C(O)NH(C-C)alkyl, —S(O)(C-C)alkyl, —S(O)NH(C-C)alkyl, and S(O)N((C-C)alkyl). Substituents may themselves be optionally substituted. As used herein, “optionally substituted” means substituted or unsubstituted, the meaning of which is described below.

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

[0085] As used herein, the term "unsubstituted" means that the particular group bears no 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. When containing two aromatic rings (such as bicyclic), the aromatic rings of the aryl group can be attached at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group can be optionally substituted at any point of attachment with one or more substituents, e.g., 1 to 5 substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C-C)alkyl, (C-C)alkyl, -O-(C-C)alkenyl, -O-(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, -OH, -O-P(O)(OH), -OC(O)(C-C)alkyl, -C(O)(C-C)alkyl, -OC(O)O(C-C)alkyl, -NH, NH((C-C)alkyl), N((C-C)alkyl), -S(O)-(C-C)alkyl, -S(O)NH(C-C)alkyl, and -S(O)N((C-C)alkyl). Substituents may themselves be optionally substituted. Additionally, when containing two fused rings, aryl groups as defined herein may have a saturated or partially unsaturated ring fused to a fully unsaturated aromatic ring. Examples of ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannurenyl, and the like.

[0087] Unless otherwise defined, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, Se, or B, with the remaining ring atoms being C. Heteroaryl, as defined herein, also means bicyclic heteroaromatic groups in which the heteroatoms are selected from N, O, S, P, Se, or B. Heteroaryl, as defined herein, also means tricyclic heteroaromatic groups containing one or more ring heteroatoms selected from N, O, S, P, Se, or B. The aromatic radicals may be optionally substituted independently 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, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triphenylmethane, and the like. Azinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl , indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl yl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ 2-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[ 4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two or more fused rings, heteroaryl groups as defined herein may have one or more saturated or partially unsaturated rings, such as a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, S, P, Se, or B, or a 6-membered heteroaromatic ring containing 1 to 3 nitrogen atoms, fused to a fully unsaturated aromatic ring, wherein 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 oxo. In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated ring may be further fused to a saturated or partially unsaturated ring as described herein.Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-1H-isoquinolinyl, 1,6-dihydro-2H-pyrazolo[3,4-c]pyridin-7-on ... 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]pyrrolidine, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, or benzo[c][1,2]oxaborol-1(3H)-olyl.

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

[0089] "Alkyl" refers to a straight or branched chain 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 iso-hexyl.

[0090] "Alkoxy" refers to a straight or branched chain 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] "Alkenyl" refers to a straight- or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. As defined herein, alkenyl can be straight-chain or branched.

[0092] "Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "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 term "alkylene" or "alkylenyl" refers to a divalent alkyl radical. Any of the above monovalent alkyl groups can be alkylene by abstraction of a second hydrogen atom from the alkyl. As defined herein, alkylene can be a C1-C6 alkylene. Alkylene can further be a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-, and the like.

[0094] "Cycloalkyl" means a group having 3 to 30 carbon atoms (e.g., C3-C 12 , C3-C 10, or 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, octahydropentalenyl, 3a,4,5,6 Examples of cycloalkyls include, but are not limited to, 7,7a-hexahydro-1H-indenyl, 1,2,3,3a-tetrahydropentalenyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.0]pentanyl, spiro[3.3]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]octanyl, 6-methylbicyclo[3.1.1]heptanyl, 2,6,6-trimethylbicyclo[3.1.1]heptanyl, adamantyl, and derivatives thereof. In the case of polycyclic cycloalkyls, only one of the rings of the cycloalkyl need be non-aromatic.

[0095] "Heterocyclyl," "heterocycle," or "heterocycloalkyl," unless otherwise specified, refers to a saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spirocyclic), or 11- to 14-membered tricyclic ring system (fused, bridged, or spirocyclic) 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.Examples of heterocycloalkyl groups are piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-diaze ... -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-1,1'-isobenzofuran]-yl, 'H-spiro[cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl , 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like.

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

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

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

[0099] As used herein, the term "amine" refers to primary (R-NH, where R is not H), secondary (R-NH, where R is not H), and tertiary (R-N, where R is not H) amines. A substituted amine is intended to mean an amine in which at least one hydrogen atom is replaced with a substituent.

[0100] As used herein, the term "amino" refers to a substituent containing at least one nitrogen atom. Specifically included within the term "amino" are -NH, -NH(alkyl) or alkylamino, -N(alkyl) or dialkylamino, amido, carbamido, urea, and sulfamido substituents.

[0101] The term "solvate" refers to a complex of varying stoichiometry formed by a solute and a solvent. For the purposes of the present invention, such a solvent may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water as well as compositions containing variable amounts of water.

[0102] The term "isomer" refers to compounds that have the same composition and molecular weight but different physical and / or chemical properties. The structural differences may be in constitution (geometric isomers) or in ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, compounds of formula (I) may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures, and individual enantiomers or diastereomers.

[0103] The present invention also provides isotopically labeled compounds of formula I, such as 2 H and 14 C) are intended to be deuterated (i.e., 2 H or D) isotopes and carbon-14 (i.e., 14 C) Isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with heavier isotopes, such as deuterium, may offer certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced required dose), and therefore may be preferred in some circumstances. Isotopically labeled compounds of Formula I can generally be prepared by replacing non-isotopically labeled reagents with appropriate isotopically labeled reagents in accordance with procedures similar to those disclosed in the following schemes and / or examples.

[0104] The present disclosure also includes pharmaceutical compositions comprising an effective amount of the disclosed compounds and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, for example, water soluble salts and water insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, and the like. The salts include, but are not limited to, isethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, embonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, diacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.

[0105] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, e.g., a monkey, chimpanzee, baboon, or rhesus monkey.

[0106] An "effective amount," when used in connection with a compound, is an amount effective to treat or prevent a disease or disorder in a subject as described herein.

[0107] The term "carrier" as used in this disclosure encompasses carriers, excipients, and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of the body of a subject to another organ or part of the body.

[0108] The term "treating" with respect to a subject refers to improving at least one symptom of the subject's disorder. Treating includes curing, ameliorating, or at least partially ameliorating the disorder.

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

[0110] The terms "administer," "administering," or "administration," as used in this disclosure, refer to either administering a disclosed compound, or a pharmaceutically acceptable salt or composition of a disclosed compound, directly to a subject, or administering a prodrug derivative or analog of the compound, or a pharmaceutically acceptable salt or composition of the compound, to a subject, allowing an equivalent amount of active compound to form in the subject's body.

[0111] The term "prodrug," as used in this disclosure, means a compound that is convertible in vivo by metabolic means (e.g., hydrolysis) to a disclosed compound.

[0112] In some embodiments, the present disclosure provides a compound 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 present disclosure provides a compound of formula I-A1: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer or tautomer thereof, where p is an integer from 0, 1, 2, 3, 4 and 5, and all other variables are as defined herein.

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

[0115] In some embodiments, the present disclosure provides compounds of formula I-B1, I-B2, I-B3, I-B3′, or I-B4: [ka] [ka] wherein ring A is a monocyclic heteroaryl containing one or more heteroatoms independently selected from N, S, and O; and each R 10 -OH, oxo, halogen, C 1-4 Alkoxy, C 1-6 Alkyl 、 C 2-6Independently selected from alkenyl, 4- to 7-membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, —NH 2 , —N(C 1-6 alkyl) 2 , —OH, —COOC 1-4 optionally further substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl; t is an integer selected from 0, 1, 2, 3, 4; and p is an integer selected from 0, 1, 2, 3, 4, 5. or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof.

[0116] In some embodiments, the present disclosure provides a compound of formula I-B1-a: [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.

[0117] In some embodiments, the present disclosure provides a compound of formula I-B1-a*: [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.

[0118] In some embodiments, the present disclosure provides a compound of formula I-B1-b: [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.

[0119] In some embodiments, the present disclosure provides a compound of formula I-B1-b*: [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.

[0120] In some embodiments, the present disclosure provides a compound of formula I-B1-c: [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.

[0121] In some embodiments, the present disclosure provides a compound of formula I-B1-c*: [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.

[0122] In some embodiments, the present disclosure provides a compound of formula I-B1-d: [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.

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

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

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

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

[0127] In some embodiments, the present disclosure provides a compound of formula I-B2-b*: [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.

[0128] In some embodiments, the present disclosure provides a compound of formula I-B2-c: [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.

[0129] In some embodiments, the present disclosure provides a compound of formula I-B2-c*: [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.

[0130] In some embodiments, the present disclosure provides a compound of formula I-B2-d: [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.

[0131] In some embodiments, the present disclosure provides a compound of formula I-B2-d*: [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.

[0132] In some embodiments, the present disclosure provides a compound of formula I-B2-e: [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.

[0133] In some embodiments, the present disclosure provides a compound of formula I-B2-e*: [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.

[0134] In some embodiments, the present disclosure provides a compound of formula I-B2-f: [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.

[0135] In some embodiments, the present disclosure provides a compound of formula I-B2-f*: [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.

[0136] In some embodiments, the present disclosure provides a compound of formula I-B2-g: [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.

[0137] In some embodiments, the present disclosure provides a compound of formula I-B2-g*: [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.

[0138] In some embodiments, the present disclosure provides a compound of formula I-B2-h: [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.

[0139] In some embodiments, the present disclosure provides a compound of formula I-B2-h*: [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.

[0140] In some embodiments, the present disclosure provides a compound of formula I-B2-i: [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.

[0141] In some embodiments, the present disclosure provides a compound of formula I-B2-i*: [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.

[0142] In some embodiments, the present disclosure provides a compound of formula I-B2-j: [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.

[0143] In some embodiments, the present disclosure provides a compound of formula I-B2-j*: [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.

[0144] In some embodiments, the present disclosure provides a compound of formula I-B2-k: [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.

[0145] In some embodiments, the present disclosure provides a compound of formula I-B2-k*: [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.

[0146] In some embodiments, the present disclosure provides a compound of formula I-B4-G1: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein X is selected from NH, O, and S; each Y is independently selected from N and CH; and R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 present disclosure provides a compound of formula I-B4-G2: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein X is selected from NH, O, and S; each Y is independently selected from N and CH; and R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0148] In some embodiments, the present disclosure provides a compound of formula I-B4-I: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0149] In some embodiments, the present disclosure provides a compound of formula I-B4-I*: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0150] In some embodiments, the present disclosure provides a compound of formula I-B4-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.

[0151] In some embodiments, the present disclosure provides a compound of formula I-B4-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.

[0152] In some embodiments, the present disclosure provides a compound of formula I-B4-Ib: [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.

[0153] In some embodiments, the present disclosure provides a compound of formula I-B4-Ib*: [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.

[0154] In some embodiments, the present disclosure provides a compound of formula I-B4-II: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 provides a compound of formula I-B4-II*: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 provides a compound of formula I-B4-II-a: [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.

[0157] In some embodiments, the present disclosure provides a compound of formula I-B4-II-a*: [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.

[0158] In some embodiments, the present disclosure provides a compound of formula I-B4-II-b: [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.

[0159] In some embodiments, the present disclosure provides a compound of formula I-B4-II-b*: [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.

[0160] In some embodiments, the present disclosure provides a compound of formula I-B4-II-c: [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.

[0161] In some embodiments, the present disclosure provides a compound of formula I-B4-II-c*: [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.

[0162] In some embodiments, the present disclosure provides a compound of formula I-B4-II-d: [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.

[0163] In some embodiments, the present disclosure provides a compound of formula I-B4-II-d*: [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.

[0164] In some embodiments, the present disclosure provides a compound of formula I-B4-II-e: [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.

[0165] In some embodiments, the present disclosure provides a compound of formula I-B4-II-e*: [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.

[0166] In some embodiments, the present disclosure provides a compound of formula I-B4-II-f: [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.

[0167] In some embodiments, the present disclosure provides a compound of formula I-B4-II-f*: [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.

[0168] In some embodiments, the present disclosure provides a compound of formula I-B4-II-g: [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.

[0169] In some embodiments, the present disclosure provides a compound of formula I-B4-II-g*: [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.

[0170] In some embodiments, the present disclosure provides a compound of formula I-B4-II-h: [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.

[0171] In some embodiments, the present disclosure provides a compound of formula I-B4-II-h*: [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.

[0172] In some embodiments, the present disclosure provides a compound of formula I-B4-II-i: [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.

[0173] In some embodiments, the present disclosure provides a compound of formula I-B4-II-i*: [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.

