Thiazole derivatives and their use as ire 1 inhibitors

Abstract

The present disclosure provides compounds and compositions that are useful as partial antagonist of IRE1α RNase (PAIR) or kinase inhibiting RNase attenuator (KIRA), such as compounds of Formula (I'): or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, and compositions comprising a compound of Formula (I'), or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient, and methods of using said compounds and compositions.

Description

THIAZOLE DERIVATIVES AND THEIR USE AS IRE 1 INHIBITORSCROSS REFERENCE

[0001] This application claims priority to U.S. Provisional Application Number 63 / 541,398 filed September 29, 2023, the contents of which are incorporated herein by reference.BACKGROUND

[0002] Chronic endoplasmic reticulum (ER) stress is a cellular response to the accumulation of misfolded proteins in the ER lumen and leads to the activation of the unfolded protein response (UPR). The dual kinase endoribonuclease IRE1 is a master regulator of cell fate decisions in cells experiencing ER stress. In mammalian cells there are two paralogs of IRE1 : IREla and IREip. IRElα / β dysregulation / hyperactivity has been implicated in a range of diseases and disorders including, but not limited to, diabetes, cancer, fibrosis, neurological, neuropsychiatric, neurodegenerative or other diseases, disorders and conditions having some association with the central nervous system, dermatologic diseases and disorders, autoimmune diseases and disorders, and inflammatory diseases and disorders.

[0003] IREla controls the response to ER stress by either initiating a pro-survival response, known as the adaptive UPR or in case of chronic ER stress induces the death of the cell, a process known as the terminal UPR. During the adaptive UPR, IREla dimerizes , leading to the splicing of X-box binding protein 1 (XBP1). Spliced XBP1 initiates expression of genes involved in protein folding and secretion but also ER-associated protein degradation. This process is part of the adaptive UPR and aims to alleviate acute ER stress and to restore homeostasis. During chronic ER stress, IREla undergoes trans-autophosphorylation and oligomerizes, causing the RNase domain to relax and lose specificity for XBP1, instead degrading hundreds of ER-localized mRNAs and miRNAs. This process is called regulated IRE1 -dependent decay (RIDD). If all measures to restore ER-homeostasis fail IREla induces the activation of apoptosis leading to programmed cell death. Shifting IREla from high-order to low-order oligomerization can shift UPR from terminal to adaptive UPR. For example, shutting down IREla activity using Kinase-Inhibiting RNase Attenuators (KIRAs), and therefore inhibiting IREla, can reverse diabetes in diabetes animal models (Morita et al., 2017, Cell Metab. 25(4): 883-897. e8). KIRAs can stabilize an ATP binding site conformation that may almost completely disrupt the ability of IREl a to form an RNase active back-to-back dimer. Unfortunately, the complete inhibition of the IREla RNase domain affects other vital cellular processes such as B-lymphocyte maturation into antibody-secreting plasma cells.

[0004] For maintaining cellular homeostasis, it is desired, for example, to have IRE1α RNase activation where adaptive XBP1 mRNA splicing remains permissible but without the initiation of RIDD. Although ATP-competitive modulators can control endogenous IRE1α RNase activity through the kinase domain, such allosteric modulators have largely been shown to enforce opposite extremes of activation states. Accordingly, there is a need for compounds that engage the IRE1α kinase domain but only partially inhibit its RNase activity.

[0005] Like IRE1α, there is an allosteric relationship between the kinase and RNase domains of IRE1β. For example, IRE1β’s RNase activity can be allosterically inhibited with ATP- competitive modulators such as KIRAs. In addition, the RNase domain of IRE1β is enzymatically active and capable of cleaving an XBP1 RNA mini-substrate in vitro. Under ER stress, rather than prioritizing XBP1 cleavage, IRE1β’s RNase primarily cleaves ER-localized mRNA encoding secretory proteins. Furthermore, IRE1β may have a distinct set of mRNA substrates from IRE1α. Thus, selective IRE1β inhibition may be an attractive target in diseases mediated by IRE1β. Accordingly, there is a need for compounds that are paralog specific and dual-IRE1α / β kinase inhibitors that attenuate RNase activity.

[0006] The compounds and compositions disclosed herein are directed toward the aforementioned needs, for example, IRE1α inhibitors that may (or may not) partially retain RNase activity while inhibiting the kinase moiety of IRE1α (Partial Antagonists of IRE1α RNase activity, PAIRs), may preserve adaptive UPR but block terminal UPR, and / or may substantially limit IRE1α activity e.g., KIRAs.