[0174] In some embodiments, the present disclosure provides a compound of formula I-B4-II-j: [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.

[0175] In some embodiments, the present disclosure provides a compound of formula I-B4-II-j*: [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.

[0176] In some embodiments, the present disclosure provides a compound of formula I-B4-III: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 provides a compound of formula I-B4-III*: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 provides a compound of formula I-B4-III-a: [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.

[0179] In some embodiments, the present disclosure provides a compound of formula I-B4-III-a*: [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.

[0180] In some embodiments, the present disclosure provides a compound of formula I-B4-III-b: [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.

[0181] In some embodiments, the present disclosure provides a compound of formula I-B4-III-b*: [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.

[0182] In some embodiments, the present disclosure provides a compound of formula I-B4-III-c: [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.

[0183] In some embodiments, the present disclosure provides a compound of formula I-B4-III-c*: [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.

[0184] In some embodiments, the present disclosure provides a compound of formula I-B4-III-d: [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.

[0185] In some embodiments, the present disclosure provides a compound of formula I-B4-III-d*: [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.

[0186] In some embodiments, the present disclosure provides a compound of formula I-B4-III-e: [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.

[0187] In some embodiments, the present disclosure provides a compound of formula I-B4-III-e*: [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.

[0188] In some embodiments, the present disclosure provides a compound of formula I-B4-III-f: [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.

[0189] In some embodiments, the present disclosure provides a compound of formula I-B4-III-f*: [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.

[0190] In some embodiments, the present disclosure provides a compound of formula I-B4-III-g: [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.

[0191] In some embodiments, the present disclosure provides a compound of formula I-B4-III-g*: [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.

[0192] In some embodiments, the present disclosure provides a compound of formula I-B4-III-h: [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.

[0193] In some embodiments, the present disclosure provides a compound of formula I-B4-III-h*: [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.

[0194] In some embodiments, the present disclosure provides a compound of formula I-B4-IV: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 provides a compound of formula I-B4-IV*: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 provides a compound of formula I-B4-IV-a: [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.

[0197] In some embodiments, the present disclosure provides a compound of formula I-B4-IV-a*: [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.

[0198] In some embodiments, the present disclosure provides a compound of formula I-B4-V: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 provides a compound of formula I-B4-V*: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 provides a compound of formula I-B4-Va: [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.

[0201] In some embodiments, the present disclosure provides a compound of formula I-B4-Va*: [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.

[0202] In some embodiments, the present disclosure provides a compound of formula I-B4-VI: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 provides a compound of formula I-B4-VI*: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 provides a compound of formula I-B4-VI-a: [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.

[0205] In some embodiments, the present disclosure provides a compound of formula I-B4-VI-a*: [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.

[0206] In some embodiments, the present disclosure provides a compound of formula I-B4-VII: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 provides a compound of formula I-B4-VII*: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 provides a compound of formula I-B4-VII-a: [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.

[0209] In some embodiments, the present disclosure provides a compound of formula I-B4-VII-a*: [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.

[0210] In some embodiments, the present disclosure provides a compound of formula I-B4-VIII: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 provides a compound of formula I-B4-VIII*: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 provides a compound of formula I-B4-VIII-a: [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.

[0213] In some embodiments, the present disclosure provides a compound of formula I-B4-VIII-a*: [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.

[0214] In some embodiments, the present disclosure provides a compound of formula I-B4-VIII-b: [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.

[0215] In some embodiments, the present disclosure provides a compound of formula I-B4-VIII-b*: [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.

[0216] In some embodiments, the present disclosure provides a compound of formula I-B4-VIII-c: [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.

[0217] In some embodiments, the present disclosure provides a compound of formula I-B4-VIII-c*: [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.

[0218] In some embodiments, the present disclosure provides a compound of formula I-B4-IX: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 provides a compound of formula I-B4-IX*: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 provides a compound of formula I-B4-IX-a: [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.

[0221] In some embodiments, the present disclosure provides a compound of formula I-B4-IX-a*: [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.

[0222] In some embodiments, the present disclosure provides a compound of formula I-B4-IX-b: [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.

[0223] In some embodiments, the present disclosure provides a compound of formula I-B4-IX-b*: [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.

[0224] In some embodiments, the present disclosure provides a compound of formula I-B4-X: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 provides a compound of formula I-B4-X*: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, or tautomer thereof, wherein R 10 is H, C 1-4 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 and optionally further substituted with one or more substituents selected from alkyl, —COOH, —CONH2, or 4-7 membered monocyclic heterocycloalkyl, wherein 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 provides a compound of formula I-B4-Xa: [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.

[0227] In some embodiments, the present disclosure provides a compound of formula I-B4-Xa*: [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.

[0228] In some embodiments, the present disclosure provides a compound of formula IC: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein 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 provides a compound of formula IC*: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein 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, the present disclosure provides a compound of formula ID: [ka] or 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 provides a compound of formula IE: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein 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 provides a compound of formula IF: [ka] or 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, compounds of the present disclosure have the formula IG [ka] and 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.

[0234] In some embodiments, the present disclosure provides a compound of formula IH: [ka] and pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein 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 provides a compound of formula II-A: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein each R 5a H, halogen, C 1-6 Alkyl, C 1-6alkoxy, where 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 provides a compound of formula II-A*: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein each R 5a H, halogen, C 1-6 Alkyl, C 1-6 alkoxy, where 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 provides a compound of formula II-B: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein each R 5a H, halogen, C 1-6 Alkyl, C 1-6 alkoxy, where 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 provides a compound of formula II-B*: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein each R 5a H, halogen, C 1-6 Alkyl, C 1-6alkoxy, where 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 provides a compound of formula II-C: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein each R 5a H, halogen, C 1-6 Alkyl, C 1-6 alkoxy, where 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 provides a compound of formula II-C*: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein each R 5a H, halogen, C 1-6 Alkyl, C 1-6 alkoxy, where 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 provides a compound of formula II-D: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein each R 5a H, halogen, C 1-6 Alkyl, C 1-6alkoxy, where 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 provides a compound of formula II-D*: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein each R 5a H, halogen, C 1-6 Alkyl, C 1-6 alkoxy, where 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 provides a compound of formula II-E: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein each R 5a H, halogen, C 1-6 Alkyl, C 1-6 alkoxy, where 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 provides a compound of formula II-E*: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein each R 5a H, halogen, C 1-6 Alkyl, C 1-6alkoxy, where 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 provides a compound of formula II-F: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein each R 5a H, halogen, C 1-6 Alkyl, C 1-6 alkoxy, where 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 provides a compound of formula II-F*: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein each R 5a H, halogen, C 1-6 Alkyl, C 1-6 alkoxy, where 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 provides a compound of formula II-G: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein each R 5a H, halogen, C 1-6 Alkyl, C 1-6alkoxy, where 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 provides a compound of formula II-G*: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein each R 5a H, halogen, C 1-6 Alkyl, C 1-6 alkoxy, where 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 provides a compound of formula II-H: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein each R 5a H, halogen, C 1-6 Alkyl, C 1-6 alkoxy, where 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 provides a compound of formula II-H*: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein each R 5a H, halogen, C 1-6 Alkyl, C 1-6alkoxy, where 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 provides a compound of formula II-I: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein each R 5a H, halogen, C 1-6 Alkyl, C 1-6 alkoxy, where 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 provides a compound of formula II-I*: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers, and tautomers thereof, wherein each R 5a H, halogen, C 1-6 Alkyl, C 1-6 alkoxy, where 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 provides compounds of formula II-J-1, II-J-2, II-J-3, II-J-4: [ka] or 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 provides compounds of formula II-J-1*, formula II-J-2*, formula II-J-3*, formula IJ-4*: [ka] or 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 provides a compound of formula II-K: [ka] or 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 provides a compound of formula II-K*: [ka] or 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 provides compounds of formula II-L-1, II-L-2: [ka] or 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 provides compounds of formula II-L-1*, II-L-2*: [ka] or 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 provides compounds of formula II-M-1, II-M-2: [ka] or 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 provides compounds of formula II-M-1*, II-M-2*: [ka] or 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 provides a compound of formula II-N: [ka] or 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 provides a compound of formula II-N*: [ka] or 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 provides a compound of formula II-O: [ka] or 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 provides a compound of formula II-O*: [ka] or 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 provides a compound of formula II-P: [ka] or 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, and all other variables are as defined herein.

[0266] In some embodiments, the present disclosure provides a compound of formula II-P*: [ka] or 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 provides a compound of formula II-R: [ka] or 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 provides a compound of formula II-R*: [ka] or 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 provides a compound of formula II-S: [ka] or 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 provides a compound of formula II-S*: [ka] or 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, halogen, or OH. In some embodiments, X is halogen or OH. In some embodiments, X is H or halogen. In some embodiments, X is H or OH. In some embodiments, X is H. In some embodiments, X is halogen. In some embodiments, X is OH.

[0272] In some embodiments, R 1 is selected from -CN, -NO2, -C(O)NHR6, C(O)N(R6)2, -C(O)OR6, or a monocyclic heteroaryl containing one or more heteroatoms independently selected from N, S, and O, wherein heteroaryl is selected from -OH, oxo, halogen, C 1-4 Alkoxy, C 1-6 Alkyl, C 2- Optionally substituted with one or more substituents selected from C6 alkenyl, or 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4Optionally further substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl.

[0273] In some embodiments, R 1 is selected from —CN, —NO2, —C(O)NHR6, C(O)N(R6)2, —C(O)OR6.

[0274] In some embodiments, R 1 is a monocyclic heteroaryl containing one or more heteroatoms independently selected from N, S, and O, and heteroaryl is selected from -OH, oxo, halogen, C 1-4 Alkoxy, C 1-6 Alkyl, C 2- Optionally substituted with one or more substituents selected from C6 alkenyl, or 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 Optionally further substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl.

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

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

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

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

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

[0280] In some embodiments, R 1is a monocyclic heteroaryl containing one or more heteroatoms independently selected from N, S, and O, and heteroaryl is selected from -OH, oxo, halogen, C 1-4 Alkoxy, C 1-6 Alkyl, C 2- Optionally substituted with one or more substituents selected from C6 alkenyl, or 4-7 membered monocyclic heterocycloalkyl, wherein alkyl or alkoxy is selected from halogen, -NH2, -N(C1-C6 alkyl)2, -OH, -COOC 1-4 Optionally further substituted with one or more substituents selected from alkyl, -COOH, -CONH2, or 4-7 membered monocyclic heterocycloalkyl.

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

[0282] In some embodiments, R 2 is H or C 1-4 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 together with the atom to which they are attached and any intervening atoms, form a 5-6 membered heterocyclyl.

[0284] In some embodiments, the present disclosure provides a compound of formula IAA: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof.

[0285] In some embodiments, the present disclosure provides a compound of formula IAA-1: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof.

[0286] In some embodiments, the present disclosure provides a compound of formula IAB: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof.

[0287] In some embodiments, the present disclosure provides a compound of formula IAB-1: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof.

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

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

[0290] In some embodiments, the present disclosure provides a compound of formula IAC: [ka] or pharmaceutically acceptable salts, solvates, prodrugs, enantiomers, stereoisomers and tautomers thereof.

[0291] In some embodiments, the present disclosure provides a compound of formula IAC-1: [ka] or 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 -cycloalkyl, or heterocyclyl. In some embodiments, R 4 is -(CH2) m -aryl, or -(CH2) m -heteroaryl. In another embodiment, R 4 Ha-(CH2) m In another embodiment, R 4 Ha-(CH2) m -heteroaryl. In another embodiment, R 4 is heterocyclyl. In other embodiments, R 4 Ha-(CH2) m In another embodiment, R 4 is cyclohexanyl.

[0293] In other embodiments, R 4 is -(CH2) m -aryl, wherein the aryl is optionally substituted with one or more halogen, OH, or NH. In other embodiments, R 4 is -(CH2) m -heteroaryl, wherein heteroaryl is optionally substituted with one or more halogen, OH, or NH. In other embodiments, R 4 is a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more halogen, OH, or NH2.

[0294] In some embodiments, each R5 is a halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogen 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), -CHC(O)N(C 1-6 alkyl), —NHC(O)CH, aryl, and heteroaryl.

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

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

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

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

[0299] In some embodiments, R 5 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] is.

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

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

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

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

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

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

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

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

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

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

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

[0313] In some embodiments, R 5 is aryl.

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

[0315] In other embodiments, at least one R 5 is halogen or —S(O)2—C1-C6 alkyl.

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

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

[0318] In some embodiments, two R 5 together with the atom to which they are attached and any intervening atoms form a 5-7 membered heterocyclyl or a 5-7 membered heteroaryl containing at least one heteroatom selected from N, O, S; the heterocyclyl or heteroaryl may be selected from one or more R 7 is optionally substituted with

[0319] In some embodiments, a fragment of a compound of formula (I) [ka] is selected from the table below. [ka] [ka]

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

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

[0322] In some embodiments, R 6 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 In another embodiment, R 7 is oxo. In other embodiments, R 7 is C 1-6 It is alkyl.

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

[0326] In other embodiments, R 9 are halogens, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 In some embodiments, R is cycloalkyl, heterocyclyl, aryl, or heteroaryl. 9 is halogen. In some embodiments, R 9 is OH. In some embodiments, R 9 is NH. In some embodiments, R 9 is C 1-6 In some embodiments, R 9 is C 1-6 In some embodiments, R 9 is C 1-6 In some embodiments, R 9 is C 2-6 In some embodiments, R is alkenyl. 9 is C 2-6 In some embodiments, R is alkynyl. 9 is C 1-6 In some embodiments, R 9 is C 3-8 In some embodiments, R 9 is heterocyclyl. In some embodiments, R 9 is aryl. In some embodiments, R 9 or heteroaryl.

[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 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 the present disclosure include: 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]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-phenyl-ethyl]amino]-5-oxazol-2-yl-pyrimidin-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-1,2,4-triazol-5-yl)pyrimidin-2-yl]-amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-triazol-5-yl)pyrimidin-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]-amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]-amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidin-2-yl]-amino]-2-methyl-benzamide; 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methyl-2-[(1-oxo-3,4-dihydro-2H-isoquinolin-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-methyl-pyrimidine-5-carboxamide; 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)-pyrimidine-5-carboxamide; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-oxazol-2-yl-pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-oxazol-2-yl-pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-triazol-5-yl)pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-triazol-5-yl)pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-1,2,4-triazol-5-yl)pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-nitro-pyrimidin-4-yl]amino]-2-phenyl-ethanol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-pyrazol-3-yl)pyrimidin-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-oxazol-2-yl-pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-oxazol-2-yl-pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidin-2-yl]-amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-triazol-5-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-triazol-5-yl)pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-1,2,4-triazol-5-yl)pyrimidin-2-yl]-amino]-N,N-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-1,2,4-triazol-5-yl)pyrimidin-2-yl]-amino]-N,2-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-1,2,4-triazol-3-yl)-pyrimidin-2-yl]amino]-2-methyl-benzamide; 2-(3-Fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-pyrimidine-5-carboxamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]-amino]-N,N-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]-amino]-N,2-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]-amino]-N,N-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]-amino]-N,2-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-pyrimidin-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-oxadiazol-2-yl)-pyrimidin-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,2,4-oxadiazol-3-yl)-pyrimidin-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidin-2-yl]-amino]-N,N-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidin-2-yl]-amino]-N,2-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidin-2-yl]-amino]-2-methyl-benzamide; 2-(3-Fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-pyrimidine-5-carboxylic acid; 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methyl-2-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-6-yl)amino]pyrimidine-5-carboxamide; 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methyl-2-[(2-methyl-3-oxo-1,4-dihydroisoquinolin-7-yl)amino]pyrimidine-5-carboxamide; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-[(1-oxo-3,4-dihydro-2H-isoquinolin-6-yl)amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-[(2-oxo-3,4-dihydro-1H-quinolin-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-phenyl-ethyl]amino]-2-[3-methyl-4-(methylcarbamoyl)-anilino]pyrimidine-5-carboxylate; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-oxazol-2-yl-pyrimidin-2-yl]-amino]benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-1,2,4-triazol-5-yl)-pyrimidin-2-yl]amino]benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-triazol-5-yl)pyrimidin-2-yl]amino]benzamide; 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-phenyl-ethyl]amino]-5-(1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidin-2-yl]amino]benzamide; (2S)-2-[[2-(4-methylsulfonylanilino)-5-oxazol-2-yl-pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(4-methylsulfonylanilino)-5-(1H-1,2,4-triazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(4-methylsulfonylanilino)-5-(1H-triazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(4-methylsulfonylanilino)-5-(1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(4-methylsulfonylanilino)-5-(1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(4-methylsulfonylanilino)-5-(1H-tetrazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 4-[[5-Ethoxycarbonyl-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methoxy-benzoic acid; 2-[3-fluoro-4-(2-hydroxy-1,1-dimethyl-ethyl)anilino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methyl-pyrimidine-5-carboxamide; Ethyl 2-(3-methyl-4-methylsulfonyl-anilino)-4-[[(1R)-1-phenylethyl]amino]pyrimidine-5-carboxylate; 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methyl-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxamide; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-pyrazol-3-yl)pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-pyrazol-3-yl)pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(4-methylsulfonylanilino)pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(3-methylsulfonylanilino)pyrimidine-5-carboxylate; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-oxazol-2-yl-pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-oxazol-2-yl-pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-triazol-5-yl)pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-triazol-5-yl)pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-1,2,4-triazol-5-yl)pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-1,2,4-triazol-5-yl)pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carbohydroxamic acid; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 2-(4-Fluoro-3-phenyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methyl-pyrimidine-5-carboxamide; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-pyrazol-3-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-pyrazol-3-yl)pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; Ethyl 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1R)-1-phenylethyl]amino]pyrimidine-5-carboxylate; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-oxazol-2-yl-pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-triazol-5-yl)pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-1,2,4-triazol-5-yl)pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; 2-(3-Fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methyl-pyrimidine-5-carboxamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; 4-[[5-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-pyrimidin-2-yl]amino]-2-methyl-benzamide; 4-[[5-(5-ethyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; N-ethyl-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-6-yl)amino]pyrimidine-5-carboxamide; 2-(3-Fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carbohydroxamic acid; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl]amino]-2-methyl-benzamide; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-6-yl)amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-[(2-methyl-3-oxo-1,4-dihydroisoquinolin-7-yl)amino]pyrimidine-5-carboxylate; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-pyrazol-3-yl)pyrimidin-2-yl]amino]benzamide; 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-phenyl-ethyl]amino]-5-oxazol-2-yl-pyrimidin-2-yl]amino]-N-methyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidin-2-yl]amino]benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-triazol-5-yl)pyrimidin-2-yl]amino]-N-methyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-1,2,4-triazol-5-yl)pyrimidin-2-yl]amino]-N-methyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-2-yl]amino]benzamide; (2S)-2-[[5-(5-methyl-1H-pyrazol-3-yl)-2-(4-methylsulfonylanilino)-pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-[3-chloro-4-(trifluoromethyl)anilino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methyl-pyrimidine-5-carboxamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-N-methyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-N-methyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl]amino]benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidin-2-yl]amino]-N-methyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidin-2-yl]amino]benzamide; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-oxazol-2-yl-pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-methyloxazol-2-yl)-2-(4-methylsulfonylanilino)-pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-(1H-1,2,4-triazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-(1H-triazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(4-methylsulfonylanilino)-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-(1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-(1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(4-methylsulfonylanilino)-pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(4-methylsulfonylanilino)-pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(4-methylsulfonylanilino)-pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-(1H-tetrazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(4-methylsulfonylanilino)-5-(1-methyltetrazol-5-yl)pyrimidin-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-methylsulfonyl-anilino)-5-oxazol-2-yl-pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-(1H-1,2,4-triazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-(1H-triazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; N-ethyl-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxamide; 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]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-methyl-pyrimidine-5-carboxamide; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-pyrazol-3-yl)pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-pyrazol-3-yl)pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-(1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-(1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; Ethyl 2-[(3,3-dioxo-1,3lambda 6-benzoxathiol-6-yl)amino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; Ethyl 2-[(3,3-dioxo-1,3lambda6-benzoxathiol-5-yl)amino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-(1H-tetrazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 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-(2-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; Ethyl 2-(4-ethylsulfonylanilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-oxazol-2-yl-pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-triazol-5-yl)pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-1,2,4-triazol-5-yl)pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; 6-[[5-(5-ethyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 6-[[5-(5-ethyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 6-[[5-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 6-[[5-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-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-phenyl-ethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-pyrazol-3-yl)pyrimidin-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-phenyl-ethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 4-[[5-(5-ethyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[5-(5-ethyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; 4-[[5-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[5-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; Ethyl 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]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-phenyl-ethyl]amino]-N-isopropyl-2-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-6-yl)amino]pyrimidine-5-carboxamide; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-oxazol-2-yl-pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(1H-triazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(1H-1,2,4-triazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; Ethyl 2-[(2-ethyl-1-oxo-3,4-dihydroisoquinolin-6-yl)amino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(1H-tetrazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; Ethyl 4-[[(1S)-1-cyclohexyl-2-hydroxy-ethyl]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-yl-pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-(1H-triazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-(1H-1,2,4-triazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-pyrazol-3-yl)pyrimidin-2-yl]amino]-N-methyl-benzamide; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-(1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-(1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidin-2-yl]amino]-N-methyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-oxazol-2-yl-pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-(1H-tetrazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-2-yl]amino]-N-methyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-triazol-5-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-1,2,4-triazol-5-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl]amino]-N-methyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-N-methyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-N-methyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 2-chloro-4-[[5-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]benzamide; 2-chloro-4-[[5-(5-ethyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidin-2-yl]amino]-N-methyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-(5-methyloxazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-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-phenyl-ethyl]amino]pyrimidine-5-carboxylate; (2S)-2-[[5-(3-ethyl-1,2,4-oxadiazol-5-yl)-2-(4-methylsulfonylanilino)-pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-ethyl-1,3,4-oxadiazol-2-yl)-2-(4-methylsulfonyl-anilino)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-(1-methyltetrazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl]amino]benzamide; 4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methyl-benzamide; 4-[[5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methyl-benzamide; (2S)-2-[[2-(4-methylsulfonylanilino)-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-(5-methyl-1H-pyrazol-3-yl)pyrimidin-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)-indolin-1-yl]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-(5-methyloxazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-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-phenyl-ethyl]amino]-N-isopropyl-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxamide; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-pyrazol-3-yl)pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-(1-methyltetrazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; Ethyl 4-[[(1S)-1-benzyl-2-hydroxy-ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]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-phenyl-ethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-oxazol-2-yl-pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-(1H-triazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-(1H-1,2,4-triazol-5-yl)pyrimidin-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-phenyl-ethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 6-[[5-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[5-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; 6-[[5-(5-ethyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[5-(5-ethyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-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-phenyl-ethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-(1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-(1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-(1H-tetrazol-5-yl)pyrimidin-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-phenyl-ethyl]amino]-2-(2-methoxy-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(3-methoxy-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; 2-(3-Fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-isopropyl-pyrimidine-5-carboxamide; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; 4-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methyl-benzamide; 4-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methyl-benzamide; 4-[[5-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[5-(5-ethyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(5-methyloxazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-[(2-isopropyl-1-oxo-3,4-dihydroisoquinolin-6-yl)amino]pyrimidine-5-carboxylate; Ethyl 2-(2-chloro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; Ethyl 2-(3-chloro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]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-thiochromen-6-yl)amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(1-methyltetrazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-(5-methyloxazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-pyrazol-3-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-(1-methyltetrazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-oxazol-2-yl-pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-triazol-5-yl)pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-1,2,4-triazol-5-yl)pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 2-chloro-4-[[5-(5-ethyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N-methyl-benzamide; 2-chloro-4-[[5-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N-methyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]benzamide; 6-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 6-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 6-[[5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 6-[[5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-tetrazol-5-yl)pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; (2S)-2-[[5-(5-ethyl-1,3,4-oxadiazol-2-yl)-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-ethyl-1,2,4-oxadiazol-5-yl)-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-isopropyl-1,2,4-oxadiazol-5-yl)-2-(4-methylsulfonylanilino)-pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-isopropyl-1,3,4-oxadiazol-2-yl)-2-(4-methylsulfonylanilino)-pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl]amino]-N-methyl-benzamide; 4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; 4-[[5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; Ethyl 4-[(3S)-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-ethyl-1,3,4-oxadiazol-2-yl)-2-(3-fluoro-4-methylsulfonyl-anilino)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-ethyl-1,2,4-oxadiazol-5-yl)-2-(3-fluoro-4-methylsulfonyl-anilino)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyrimidin-2-yl]amino]-2-methyl-benzamide; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-(5-methyloxazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-2-yl]amino]-2-methyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl]amino]-2-methyl-benzamide; [2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-5-yl]-pyrrolidin-1-yl-methanone; 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-(2-methoxyethyl)-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxamide; 6-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 6-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 6-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 6-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one;; 7-[[5-(5-ethyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 7-[[5-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-(1-methyltetrazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; Ethyl 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[3-(hydroxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]pyrimidine-5-carboxylate; N-Cyclopentyl-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-6-yl)amino]pyrimidine-5-carboxamide; 2-chloro-4-[[5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]benzamide; 2-chloro-4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]benzamide; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 4-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; 4-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; (2S)-2-[[5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-2-(4-methylsulfonylanilino)-pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-(4-methylsulfonylanilino)-pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-(3-Fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-(2-methoxyethyl)-pyrimidine-5-carboxamide; 2-(3-Fluoro-4-methylsulfonyl-anilino)-N-(2-hydroxyethyl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methyl-pyrimidine-5-carboxamide; Ethyl 4-[[(1S)-1-(4-cyclophenyl)-2-hydroxy-ethyl]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-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(5-ethyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-pyrazol-3-yl)pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-(3-ethyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-(5-ethyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyloxazol-2-yl)pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1H-1,2,4-triazol-3-yl)pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-N-methyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-N-methyl-benzamide; 2-chloro-4-[[5-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 2-chloro-4-[[5-(5-ethyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-chloro-benzamide; 4-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-chloro-benzamide; 6-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; 6-[[5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1-methyltetrazol-5-yl)pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; (2S)-2-[[5-(5-isopropyl-1,3,4-oxadiazol-2-yl)-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-isopropyl-1,2,4-oxadiazol-5-yl)-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-2-(4-methylsulfonylanilino)-pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-2-(4-methylsulfonylanilino)-pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; N-Cyclopentyl-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxamide; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl]amino]-3,4-dihydro-1H-quinolin-2-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-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-methylsulfonyl-anilino)-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl]amino]-N,2-dimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 6-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; 6-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-1-one; 7-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-(5-ethyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-(3-ethyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-chloro-4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N-methyl-benzamide; 2-chloro-4-[[5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N-methyl-benzamide; 4-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyrimidin-2-yl]amino]benzamide; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-[(3-isopropyl-2,5-dioxo-3,4-dihydro-1H-1,4-benzodiazepin-7-yl)amino]pyrimidine-5-carboxylate; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-2-yl]amino]benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl]amino]benzamide; 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)-N-methylsulfonyl-pyrimidine-5-carboxamide; (2S)-2-[[2-(4-methylsulfonylanilino)-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-[3-chloro-4-(trifluoromethyl)anilino]-N-cyclopentyl-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-pyrimidine-5-carboxamide; (2S)-2-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-(3-fluoro-4-methylsulfonyl-anilino)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-2-(3-fluoro-4-methylsulfonyl-anilino)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(4-methylsulfonylanilino)-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(4-methylsulfonylanilino)-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-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-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 4-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-chloro-N-methyl-benzamide; 4-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-chloro-N-methyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 7-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 7-[[5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 6-[[5-(5-ethyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[5-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; (2S)-2-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-(3-Fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methylsulfonyl-pyrimidine-5-carboxamide; 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)-N-(2,2,2-trifluoroethyl)-pyrimidine-5-carboxamide; Ethyl 4-[[(1S)-1-(hydroxymethyl)-2-(1H-indol-3-yl)ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyrimidin-2-yl]amino]-2-methyl-1,4-dihydro-isoquinolin-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyrimidin-2-yl]amino]-2-methyl-3,4-dihydro-isoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-2-yl]amino]-2-methyl-1,4-dihydro-isoquinolin-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-2-yl]amino]-2-methyl-3,4-dihydro-isoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl]amino]-2-methyl-1,4-dihydroisoquinolin-3-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl]amino]-2-methyl-3,4-dihydroisoquinolin-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-oxadiazol-5-yl]-2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-2-(3-fluoro-4-methylsulfonyl-anilino)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-2-(3-fluoro-4-methylsulfonyl-anilino)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; 4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl]amino]-N,N,2-trimethyl-benzamide; 7-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 7-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-chloro-4-[[5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 2-chloro-4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyrimidin-2-yl]amino]-N-methyl-benzamide; (2S)-2-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl]amino]-N-methyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-2-yl]amino]-N-methyl-benzamide; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-methyl-4-methylsulfonyl-anilino)-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]pyrimidin-4-yl]amino]-2-phenyl-ethanol; 4-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-chloro-N,N-dimethyl-benzamide; 4-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-chloro-N,N-dimethyl-benzamide; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 7-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; (2S)-2-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-2-(3-chloro-4-methylsulfonyl-anilino)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-2-(3-chloro-4-methylsulfonyl-anilino)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-2H-thiochromen-6-yl)amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; 6-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[5-[3-(difluoromethyl)-1,2,4-oxadiazol-5-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 2-chloro-4-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl]amino]-N,N-dimethyl-benzamide; 6-[[5-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-chloro-4-methylsulfonyl-anilino)-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-2-yl]amino]-1,1-dioxo-3,4-dihydro-2H-thiochromen-4-ol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; Ethyl 2-(4-carbamoyl-3-chloro-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]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-phenyl-ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]hexanoate; Ethyl 6-[5-[2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]hexanoate; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-methylsulfonyl-pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-[(1-oxoisoindolin-5-yl)amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-[(1-oxo-2,3,4,5-tetrahydro-2-benzazepin-7-yl)amino]pyrimidine-5-carboxylate; 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-[(1-oxo-3,4-dihydro-2H-isoquinolin-6-yl)amino]pyrimidine-5-carbonitrile; Ethyl 4-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-2-[(1-oxo-3,4-dihydro-2H-isoquinolin-6-yl)amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-(4-methoxyphenyl)ethyl]amino]-2-[(1-oxo-3,4-dihydro-2H-isoquinolin-6-yl)amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-(3-methoxyphenyl)ethyl]amino]-2-[(1-oxo-3,4-dihydro-2H-isoquinolin-6-yl)amino]pyrimidine-5-carboxylate; 5-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]isoindolin-1-one; 5-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino]isoindolin-1-one; Ethyl 2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]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-oxadiazol-5-yl)pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; Ethyl 2-[[5-ethoxycarbonyl-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]-(1-oxo-2,3,4,5-tetrahydro-2-benzazepin-7-yl)amino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate; 2-(3-fluoro-4-methylsulfonyl-anilino)-9-[(1S)-2-hydroxy-1-phenyl-ethyl]-7H-purin-8-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-3,3-dimethyl-2,4-dihydroisoquinolin-1-one; 5-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-3,3-dimethyl-isoindolin-1-one; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-vinyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-2-(2-trimethylsilylethoxymethyl)-3,4-dihydroisoquinolin-1-one; [6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-1-oxo-3,4-dihydroisoquinolin-2-yl]methyl 2,2-dimethylpropanoate; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]amino]-2-(2-trimethylsilylethoxymethyl)-3,4-dihydroisoquinolin-1-one; (2S)-2-[[5-[3-[(dimethylamino)methyl]-1,2,4-oxadiazol-5-yl]-2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]pyrimidin-4-yl]amino]-2-phenyl-ethanol; 6-[[4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1-methylpyrazol-4-yl)pyrimidin-2-yl]amino]-3,4-dihydro-2H-isoquinolin-1-one; 5-[[5-[3-[(dimethylamino)methyl]-1,2,4-oxadiazol-5-yl]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidin-2-yl]amino]isoindolin-1-one; (2S)-2-[[2-[(1,1-dioxo-3,4-dihydro-2H-thiochromen-6-yl)amino]-5-[3-(pyrrolidin-1-ylmethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-4-yl]amino]-2-phenyl-ethanol; 5-[[4-[[(1S)-2-Hydroxy-1-phenyl-ethyl]amino]-5-[3-(pyrrolidin-1-ylmethyl)-1,2,4-oxadiazol-5-yl]pyrimidin-2-yl]amino]isoindolin-1-one or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