[0007] Also disclosed herein are methods of using said compounds and compositions in the treatment and prevention of IRE1α / β-mediated diseases and disorders. SUMMARY

[0008] The present disclosure provides, in general, compounds and compositions that are useful as partial antagonists of IRE1α RNase (PAIR) or kinase inhibiting RNase attenuators (KIRA), and methods of using said compounds and compositions. Furthermore, the present disclosure contemplates using the disclosed compounds and compositions as PAIR or KIRA in the treatment and prevention of diseases and disorders, such as cancer, fibrosis, diabetes, neurological, neuropsychiatric, neurodegenerative or other diseases, disorders and conditions having some association with the central nervous system, dermatologic diseases and disorders, rheumatologic / autoimmune diseases and disorders, and inflammatory diseases and disorders, or in the treatment and prevention of diseases and disorders where partial antagonism of IRE1α RNase and / or attenuation of RNase activity is desired.

[0009] For example, the present disclosure provides a compound of Formula (I’):or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, wherein X1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl; Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl; L1is selected from the group consisting of -NRB-S(=O)2-, -S(=O)2-NRB-, -NRB-, - NRBC(=O)-, -C(=O)NRB-, -NRBC(=O)NRB-, -O-, and bond; R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1- C6haloalkyl; R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, C1-C6haloalkoxy, C3-C4cycloalkyl, and oxo, wherein the C1-C6alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl;R5is selected from the group consisting of C1-C6alkyl, C2-C4alkenyl, C2-C4alkynyl, C1- C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, phenyl, 4-12 membered monocyclic or bicyclic heterocyclyl, and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the C1-C6alkyl is optionally substituted with cyano or a C3-C8cycloalkyl further optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine, wherein the phenyl or 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; or R4and R5together with the atoms to which R4and R5are attached to and contiguous atoms, form a 5-6 membered heterocyclyl optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6haloalkyl, and oxo; n is integer 0-2; m is integer 0-4; and p is integer 0-4; provided that i) when L1is -NH-S(=O)2-, -NH-C(=O)-, or -C(=O)-NH-, X1is N, X2is -O- , and ring A is N-containing 6-7 membered heterocyclyl optionally comprising an additional ring O atom, then R5is not phenyl substituted with -Cl; and ii) when L1is -NH-S(=O)2-, X1is N, X2is -O-, ring A is N-containing 6-membered heterocyclyl, m is 0 or 1, R3is F, ring B is naphthyl, p is 1 or 2, and each R4is methyl or F, then R5is not C1-C4alkyl or C2-C4haloalkyl.

[0010] In some embodiments, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof, whereinX1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl; Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl; L1is selected from the group consisting of -NRB-S(=O)2-, -S(=O)2-NRB-, -NRB-, - NRBC(=O)-, -C(=O)NRB-, and bond; R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1- C6haloalkyl; R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, and C1-C6haloalkoxy, wherein the C1-C6alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl; R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, phenyl, 4-12 membered monocyclic or bicyclic heterocyclyl, and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy, wherein the phenyl or 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy;n is integer 0-2; m is integer 0-4; and p is integer 0-4; provided that when L1is -NH-S(=O)2- or -NH-C(=O)-, X1is N, X2is -O-, A is N-containing 6-membered heterocyclyl, and m is 0, then R5is not phenyl substituted with -Cl.

[0011] Also provided herein, in some embodiments, is a compound of Formula (II’):or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, wherein X1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl; Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl; L1is selected from the group consisting of -NRB-S(=O)2-, -S(=O)2-NRB-, -NRB-, - NRBC(=O)-, -C(=O)NRB-, -NRBC(=O)NRB-, -O-, and bond; R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1- C6 haloalkyl; R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy;R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, C1-C6haloalkoxy, C3-C4cycloalkyl, and oxo, wherein the C1-C6alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl; when L1is selected from the group consisting of -S(=O)2-NRB-, -NRB-, -NRBC(=O)-, - C(=O)NRB-, -NRBC(=O)NRB-, and -O-, R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, and 4-12 membered monocyclic or bicyclic heterocyclyl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl further optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine; when L1is -NRB-S(=O)2-, R5is selected from the group consisting of C1-C6heteroalkyl, C3-C8cycloalkyl, 4-12 membered monocyclic or bicyclic heterocyclyl, and C1-C6alkyl substituted with C3-C8cycloalkyl further optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine; and when L1is bond, R5is 4-12 membered monocyclic or bicyclic heterocyclyl optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine; or R4and R5together with the atoms to which R4and R5are attached to and contiguous atoms, form a 5-6 membered heterocyclyl optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6haloalkyl, and oxo; n is integer 0-2; m is integer 0-4; andp is integer 0-4.