[0336] In some embodiments, the compound is: 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methyl-2-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-6-yl)amino]pyrimidine-5-carboxamide; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-[(1-oxo-3,4-dihydro-2H-isoquinolin-6-yl)amino]pyrimidine-5-carboxylate; Ethyl 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-pyrimidine-5-carboxylate; 2-(3-Fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methyl-pyrimidine-5-carboxamide; 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methyl-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxamide; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-6-yl)amino]pyrimidine-5-carboxylate; Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; N-ethyl-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxamide; 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)-N-(2,2,2-trifluoroethyl)-pyrimidine-5-carboxamide; N-ethyl-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-6-yl)amino]pyrimidine-5-carboxamide; 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-methylsulfonyl-anilino)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; 2-(3-Fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxamide; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-(1,3,4-oxadiazol-2-yl)pyrimidin-4-yl]amino]-2-phenyl-ethanol; (2S)-2-[[2-(3-fluoro-4-methylsulfonyl-anilino)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-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-dihydroisoquinolin-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.

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

[0338] Compounds of the present invention, and their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs, may exist in their tautomeric form (for example, as an amide or imino ether), and all such tautomeric forms are contemplated herein as part of the present invention.

[0339] The compounds of the present invention may contain asymmetric or chiral 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 the cis- and trans-forms, as well as mixtures, are encompassed within the scope of the present invention. Each compound disclosed herein includes all enantiomers that conform to the compound's general structure. 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] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers to the 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] It is also possible that compounds of the present invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

[0342] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the present compounds (including salts, solvates, esters, and prodrugs of the compounds, and salts, solvates, and esters of the prodrugs), including, for example, enantiomers (which may exist even when no asymmetric carbon is present), rotameric forms, atropisomers, and diastereomeric forms, which may exist due to asymmetric carbons on various substituents, are contemplated within the scope of the present invention, as are positional isomers (e.g., 4-pyridyl, 3-pyridyl, etc.). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, keto-enol and imine-enamine forms of the compounds are all included in the invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be mixed, for example, as a racemate or with all other or selected stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations. Use of the terms "salts," "solvates," "esters," "prodrugs," and the like, is intended to apply equally to enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrug salts, solvates, esters and prodrugs of the compounds of the invention.)

[0343] The compounds of formula I may form salts which are also within the scope of the present invention, and reference herein to a compound of formula I is understood to include reference to salts thereof, unless otherwise specified.

[0344] The present invention relates to compounds that are modulators of hematopoietic progenitor kinase 1 (HPK1).

[0345] In one embodiment, the compounds of the invention are inhibitors of hematopoietic progenitor kinase 1 (HPK1).

[0346] In some embodiments, the compounds of Formula I are selective inhibitors of hematopoietic progenitor kinase 1 (HPK1).

[0347] The present invention relates to compounds that are modulators of hematopoietic progenitor kinase 1 (HPK1).

[0348] In one embodiment, the compounds of the invention are inhibitors of hematopoietic progenitor kinase 1 (HPK1).

[0349] In some embodiments, the compounds of Formula I are selective inhibitors of hematopoietic progenitor kinase 1 (HPK1).

[0350] The present invention relates to compounds that are modulators of the leucine-rich repeat kinase 2 (LRRK2) protein.

[0351] In one embodiment, the compounds of the invention are inhibitors of the leucine-rich repeat kinase 2 (LRRK2) protein.

[0352] In some embodiments, the compounds of Formula I are selective inhibitors of the leucine-rich repeat kinase 2 (LRRK2) protein.

[0353] The present invention relates to compounds that are modulators of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0354] In one embodiment, the compounds of the invention are inhibitors of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0355] In some embodiments, the compounds of Formula I are selective inhibitors of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0356] The present invention relates to compounds that are modulators of interleukin-1 receptor-associated kinase 1 (IRAK1).

[0357] In one embodiment, the compounds of the invention are inhibitors of interleukin-1 receptor-associated kinase 1 (IRAK1).

[0358] In some embodiments, the compounds of Formula I are selective inhibitors of interleukin-1 receptor-associated kinase 1 (IRAK1).

[0359] The present invention relates to compounds that are modulators of interleukin-1 receptor-associated kinase 4 (IRAK4).

[0360] In one embodiment, the compounds of the invention are inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4).

[0361] In some embodiments, the compounds of Formula I are selective inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4).

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

[0363] In one embodiment, the compounds of the present invention are inhibitors of Janus kinases (JAKs), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2).

[0364] In some embodiments, the inhibitor is a selective inhibitor of Janus kinases (JAKs), 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 pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and to pharmaceutical compositions comprising one or more compounds described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof. Compound synthesis method

[0366] The compounds of the invention may be made in a variety of ways, including standard chemistry. Suitable synthetic routes are illustrated in the schemes set out below.

[0367] Compounds of formula (I) can be prepared by methods known in the art of organic synthesis, as defined in part by the synthetic schemes below. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," Third Edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods readily apparent to those skilled in the art. The presence of a stereocenter in a compound of formula (I) will be recognizable by those skilled in the art by the selection process and reaction conditions and sequences. Accordingly, the present invention (unless specified in the synthesis) encompasses both possible stereoisomers, including not only racemates but also individual enantiomers and / or diastereomers. When 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. Separation of the final product, an intermediate, or a starting material can 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 made from commercially available starting materials or can be 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, or modifications thereof that will be understood by those skilled in the art, along with synthetic methods known in the art of organic synthetic chemistry.Suitable methods include, but are not limited to, the methods described below.The compounds of the present invention can be synthesized according to the steps outlined in General Procedure A, involving the assembly intermediates or compounds of different sequences.The starting materials are commercially available or prepared by any of the known procedures reported in the literature, or as shown below.

[0370] General Procedure A [ka] Methods of Use of the Disclosed Compounds

[0371] Another aspect of the present invention relates to a method for treating a disease or disorder associated with the regulation of hematopoietic progenitor kinase 1 (HPK1), comprising administering to a patient in need of treatment for a disease or disorder associated with the regulation of HPK1 an effective amount of a composition or compound of formula (I).

[0372] In another aspect, the present invention relates to a method for inhibiting hematopoietic progenitor kinase 1 (HPK1), the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

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

[0374] The present invention also relates to the use of an inhibitor of hematopoietic progenitor kinase 1 (HPK1) for the preparation of a medicament for use in the treatment, prevention, inhibition or elimination of a disease or condition mediated by HPK1, wherein the medicament comprises a compound of formula (I).

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

[0376] Another aspect of the present invention relates to a compound of formula (I) for use in the manufacture of a medicament for the treatment of a disease associated with the inhibition of hematopoietic progenitor kinase 1 (HPK1).

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

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

[0379] In another aspect, the present invention relates to a method for inhibiting leucine-rich repeat kinase 2 (LRRK2) protein, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

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

[0381] The present invention also relates to the use of an inhibitor of leucine-rich repeat kinase 2 (LRRK2) for the preparation of a medicament for use in the treatment, prevention, inhibition or elimination of a disease or condition mediated by LRRK2 protein, wherein the medicament comprises a compound of formula (I).

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

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

[0384] In another aspect, the present invention relates to the use of compounds of formula (I) in the treatment of diseases associated with the inhibition of the 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 associated with regulation of the FMS-like tyrosine kinase 3 (FLT3) gene, comprising administering to a patient in need of treatment for a disease or disorder associated with regulation of FLT3 an effective amount of a composition or compound of formula (I).

[0387] In another aspect, the present invention relates to a method for inhibiting the FMS-like tyrosine kinase 3 (FLT3) gene, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

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

[0389] The present invention also relates to the use of an inhibitor of FLT3 for the preparation of a medicament for use in the treatment, prevention, inhibition or elimination of a disease or condition mediated by the FMS-like tyrosine kinase 3 (FLT3) gene, wherein the medicament comprises a compound of formula (I).

[0390] In another aspect, the present invention relates to a method for manufacturing a medicament for treating, preventing, inhibiting or eliminating a disease or condition mediated by the FMS-like tyrosine kinase 3 (FLT3) gene, wherein the medicament 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 medicament for the treatment of a disease associated with the inhibition of the FMS-like tyrosine kinase 3 (FLT3) gene.

[0392] In another aspect, the present invention relates to the use of compounds of formula (I) in the treatment of diseases associated with the 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 associated with the regulation of interleukin-1 receptor-associated kinase 1 (IRAK1), comprising administering to a patient in need of treatment for a disease or disorder associated with the regulation of IRAK1 an effective amount of a composition or compound of formula (I).

[0395] In another aspect, the present invention relates to a method for inhibiting interleukin-1 receptor-associated kinase 1 (IRAK1), the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

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

[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 medicament for use in the treatment, prevention, inhibition or elimination of a disease or condition mediated by IRAK1, wherein the medicament comprises a compound of formula (I).

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

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

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

[0401] Another aspect of the present invention relates to a method for treating a disease or disorder associated with the regulation of interleukin-1 receptor-associated kinase 4 (IRAK4), comprising administering to a patient in need of treatment for a disease or disorder associated with the regulation of IRAK4 an effective amount of a composition or compound of formula (I).

[0402] In another aspect, the present invention relates to a method for inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

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

[0404] The present invention also relates to the use of an inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) for the preparation of a medicament for use in the treatment, prevention, inhibition or elimination of a disease or condition mediated by IRAK4, wherein the medicament comprises a compound of formula (I).

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

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

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

[0408] Another aspect of the present invention relates to a method for treating a disease or disorder associated with the regulation 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 associated with the regulation of JAKs an effective amount of a composition or compound of formula (I).

[0409] In another aspect, 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 to a patient in need thereof an effective amount of a compound of formula (I).

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

[0411] The present invention also relates to the use of an inhibitor of Janus kinase (JAK), including Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2), for the preparation of a medicament for use in the treatment, prevention, inhibition, or elimination of a disease or condition mediated by JAK, wherein the medicament comprises a compound of formula (I).

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

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

[0414] Another aspect of the present invention relates to the use of compounds of formula (I) in the treatment of diseases 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).

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

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

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

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

[0419] Another aspect of the present invention relates to a method for treating cancer, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

[0420] Another aspect of the present invention relates to a method for treating or preventing cancer, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I).

[0421] In one embodiment, the present invention relates to the use of an inhibitor of hematopoietic progenitor kinase 1 (HPK1) for the preparation of a medicament for use in the treatment, prevention, inhibition or elimination of a disease or disorder related to cancer.

[0422] In some embodiments, the disease, disorder, or condition is selected from cancer, an autoimmune disease, an inflammatory disease, a viral infection, male fertility control, benign hyperplasia, sepsis, a vascular disorder, atherosclerosis, and a neurodegenerative disorder.

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

[0424] In some embodiments, the cancer is selected from bladder cancer, bone cancer, brain cancer, breast cancer, heart cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, stomach cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymic 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 condition is an autoimmune disease selected from chronic obstructive pulmonary disease (COPD), asthma, bronchitis, lupus, dermatomyositis, Sjogren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type 1 diabetes and its associated complications, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto's thyroiditis and autoimmune thyroiditis), contact dermatitis, as well as eczematous dermatitis, inflammatory bowel disease, interferonopathy, atherosclerosis, and amyotrophic lateral sclerosis.

[0427] In some embodiments, the asthma is selected from chronic asthma, severe asthma, intrinsic asthma, extrinsic asthma, dust asthma, and infantile asthma.

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

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

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

[0431] In some embodiments, the 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 disease.

[0433] In some embodiments, the inflammatory disease is selected from rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease, chronic obstructive pulmonary disease (COPD), inflammatory liver disease, inflammatory bowel disease, endotoxin-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, the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis.

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

[0438] In some embodiments, the viral infection is an infection caused by a virus selected from human adenovirus, human cytomegalovirus, Kaposi's sarcoma-associated herpesvirus, hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus, human immunodeficiency virus (HIV), HPS-associated hantavirus, Sin Nombre virus, rotavirus, echovirus, foot-and-mouth disease virus, coxsackievirus, West Nile virus, Ebola virus, Ross River virus, human papillomavirus, and coronavirus.

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

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

[0441] In some embodiments, the disease, disorder, or condition is male fertility control.

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

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

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

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

[0446] In some embodiments, the vascular disorder is selected from erythematous pain, peripheral arterial 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, the 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, the neurodegenerative disease is a disease, disorder, or symptom selected from Alzheimer's disease, vascular dementia, frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), dementia with Lewy bodies, collagen-predominant senile dementia, Pick's disease (PiD), argyrophilic grain disease, amyotrophic lateral sclerosis (ALS), other motor neuron diseases, Guam Parkinson's disease-dementia complex, FTDP-17, Ritiko-Bodidig disease, multiple sclerosis, traumatic brain injury (TBI), and Parkinson's disease.

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

[0452] The compounds of the disclosed invention can be administered in an effective amount to treat or prevent a disorder in a subject and / or to prevent its onset.

[0453] Administration of the disclosed compounds can be via any mode of administration for therapeutic agents, including systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical modes of administration.

[0454] Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid, or liquid dosage forms, such as, for example, injections, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, solutions, suspensions, and the like, optionally in unit dosage amounts, consistent with conventional pharmaceutical practice. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, or intramuscular form, all of which forms well known to those of ordinary skill in the pharmaceutical arts can be used.

[0455] Exemplary pharmaceutical compositions comprise a compound of the invention in a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier, such as a) a diluent, such as purified water, triglyceride oil, such as hydrogenated or partially hydrogenated vegetable oil or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, such as EPA or DHA, or esters, triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, such as 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) a binder, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, Magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if desired; d) disintegrating agents 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 dispersing agents such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul G-12, captex 355, gelucire, vitamin ETGPS or other acceptable emulsifiers; and / or g) agents that enhance absorption of the compound, such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG 400, PEG 200.

[0456] Liquid, particularly injectable compositions can be prepared, for example, by dissolving, dispersing, etc. For example, the disclosed compounds are dissolved or mixed in a pharmaceutically acceptable solvent, such as water, saline, aqueous dextrose, glycerol, ethanol, etc., to form an injectable 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 can be prepared from fatty emulsions or suspensions; polyalkylene glycols such as propylene glycol are used as the carrier.

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

[0459] The disclosed compounds can also be delivered by using monoclonal antibodies as individual carriers to which the disclosed compounds are bound. The disclosed compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidophenol, or polyethylene oxide polylysine substituted with palmitoyl residues. Furthermore, the disclosed compounds can be coupled to classes of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyepsiloncaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels. In embodiments, the disclosed compounds are not covalently bound to polymers, such as polycarboxylic acid polymers or polyacrylates. Parenteral injection administration is generally used via subcutaneous, intramuscular, or intravenous injection and infusion. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for dissolving in liquid prior to 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 comprise an excipient, diluent, or surfactant. In some embodiments, the pharmaceutical composition may further comprise an additional pharmaceutically active agent. In some embodiments, the additional therapeutic agent is selected from an immune checkpoint inhibitor, a cell-based therapy, and a cytokine therapy.

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

[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, the cell-based therapy is a cancer vaccine.

[0465] In some embodiments, the cancer vaccine is selected from an anti-tumor vaccine or a neoantigen-based vaccine.

[0466] Cell-based therapies typically involve removing immune cells from the blood or tumor of a cancer-afflicted subject, where the tumor-specific immune cells are activated, expanded, and then infused back into the cancer-afflicted 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, the cancer vaccine is based on natural killer cells.

[0469] In some embodiments, the cancer vaccine is based on lymphokine-activated killer cells.

[0470] In some embodiments, the cancer vaccine is based on cytotoxic T cells.

[0471] In some embodiments, the cancer vaccine is dendritic cell-based.

[0472] In some embodiments, the cell-based therapy is selected from CAR-T therapy (e.g., chimeric antigen receptor T cells, which are T cells engineered to target a specific antigen), TIL therapy (e.g., administration of tumor-infiltrating lymphocytes), and TCR gene therapy.

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

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

[0475] The compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the pharmaceutical compositions of the present invention can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the disclosed compounds by weight or volume.

[0476] Dosage regimens utilizing the disclosed compounds are selected according to a variety of factors, including the type, species, age, weight, sex, and condition of the patient; the severity of the condition being treated; the route of administration; the patient's renal or hepatic function; and the particular disclosed compound being employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the agent required to prevent, counter, or arrest the progression of the condition.