[0012] Provided herein, in some embodiments, is a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein X1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl; Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl; L1is selected from the group consisting of -NRB-S(=O)2-, -S(=O)2-NRB-, -NRB-, - NRBC(=O)-, -C(=O)NRB-, and bond; R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1- C6haloalkyl; R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, and C1-C6haloalkoxy, wherein the C1-C6alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl;R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, and 4-12 membered monocyclic or bicyclic heterocyclyl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; n is integer 0-2; m is integer 0-4; and p is integer 0-4.

[0013] Also provided herein, in some embodiments, is a compound of Formula (III):or a pharmaceutically acceptable salt thereof, wherein X1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl; Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl; R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1- C6haloalkyl;R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, and C1-C6haloalkoxy, wherein the C1-C6alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl; R5is C3-C8cycloalkyl optionally substituted with 1-4 substituents selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; n is integer 0-2; m is integer 0-4; and p is integer 0-4.

[0014] Also provided herein, in some embodiments, is a compound of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein X1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl; Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic orbicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl; R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1- C6haloalkyl; R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, and C1-C6haloalkoxy, wherein the C1- C6alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl; R5is C1-C4alkyl- C3-C6cycloalkyl or C1-C4haloalkyl; n is integer 0-2; m is integer 0-4; and p is integer 0-4, provided that when X1is N, X2is -O-, ring A is N-containing 6-membered heterocyclyl, m is 0 or 1, R3is F, ring B is naphthyl, p is 1 or 2, and each R4is methyl or F, then R5is not C2-C4haloalkyl.

[0015] In some embodiments, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or diluent.

[0016] In another aspect, disclosed herein is a method of treating an inositol-requiring enzyme 1α (IRE1α) modulated disease or disorder in a subject in need thereof, the method comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, to the subject.

[0017] Also provided herein is a method of treating an inositol-requiring enzyme 1β (IRE1β) modulated disease or disorder in a subject in need thereof, the method comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, to the subject.

[0018] Further provided herein is a method of treating an inositol-requiring enzyme 1β (IRE1β) and inositol-requiring enzyme 1α (IRE1α) modulated disease or disorder in a subject in need thereof, the method comprising administering an effective amount of a compound describedherein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, to the subject.

[0019] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing Detailed Description, Examples, and Claims. DETAILED DESCRIPTION Definitions

[0020] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one skilled in the art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated in order to facilitate the understanding of the present disclosure.

[0021] It is understood that the definitions provided herein are not intended to be mutually exclusive. Accordingly, some chemical moieties may fall within the definition of more than one term.

[0022] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents, positions of substituents and / or variables are permissible if such combinations result in stable compounds.

[0023] It is understood that substituents and substitution patterns on the disclosed compounds can be selected by an ordinary skilled person in the art to result in chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure is the result.

[0024] As used herein, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not.

[0025] When a range of values is listed, it is intended to encompass each value and sub–range within the range. For example, “C1-C6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1- C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6alkyl.

[0026] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C1-C6alkyl, C1-C4alkyl, and C1-C3alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl- 1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl, etc.

[0027] The term “heteroalkyl” as used herein refers to an “alkyl” group in which at least one carbon atom has been replaced with a heteroatom such as an O, N, or S atom. The heteroatom(s) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. The heteroalkyl may be, for example, an –O- C1-C10alkyl group, an -C1-C6alkylene-O-C1-C6alkyl group, or a C1-C6alkylene-OH group. One type of heteroalkyl group is an “alkoxy” group.

[0028] The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as C1-C6alkoxy, and C2-C6alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy, etc.

[0029] As used herein, the term "haloalkyl" refers to an alkyl group (as defined above) that is substituted with one or more halogens. A monohaloalkyl radical, for example, may have a chlorine, bromine, iodine or fluorine atom. Dihalo and polyhaloalkyl radicals may have two or more of the same or different halogen atoms. Examples of haloalkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl and the like.