[0477] Effective dosages of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5,000 mg of the disclosed compounds required to treat the symptoms. Compositions for in vivo or in vitro use can include about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1,000, 1,250, 2,500, 3,500, or 5,000 mg of the disclosed compounds, or any range from one amount to another listed in the dosage list. In one embodiment, the composition is in the form of a scoreable tablet. [Example]

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

[0479] JPEG2024535867000184.jpg200155

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

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

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

[0483] JPEG2024535867000185.jpg213170JPEG2024535867000186.jpg252170JPEG2024535867000187.jpg219170JPEG2024535867000188.jpg216170JPEG2024535867000189.jpg248170JPEG2024535867000190.jpg234170JPEG2024535867000191.jpg216170JPEG2024535867000192.jpg255170JPEG2024535867000193.jpg234170JPEG2024535867000194.jpg255170JPEG2024535867000195.jpg222170JPEG2024535867000196.jpg252170JPEG2024535867000197.jpg243170JPEG2024535867000198.jpg245170JPEG2024535867000199.jpg210170JPEG2024535867000200.jpg252170JPEG2024535867000201.jpg245170JPEG2024535867000202.jpg252170JPEG2024535867000203.jpg234170JPEG2024535867000204.jpg251170JPEG2024535867000205.jpg234170JPEG2024535867000206.jpg234170JPEG2024535867000207.jpg252170JPEG2024535867000208.jpg243170JPEG2024535867000209.jpg251170JPEG2024535867000210.jpg234170JPEG2024535867000211.jpg216170JPEG2024535867000212.jpg248170JPEG2024535867000213.jpg234170JPEG2024535867000214.jpg216170JPEG2024535867000215.jpg216170JPEG2024535867000216.jpg216170JPEG2024535867000217.jpg252170JPEG2024535867000218.jpg216170JPEG2024535867000219.jpg248170JPEG2024535867000220.jpg216170JPEG2024535867000221.jpg234170JPEG2024535867000222.jpg216170JPEG2024535867000223.jpg245170JPEG2024535867000224.jpg243170JPEG2024535867000225.jpg251170JPEG2024535867000226.jpg251170JPEG2024535867000227.jpg251170JPEG2024535867000228.jpg234170JPEG2024535867000229.jpg243170JPEG2024535867000230.jpg210170JPEG2024535867000231.jpg251170JPEG2024535867000232.jpg234170JPEG2024535867000233.jpg243170JPEG2024535867000234.jpg225170JPEG2024535867000235.jpg216170JPEG2024535867000236.jpg216170JPEG2024535867000237.jpg225170JPEG2024535867000238.jpg234170JPEG2024535867000239.jpg225170JPEG2024535867000240.jpg243170JPEG2024535867000241.jpg243170JPEG2024535867000242.jpg216170JPEG2024535867000243.jpg210170JPEG2024535867000244.jpg216170JPEG2024535867000245.jpg234170JPEG2024535867000246.jpg243170JPEG2024535867000247.jpg255170JPEG2024535867000248.jpg243170JPEG2024535867000249.jpg252170JPEG2024535867000250.jpg234170JPEG2024535867000251.jpg243170JPEG2024535867000252.jpg251170JPEG2024535867000253.jpg251170JPEG2024535867000254.jpg225170JPEG2024535867000255.jpg252170JPEG2024535867000256.jpg255170JPEG2024535867000257.jpg252170JPEG2024535867000258.jpg234170JPEG2024535867000259.jpg227170JPEG2024535867000260.jpg227170JPEG2024535867000261.jpg243170JPEG2024535867000262.jpg251170JPEG2024535867000263.jpg243170JPEG2024535867000264.jpg251170JPEG2024535867000265.jpg251170JPEG2024535867000266.jpg234170JPEG2024535867000267.jpg243170JPEG2024535867000268.jpg234170JPEG2024535867000269.jpg234170JPEG2024535867000270.jpg243170JPEG2024535867000271.jpg216170JPEG2024535867000272.jpg234170JPEG2024535867000273.jpg234170JPEG2024535867000274.jpg251170JPEG2024535867000275.jpg251170JPEG2024535867000276.jpg225170JPEG2024535867000277.jpg225170JPEG2024535867000278.jpg251170JPEG2024535867000279.jpg251170JPEG2024535867000280.jpg225170JPEG2024535867000281.jpg243170JPEG2024535867000282.jpg243170JPEG2024535867000283.jpg245170JPEG2024535867000284.jpg252170JPEG2024535867000285.jpg216170JPEG2024535867000286.jpg251170JPEG2024535867000287.jpg216170JPEG2024535867000288.jpg225170JPEG2024535867000289.jpg243170JPEG2024535867000290.jpg251170JPEG2024535867000291.jpg225170JPEG2024535867000292.jpg251170JPEG2024535867000293.jpg251170JPEG2024535867000294.jpg243170JPEG2024535867000295.jpg243170JPEG2024535867000296.jpg243170JPEG2024535867000297.jpg251170JPEG2024535867000298.jpg234170JPEG2024535867000299.jpg234170JPEG2024535867000300.jpg243170JPEG2024535867000301.jpg243170JPEG2024535867000302.jpg234170JPEG2024535867000303.jpg216170JPEG2024535867000304.jpg251170JPEG2024535867000305.jpg234170JPEG2024535867000306.jpg251170JPEG2024535867000307.jpg251170JPEG2024535867000308.jpg243170JPEG2024535867000309.jpg243170JPEG2024535867000310.jpg255170JPEG2024535867000311.jpg252170JPEG2024535867000312.jpg255170JPEG2024535867000313.jpg255170JPEG2024535867000314.jpg225170JPEG2024535867000315.jpg251170JPEG2024535867000316.jpg245170JPEG2024535867000317.jpg225170JPEG2024535867000318.jpg216170JPEG2024535867000319.jpg243170J PEG2024535867000320.jpg216170JPEG2024535867000321.jpg255170JPEG2024535867000322.jpg255170JPEG2024535 867000323.jpg225170JPEG2024535867000324.jpg216170JPEG2024535867000325.jpg216170JPEG2024535867000326. jpg251170JPEG2024535867000327.jpg251170JPEG2024535867000328.jpg216170JPEG2024535867000329.jpg210170.

[0484] General Synthetic Procedures and Examples of Compound Preparation.

[0485] Preparation of monochlorides.

[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-phenylethan-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 h and concentrated under reduced pressure. The residue was subjected to silica gel CC elution with a mixture of EtOAc and n-hexane (1:2) to give 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-phenylethan-1-ol. The product was analyzed by LCMS: [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) was added (R)-1-phenyl-ethylamine (60 mg, 0.497 mmol) and DIPEA (64 mg, 0.497 mmol) at room temperature. After stirring the reaction for 3 hours, the mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography (EtOAc:n-hexane = 1:2) to give P3 (54 mg, 39% yield). The product was analyzed by LCMS.

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

[0490] Preparation 5: Ethyl 2-chloro-4-{[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidine-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-phenylethan-1-ol. The product was analyzed by LCMS.

[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-phenylethan-1-ol. The product was analyzed by LCMS.

[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-phenylpropan-1-ol instead of (S)-2-amino-2-phenylethan-1-ol. The product was analyzed by LCMS.

[0493] Preparation 8: Ethyl 2-chloro-4-{[(1S)-1-(4-cyclophenyl)-2-hydroxyethyl]-amino}pyrimidine-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-phenylethan-1-ol. The product was analyzed by LCMS.

[0494] Preparation 9: Ethyl 2-chloro-4-[(2-fluoro-1-phenylethyl)amino]pyrimidine-5-carboxylate [ka] The compound was synthesized according to the procedure described in Preparation 1, using 2-fluoro-1-phenylethanamine instead of (S)-2-amino-2-phenylethan-1-ol. The product was analyzed by LCMS.

[0495] Preparation 10: Ethyl 2-chloro-4-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidine-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-phenylethan-1-ol. The product was analyzed by LCMS.

[0496] Preparation 11: Ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-(pyridin-3-ylmethyl)ethyl]amino}pyrimidine-5-carboxylate [ka] The compound was synthesized according to the procedure described in Preparation 1, using (2S)-2-amino-3-pyridin-3-ylpropan-1-ol instead of (S)-2-amino-2-phenylethan-1-ol. The product was analyzed by LCMS.

[0497] Preparation 12: Ethyl 2-chloro-4-[3-(hydroxymethyl)-3,4-dihydro-1H-isoquinolin-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) was added 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (81 mg, 0.497 mmol) and DIPEA (64 mg, 0.497 mmol) at room temperature. After stirring the reaction for 3 h, the mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography (EtOAc:n-hexane = 1:2) to give 2 (50 mg, 32% yield). The product was analyzed by LCMS only.

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

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

[0500] Preparation 15: (2S)-2-[(2-chloro-5-nitro-pyrimidin-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) was added (S)-2-amino-2-phenylethan-1-ol (0.77 g, 5.67 mmol) and DIPEA (0.73 g, 5.67 mmol) at room temperature. After stirring the reaction for 3 h, the mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography (DCM:EtO = 4:1) to give P15 (1.1 g, 73% yield). 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 displacement of the second chlorine.

[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]amino}pyrimidine-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 min under microwave irradiation, diluted with EtOAc (10 mL), washed with 10% aqueous NaHCO, brine, dried over NaSO, and concentrated under reduced pressure. The residue was subjected to silica CC elution with a mixture of EtOAc and n-hexane (1:1) to give 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 LCMS.

[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 LCMS.

[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 LCMS.

[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 LCMS.

[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 LCMS.

[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 LCMS.

[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 LCMS.

[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 LCMS.

[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 LCMS.

[0512] Preparation 26: Ethyl 4-{[(1S)-2-hydroxy-1-(pyridin-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-(pyridin-3-ylmethyl)ethyl]amino}pyrimidine-5-carboxylate instead of ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (see Preparation 11). The product was analyzed by LCMS.

[0513] Preparation 27: Ethyl 4-[(2S)-2-(hydroxymethyl)-2,3-dihydro-1H-indol-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-indol-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 LCMS.

[0514] Preparation 28: Ethyl 4-{[(1S)-2-hydroxy-1-(1H-indol-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-indol-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 LCMS.

[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]amino}pyrimidine-5-carboxylate (Preparation 1; 1.0 g, 0.0031 mol) in dioxane (20 ml) was added 3-fluoro-4-(methylsulfonyl)aniline (0.59 g, 0.0031 mol) and TsOH (0.59 g, 0.0031 mmol). The reaction mixture was stirred at 100 °C for 30 minutes under microwave irradiation, cooled to room temperature, and concentrated in vacuo. The residue was dissolved in EtOAc (20 ml), washed with aqueous NaHCO (5%), and dried over sodium sulfate. The organic layer was evaporated in vacuo, and the crude product was purified by column chromatography (eluting with DCM / EtO) to give compound 210 as a solid. Yield: 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-HO (34 mg, 0.177 mmol) was added. The tube was capped and irradiated at 110 °C for 30 min. The reaction mixture was diluted with EtOAc (10 ml), washed with 10% NaHCO solution, brine, dried over NaSO, and concentrated to give a residue. The residue was purified by silica gel column chromatography (EtOAc:n-hexane = 1:1) to give compound 97 (29 mg, 36% yield). 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-HO (64 mg, 0.335 mmol) was added. The vial was capped and irradiated at 110 °C for 30 min. The reaction mixture was diluted with EtOAc (10 mL), washed with 10% NaHCO solution, brine, dried over NaSO, and concentrated to give a residue. The residue was purified by silica gel column chromatography (EtOAc:n-hexane = 1:1) to give compound 298 (75 mg, 46% yield). 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 compound was synthesized according to the procedure described in Preparation 16, using ethyl 4-{[(1S)-1-benzyl-2-hydroxyethyl]amino}-2-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 compound was synthesized according to the procedure described in Preparation 16, using ethyl 2-chloro-4-[(2-fluoro-1-phenylethyl)amino]pyrimidine-5-carboxylate (see Preparation 9) 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 + ] 477.

[0520] Preparation 34: Ethyl 4-{[(1S)-2-hydroxy-1-(pyridin-3-ylmethyl)ethyl]amino}-2-{[3-fluoro-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate [ka] The compound was synthesized according to the procedure described in Preparation 16, using ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-(pyridin-3-ylmethyl)ethyl]amino}pyrimidine-5-carboxylate (see Preparation 11) 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 + ] 490.

[0521] Preparation 35: Ethyl 2-(3-fluoro-4-methylsulfonyl-anilino)-4-[3-(hydroxymethyl)-3,4-dihydro-1H-isoquinolin-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-HO (27 mg, 0.144 mmol) was added. The vial was capped and irradiated at 110 °C for 30 min. The reaction mixture was diluted with EtOAc (10 mL), washed with 10% NaHCO solution, brine, dried over NaSO, and concentrated to give a residue. The residue was purified by silica gel column chromatography (EtOAc:n-hexane = 1:1) to give compound 388 (12 mg, 17% yield). 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-indol-1-yl]-2-{[3-fluoro-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate [ka] The compound was synthesized according to the procedure described in Preparation 16, using ethyl 2-chloro-4-[(2S)-2-(hydroxymethyl)-2,3-dihydro-1H-indol-1-yl]pyrimidine-5-carboxylate (see Preparation 13) 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 + ] 487.

[0523] Preparation 37: Ethyl 4-{[(1S)-2-hydroxy-1-(1H-indol-3-ylmethyl)ethyl]amino}-2-{[3-fluoro-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate [ka] The compound was synthesized according to the procedure described in Preparation 16, using ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-(1H-indol-3-ylmethyl)ethyl]amino}pyrimidine-5-carboxylate (see Preparation 14) 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 + ] 528.

[0524] Preparation 38: Ethyl 4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-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) was added 60% NaH (0.290 g, 7.30 mmol), and the mixture was stirred at room temperature for 30 minutes. Then, SEMCl (1.21 g, 7.30 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was poured into water (200 ml) and extracted with EtO (2 × 30 ml). The organic layer was washed with water, dried over NaSO, and concentrated to give a residue. The residue was purified by silica gel column chromatography (DCM:EtO = 10:1) to give P38.2 (0.710 g, 30% yield). 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. To a mixture of P38.2 (0.710 g, 1.99 mmol) and 1,1-diphenylmethanimine (0.360 g, 2.00 mmol) in dioxane (20 ml) was added NaOtBu (0.380 g, 4.00 mmol), and a stream of argon was passed through the solution. 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 EtOAc (100 ml), the organic layer was separated, and the aqueous layer was extracted with EtOAc (50 ml). The combined organic layers were washed with water, dried over Na2SO4, and concentrated to give a residue. The residue was purified by silica gel column chromatography (DCM:Et2O=10:1) to give P38.3 (0.34 g, 34% yield) and P38.4 (0.290 g, 46% yield). 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. To a solution of compound P38.3 (0.310 g, 0.200 mmol) and hydroxylamine hydrochloride (0.100 g, 1.40 mmol) in MeOH (5 ml), 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 layers were washed with water, dried over NaSO, and concentrated to give a residue. The residue was purified by silica gel column chromatography (DCM: EtOAc = 2:1) to give P38.4 (0.120 g, 60% yield). 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. To a mixture of compound P38.4 (0.400 g, 1.37 mmol) and ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (0.440 g, 1.37 mmol, Preparation 1) in dioxane (10 mL) in a vial, Cs2CO3 (0.890 g, 2.74 mmol) was added, and a stream of argon 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 irradiated at 100 °C for 1 h. The mixture was then diluted with water (20 mL) and EtOAc (10 mL), the organic layer was separated, and the aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated to give a residue. The residue was purified by silica gel column chromatography (DCM: EtOAc = 2:1) to give 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) was added TFA (0.2 ml), and the mixture was stirred at room temperature for 16 hours. The solution was then diluted with 10% NaHCO solution, and the organic layer was separated, washed with water, dried over NaSO, and concentrated to give a residue. The residue was purified by HPLC to give compound 45 (5 mg, 6% yield). 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. To 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 added a solution of K2CO3 (2.50 g, 18.18 mmol) in water (5 mL), and the solution was purged with argon. Tetrakis(III) (0.50 g, 0.45 mmol) was added, and the mixture was refluxed under argon for 48 h. The mixture was then diluted with water (20 mL) and EtOAc (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated to give a residue. The residue was purified by silica gel column chromatography (EtOAc:n-hexane = 1:10) to give P39.2 (1.57 g, 77% yield) 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 under H (5 bar) at room temperature for 16 h. The mixture was then filtered through a pad of Celite, and the filtrate was concentrated to give P39.3 (1.05 g, 80% yield) 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. 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, TsOH·HO (0.413 g, 2.175 mmol) was added. The vial was capped and irradiated at 110 °C for 30 min. The reaction mixture was diluted with EtOAc (10 mL), washed with 10% NaHCO solution, brine, dried over NaSO, and concentrated to give a residue. The residue was purified by silica gel column chromatography (EtOAc:n-hexane = 1:1) to give Compound 195 (0.720 g, 71% yield) 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 according to the procedure described in Preparation 16, using 3-chloro-4-(trifluoromethyl)aniline instead of 4-sulfonylmethyl-3-methylaniline. 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-tetrahydroisoquinolin-6-yl)amino]pyrimidine-5-carboxylate (Compound 122) [ka]

[0536] Synthesis of P41.2. To a mixture of 6-bromo-3,4-dihydroisoquinolin-1(2H)-one P41.1 (1.00 g, 4.42 mmol) in DMF (20 ml) was added 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 cold 10% citric acid solution (100 ml) and extracted with EtOAc (2 × 20 ml). The organic layer was washed with water, 10% NaHCO3 solution, brine, dried over Na2SO4, and concentrated to give a residue. The residue was purified by silica gel column chromatography (EtOAc:n-hexane = 1:1) to give P41.2 (0.65 g, 61% yield) 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) was added 1,1-diphenylmethanimine (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) at room temperature under an argon atmosphere. After stirring the solution at 100 °C overnight, the mixture was cooled, diluted with 10% HCl (10 mL), and stirred at room temperature for 2 h. The solution was then filtered through a pad of Celite, 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 solution of 10% Na2CO3 and extracted with DCM (3 x 10 ml). The organic layer was washed with water, dried over Na2SO4, and concentrated to give a residue. The residue was recrystallized from Et2O to give P41.3 (345 mg, 86% yield) 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. To a solution of P41.3 (200 mg, 1.13 mmol) and ethyl 2-chloro-4-{[(1R)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (27 mg, 1.13 mmol) in dioxane (3 mL) in a vial, TsOH-HO (215 mg, 1.13 mmol) was added. The vial was capped and irradiated at 110 °C for 30 min. The reaction mixture was diluted with EtOAc (10 mL), washed with 10% NaHCO solution, brine, dried over NaSO, and concentrated to give a residue. The residue was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give Compound 122 (290 mg, 55% yield) 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 according to the procedure described in Preparation 16, using 2-(4-amino-2-fluorophenyl)-2-methylpropan-1-ol instead of 4-sulfonylmethyl-3-methylaniline. 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 according to the procedure described in Preparation 16, using 2-(4-amino-2-chlorophenyl)-2-methylpropan-1-ol instead of 4-sulfonylmethyl-3-methylaniline. LCMS: [MH + ] 485.

[0541] Preparation 44: Ethyl 4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-[(2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-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-dihydroisoquinolin-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-phenyl-ethyl]amino]pyrimidin-2-yl]amino]-2-methoxy-benzoic 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 according to the procedure described in Preparation 16, using 4-(methylsulfonyl)aniline instead of 4-sulfonylmethyl-3-methylaniline. 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-(propan-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-dihydroisoquinolin-6-yl)amino]-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]pyrimidine-5-carboxylate - Compound 218. [ka]

[0554] Synthesis of P56.2. To a mixture of 6-bromo-3,4-dihydroisoquinolin-1(2H)-one P56.1 (0.500 g, 1.88 mmol) in DMF (20 ml) was added 60% NaH (0.112 g, 2.82 mmol), and the mixture was stirred at room temperature for 30 minutes. EtI (0.44 g, 2.82 mmol) was then added, and the mixture was stirred at room temperature for 16 hours. The mixture was poured into cold 10% citric acid solution (100 ml) and extracted with EtOAc (2 × 20 ml). The organic layer was washed with water, 10% NaHCO3 solution, brine, dried over Na2SO4, and concentrated to give a residue. The residue was purified by silica gel column chromatography (EtOAc:n-hexane = 1:1) to give P56.2 (0.48 g, 85% yield). 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) was added 1,1-diphenylmethanimine (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) at room temperature under an argon atmosphere. After stirring the solution at 100 °C overnight, 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 pad of Celite, 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 solution of 10% Na2CO3 and extracted with DCM (3 x 10 ml). The organic layer was washed with water, dried over Na2SO4, and concentrated to give a residue. The residue was recrystallized from Et2O to give P56.3 (150 mg, 42% yield). 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. To a solution of P56.3 (150 mg, 0.79 mmol) and ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (Preparation 1, 254 mg, 0.79 mmol) in dioxane (3 mL) in a vial, TsOH-HO (150 mg, 0.79 mmol) was added. The vial was capped and irradiated at 110 °C for 30 min. The reaction mixture was diluted with EtOAc (10 mL), washed with 10% NaHCO solution, brine, dried over NaSO, and concentrated to give a residue. The residue was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give Compound 218 (135 mg, 36% yield). 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-phenyl-ethyl]amino]-2-[(2-isopropyl-1-oxo-3,4-dihydroisoquinolin-6-yl)amino]pyrimidine-5-carboxylate - Compound 316. [ka]

[0558] Synthesis of P57.2. To a solution of 6-bromo-3,4-dihydroisoquinolin-1(2H)-one P57.1 (0.500 g, 1.88 mmol) in DMF (20 ml) was added 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 cold 10% citric acid solution (100 ml) and extracted with EtOAc (2 × 20 ml). The organic layer was washed with water, 10% NaHCO3 solution, brine, dried over Na2SO4, and concentrated to give a residue. The residue was purified by silica gel column chromatography (EtOAc:n-hexane = 1:1) to give P57.2 (0.34 g, 72% yield). 1 H NMR (400 MHz, DMSO-d6): δ 7.77 (d, J=7.9 Hz, 1H), 7.54-7.51 (m, 2H), 4.86-4.80 (m, 1H), 3.41 (t, J=6.7 Hz, 2H), 2.92 (t, J=6.2 Hz, 2H), 1.12 (d, J=6.7 Hz, 6H).

[0559] Synthesis of P57.3. To a solution of P57.2 (340 mg, 1.89 mmol) in dioxane (5 mL, degassed) was added 1,1-diphenylmethanimine (275 mg, 1.52 mmol), NaOtBu (243 mg, 3.78 mmol), BINAP (58 mg, 0.127 mmol), and Pd2(dba)3 (58 mg, 0.063 mmol) at room temperature under an argon atmosphere. After stirring the solution at 100 °C overnight, the mixture was cooled, diluted with 10% HCl (10 mL), and stirred at room temperature for 2 h. The solution was then filtered through a pad of Celite, 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 solution of 10% Na2CO3 and extracted with DCM (3 × 10 mL). The organic layer was washed with water, dried over NaSO, and concentrated to give a residue, which was recrystallized from EtO to give P57.3 (145 mg, 56% yield). 1 H NMR (400 MHz, DMSO-d6): δ 7.53 (d, J=8.4 Hz, 1H), 6.44 (dd, J1=8.6 Hz, J2=2.1 Hz, 1H), 6.32 (s, 1H), 5.61 (br, 2H), 4.84-4.77 (m, 1H), 3.38 (t, J=6.6 Hz, 2H), 2.71 (t, J=6.4 Hz, 2H), 1.07 (d, J=6.6 Hz, 6H).

[0560] Synthesis of Compound 316. To a solution of P57.3 (145 mg, 0.71 mmol) and ethyl 2-chloro-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate (228 mg, 0.71 mmol) in dioxane (3 mL) in a vial, TsOH-HO (135 mg, 0.71 mmol) was added. The vial was capped and irradiated at 110 °C for 30 min. The reaction mixture was diluted with EtOAc (10 mL), washed with 10% NaHCO solution, brine, dried over NaSO, and concentrated to give a residue. The residue was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give Compound 316 (145 mg, 40% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.98 (d, J=7.2 Hz, 1H), 8.62 (s, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.52-7.50 (m, 2H), 7.38-7.32 (m, 4H), 7.25-7.21 (m, 1H), 5.29-5.25 (m, 1H), 5.15 (t, J=4.8 Hz, 1H), 4.88-4.80 (m, 1H), 4.31 (q, J=7.2 Hz, 2H), 3.87-3.82 (m, 1H), 3.75-3.70 (m, 1H), 3.38 (t, J=6.6 Hz, 2H), 2.88-2.78 (m, 2H), 1.33 (t, J=7.1 Hz, 3H), 1.13 (d, J=6.7 Hz, 6H).

[0561] Preparation of carbonic acid.

[0562] Preparation 58: 4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-{[3-methyl-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylic acid [ka] A solution of KOH (0.223 g, 3.98 mmol) in HO (1 mL) was added to a solution of ethyl 4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-{[3-methyl-4-(methylsulfonyl)phenyl]-amino}pyrimidine-5-carboxylate (0.75 g, 1.55 mmol) in EtOH (5 mL). The mixture was stirred at ambient temperature for 16 h, concentrated under reduced pressure, diluted with HO (3 mL), and acidified with 10% citric acid solution. The formed precipitate was filtered, washed with HO, and dried at 50 °C to give 0.48 g (70%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.86 (br, 1H), 10.00 (s, 1H), 9.14 (d, J=7.9 Hz, 1H), 8.60 (s, 1H), 7.73-7.66 (m, 2H), 7.57 (s, 1H), 7.39-7.22 (m, 5H), 5.29-5.11 (m, 2H), 3.86-3.70 (m, 2H), 3.14 (s, 3H), 2.54 (s, 3H).

[0563] Preparation 59: 2-{[3-fluoro-4-(methylsulfonyl)phenyl]amino}-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylic acid - Compound 42 [ka] 1N NaOH (7 ml, 0.007 mol) was added to a solution of compound 210 (1.4 g, 0.0029 mol) in EtOH (10 ml), and the reaction mixture was stirred at room temperature overnight. EtOH was evaporated. The residue was acidified with dilute HCl. The solid formed was collected by filtration and washed with water and dry ether to give the pure acid-compound 42. Yield: 1.0 g, 77%. 1 H NMR (400 MHz, DMSO-d6): δ 12.96 (br, 1H), 10.39 (s, 1H), 9.20 (d, J=8.2 Hz, 1H), 8.67 (s, 1H), 7.78 (d, J=13.3 Hz, 1H), 7.65 (t, J=8.3 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.39-7.21 (m, 5H), 5.23-5.19 (m, 2H), 3.88-3.68 (m, 2H), 3.25 (s, 3H).

[0564] Preparation 60: 4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-[(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]pyrimidine-5-carboxylic acid [ka] To a solution of compound 122 (250 mg, 0.54 mmol) in EtOH (2 mL) was added a solution of KOH (75 mg, 1.35 mmol) in HO (0.5 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was then concentrated, diluted with HO (3 mL), and acidified with 10% citric acid solution. The solid was filtered, washed with HO, and dried at 50 °C to give the title compound (175 mg, 75% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): 12.71 (br., 1H), 9.84 (s, 1H), 9.11-9.10 (m, 1H), 8.58 (s, 1H), 7.70 (d, J=Hz, 1H), 7.54-7.51 (m, 2H), 7.37-7.22 (m, 5H), 5.29-5.25 (m, 1H), 5.12-5.09 (m, 1H), 3.85-3.70 (m, 2H), 3.53-3.48 (m, 2H), 3.01-2.84 (m, 5H).

[0565] Preparation 61: 2-[(6-fluorobiphenyl-3-yl)amino]-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylic acid [ka] The compound was synthesized according to the procedure described in Preparation 58, using ethyl 2-[(6-fluorobiphenyl-3-yl)amino]-4-{[(1S)-2-hydroxy-1-phenylethyl]amino}pyrimidine-5-carboxylate instead of ethyl 4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-2-{[3-methyl-4-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxylate. 1H NMR (400 MHz, DMSO-d6): δ 12.70 (br., 1H), 9.76 (br., 1H), 9.11-9.09 (m, 1H), 8.56 (s, 1H), 7.80-7.77 (m, 1H), 7.57-7.43 (m, 6H), 7.25-7.12 (m, 6H), 5.20-5.13 (m, 2H), 3.79-3.75 (m, 1H), 3.62-3.59 (m, 1H).

[0566] Preparation 62: 2-{[3-chloro-4-(trifluoromethyl)phenyl]amino}-4-{[(...

Claims

1. A compound of formula (I): 【Chemical 1】 Or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer or tautomer thereof. [Wherein, X is H, halogen, or OH, provided that when R ４ is unsubstituted phenyl and X is H, R １ is C(O)OR ６ ; R １ is selected from -CN, -NO ２ ６ , -C(O)NHR ６ ６ , C(O)N(R ６ ２ ), -C(O)OR ２ ６ , -S(O) ２ C ２ alkyl or a monocyclic heteroaryl containing one or more heteroatoms independently selected from N, S, and O, said heteroaryl being optionally substituted with one or more substituents selected from -OH, oxo, halogen, C １－６ alkoxy, C １－４ alkyl １－６ C 、 alkenyl, or 4-7 membered monocyclic heterocycloalkyl, said alkyl or alkoxy being optionally further substituted with one or more substituents selected from halogen, -NH ２－６ ２ , -N(C ２ -C １ -C ６ alkyl), -OH, -COOC ２ alkyl, -COOH, -CONH １－４ ２ or 4-7 membered monocyclic heterocycloalkyl; ２ R is H or C １－４ alkyl; or ２ １－４ ２ ８ R and R together with the atoms to which they are attached and any intervening atoms form a 5-6 membered heterocyclyl; ２ ８ ８ ３ ３ R is H; or ３ ３ R is ３ and R ８ together with the atoms to which they are attached and any intervening atoms form a 5-6 membered cycloalkyl; R ４ is selected from -(CH ２ ) ｍ -aryl, -(CH ２ ) ｍ -heteroaryl, heterocyclyl, wherein said aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more R ８ ; Each R ５ is independently selected from halogen, C １－６ alkyl 、 C １－６ alkoxy, C １－６ haloalkyl, oxyC 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 , -CH ２ C(O)NH ２ , -CH ２ C(O)NH(C １－６ alkyl), -CH ２ C(O)N(C １－６ alkyl) ２ , -NHC(O)CH ３ , aryl, heteroaryl; or Two R ５ together with the atoms to which they are attached and any intervening atoms form a 6-7 membered heterocyclyl or 5-7 membered heteroaryl containing at least one heteroatom selected from N, O, S; said cycloalkyl or heterocyclyl is optionally substituted with one or more R ７ ; Each R ６ is independently selected from H, OH, C １－６ alkyl, -S(O) ２ -C １－６Alkyl 、 C ３－８ Independently selected from cycloalkyl, heterocyclyl, or heteroaryl, wherein said alkyl, alkoxy, heteroaryl, or heterocyclyl is optionally substituted with one or more R ９ ; or Two Rs ６ Together with the atoms to which they are attached and any intervening atoms form a 4- to 8-membered heterocyclyl; Each R ７ Is independently selected from OH, halogen, C １－６ Alkyl, aryl, oxyC １－６ Alkyl, -CH ２ OC(O)C １－６ Alkyl, or -CH ２ OCH ２ CH ２ Si(CH ３ ) ３ ; Each R ８ Is independently selected from halogen, OH, NH ２ , C １－６ Alkyl, -OC １－６ Alkyl, -NHC １－６ Alkyl, -N(C １－６ Alkyl) ２ ; Each R ９ Is independently selected from halogen, OH, NH ２ , C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－８ Cycloalkyl, heterocyclyl, aryl, or heteroaryl; and m and n are integers independently selected from 0, 1, 2, 3, 4, 5, and 6, Herein, Aryl is a cyclic aromatic hydrocarbon group in which 1 to 3 aromatic rings are fused or singly bonded to each other; 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; Heterocyclyl is a saturated or partially unsaturated 3- to 10-membered monocyclic, 7- to 12-membered bicyclic (fused ring, bridged ring, or spiro ring), or 11- to 14-membered tricyclic ring system (fused ring, bridged ring, or spiro ring) having one or more heteroatoms independently selected from O, N, S, P, Se, or B. ]

2. The compound is of formula I-A: [Chemical Formula 2] The compound according to 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, 5, and all other variables are as defined herein.]

3. The compound is of formula I-A1: [Chemical Formula 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, and all other variables are as defined herein.]

4. The compound is of formula I-B1, I-B2, I-B3, I-B3', or I-B4: [Chemical Formula 4-1] [Chemical Formula 4-2] wherein ring A represents a monocyclic heteroaryl containing one or more heteroatoms independently selected from N, S, and O, and R １０ is independently -OH, oxo, halogen, C １－４ alkoxy, C １－６Alkyl, 4- to 7-membered monocyclic heterocycloalkyl; t is an integer selected from 0, 1, 2, 3, 4; p is an integer selected from 0, 1, 2, 3, 4, and 5, and all other variables are as defined herein, the compound according to claim 1.

5. The compound is of formula I-C: 【Chemical Formula 5】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer, and tautomer thereof. [In the formula, ring B is a 6- to 7-membered heterocyclyl containing at least one heteroatom selected from N, O, S; w is an integer selected from 0, 1, 2, and 3; and all other variables are as defined herein.]

6. The compound is of formula I-D: 【Chemical Formula 6】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, enantiomer, stereoisomer, and tautomer thereof. [In the formula, 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.]

7. The compound is of formula I-E: 【Chemical Formula 7】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, enantiomer, stereoisomer, and tautomer thereof. [In the formula, 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.]

8. The compound is of formula I-F: 【Chemical Formula 8】 The compound according to claim 7, 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, and all other variables are as defined herein.]

9. wherein the compound is of formula I-G 【Chemical Formula 9】 The compound according to 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, and 5.]

10. wherein the compound is of formula I-H: 【Chemical Formula 10】 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.]

11. R １ The compound according to claim 1, wherein R is selected from the following group: 【Chemical Formula 11-1】 【Chemical Formula 11-2】 【Chemical Formula 11-3】

12. wherein the group 【Chemical Formula 12-1】 is selected from the groups shown below, the compound according to claim 1. 【Chemical Formula 12-2】 【Chemical Formula 12-3】 【Chemical Formula 12-4】

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

14. The compound according to claim 1, selected from the group consisting of: 4-[[(1S)-2-Hydroxy-1-phenyl-ethyl]amino]-N-methyl-2-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-6-yl)amino]pyrimidine-5-carboxamide; Ethyl 4-[[(1S)-2-Hydroxy-1-phenyl-ethyl]amino]-2-[(1-oxo-3,4-dihydro-2H-isoquinolin-6-yl)amino]pyrimidine-5-carboxylate; (S)-4-(((2-Hydroxy-1-phenylethyl)amino)-N-isopropyl-2-((1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-5-carboxamide; (S)-Ethyl 2-(3-Fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-pyrimidine-5-carboxylate; (S)-2-(3-Fluoro-4-methylsulfonyl-anilino)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methyl-pyrimidine-5-carboxamide; (S)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-N-methyl-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxamide; (S)-Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-6-yl)amino]pyrimidine-5-carboxylate; (S)-Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; (S)-N-Ethyl-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)pyrimidine-5-carboxamide; (S)-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(3-methyl-4-methylsulfonyl-anilino)-N-(2,2,2-trifluoroethyl)-pyrimidine-5-carboxamide; (S)-N-Ethyl-4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-6-yl)amino]pyrimidine-5-carboxamide; (S)-Ethyl 4-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-2-(3-methoxy-4-methylsulfonyl-anilino)pyrimidine-5-carboxylate; (S)-Ethyl 2-(4-Ethylsulfonyl-anilino)-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 - methylsulfonyl - anilino) - 5 - (3 - methyl - 1,2,4 - oxadiazol - 5 - yl)pyrimidin - 4 - yl]amino] - 2 - phenyl - ethanol; 2 - (3 - fluoro - 4 - methylsulfonyl - anilino) - 4 - [[(1S) - 2 - hydroxy - 1 - phenyl - ethyl]amino]pyrimidine - 5 - carboxamide; (2S) - 2 - [[2 - (3 - fluoro - 4 - methylsulfonyl - anilino) - 5 - (1,3,4 - oxadiazol - 2 - yl)pyrimidin - 4 - yl]amino] - 2 - phenyl - ethanol; (2S) - 2 - [[2 - (3 - fluoro - 4 - methylsulfonyl - anilino) - 5 - (3 - methyl - 1,2,4 - oxadiazol - 5 - yl)pyrimidin - 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 - dihydroisoquinolin - 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. Claim 15 A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier. Claim 16 The pharmaceutical composition according to claim 15, further comprising an additional pharmaceutically active agent. Use of a compound according to any one of claims 1 to 14 in the preparation of a medicament for inhibiting hematopoietic progenitor kinase 1 (HPK1), wherein the compound is administered to a subject. Use of a compound according to any one of claims 1 to 14 in the preparation of a medicament for treating a disease or disorder associated with inhibition of hematopoietic progenitor kinase 1 (HPK1), wherein the compound is administered to a subject. Use of a compound according to any one of claims 1 to 14 in the preparation of a medicament for treating a disease, disorder, or symptom, wherein the compound is administered to a subject in need of treatment. Claim 20 The use according to claim 19, wherein the disease, disorder, or symptom is selected from cancer, autoimmune disease, inflammatory disease, viral infection, male reproductive ability control, benign hyperplasia, sepsis, vascular disorder, atherosclerosis, and neurodegenerative disorder.

21. The use according to claim 20, wherein the disease, disorder, or symptom is 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 cancer, thymic carcinoma, thymoma, 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).

22. The use according to claim 17, wherein the subject is a mammal.

23. The use according to claim 22, wherein the subject is a human.

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