[0030] As used herein, the term "haloalkoxy" refers to radicals wherein one or more of the hydrogen atoms of the alkoxy group (as defined above) are substituted with one or more halogens. Representative examples of "haloalkoxy" groups include, but are not limited to, difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3) or trifluoroethoxy (-OCH2CF3).

[0031] As used herein, the term “carbocyclyl” or “carbocyclic” refers to a radical of a non– aromatic cyclic (monocyclic or bicyclic) hydrocarbon group having, for example, 3-10, 3-8, 3-6, or 4-6 ring carbons, referred to as C3-C10carbocyclyl, C3-C8carbocyclyl, C3-C6carbocyclyl, or C4-C6carbocyclyl, respectively. Exemplary C3-C6carbocyclyl groups include, without limitation,cyclopropyl (C3),cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8carbocyclyl groups include, without limitation, the aforementioned C3-C6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-C10carbocyclyl groups include, without limitation, the aforementioned C3- C6and C3-C8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro–1H–indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. The carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. The carbocyclyl group includes bridged, fused, and spirocyclic rings.

[0032] The term “cycloalkyl” as used herein refers to a saturated cyclic (monocyclic or bicyclic) hydrocarbon group having, for example, 3-10, 3-6, or 4-6 carbons, referred to herein as C3-C10cycloalkyl, C3-C6cycloalkyl, or C4-C6cycloalkyl, respectively, and includes bridged, fused, and spirocyclic rings. Exemplary cycloalkyl groups include, but are not limited to, adamantanyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, etc.

[0033] As used herein, the term “cyano” refers to the group -CN.

[0034] As used herein, the terms “hydroxy” and “hydroxyl” refer to the group -OH.

[0035] As used herein, the term “amine” refers to -NH2.

[0036] As used herein, the term “nitro” refers to the group -NO2.

[0037] As used herein, the term “oxo” refers to the group (=O) or (O).

[0038] As used herein, the terms “halo” and “halogen” are used in the conventional sense to refer to a fluoro, chloro, bromo, or iodo substituent.

[0039] As used herein, the term "alkylamino" refers to an amino group, as defined above, substituted with an alkyl group.

[0040] As used herein, the term "dialkylamino" refers to an amino group, as defined above, substituted with two alkyl groups.

[0041] As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-C14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbonatoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.

[0042] As used herein, the term “heteroaryl” refers to a monocyclic or bicyclic aromatic 5-12 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, and pyrimidine, etc.

[0043] As used herein, the term “heterocyclyl” or “heterocyclic” refers to a saturated or partially unsaturated, monocyclic or bicyclic ring structures, including bridged, fused, or spirocyclic rings, and whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl, aryl, or heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Examples of heterocyclyl rings include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, and dihydrofuran, etc.

[0044] As used herein, a dash (“–”) that is not between two letters or symbols refers to a point of bonding or attachment for a substituent. For example, –NH2is attached through the nitrogen atom.

[0045] In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.

[0046] As used herein, the term “pharmaceutically acceptable salt” refers to a salt which is acceptable for administration to a subject. It is understood that such salts, with counter ions, will have acceptable mammalian safety for a given dosage regime. Such salts can also be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids, and may comprise organic and inorganic counter ions. The neutral forms of the compounds described herein may be converted to the corresponding salt forms by contacting the compound with a base or acid and isolating the resulting salts.

[0047] Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.

[0048] Other examples of salts include anions of the compounds of the present disclosure compounded with a suitable cation such as N+, NH4+, and NW4+(where W can be a C1-C8alkyl group), and the like. For therapeutic use, salts of the compounds of the present disclosure can be pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0049] Compounds disclosed herein that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

[0050] Compounds disclosed herein that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.

[0051] Compounds disclosed herein that include a basic or acidic moiety can also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure can contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.

[0052] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “(-),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

[0053] Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixtureof stereoisomers during the creation of a new stereocenter or during the transformation of a pre- existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations, and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0054] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.

[0055] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. Substituents around a carbocyclic or heterocyclic ring may be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans.”

[0056] Unless the specific stereochemistry is expressly indicated, all chiral, diastereomeric, and racemic forms of a compound are intended. Thus, compounds described herein include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Racemic mixtures of (R)-enantiomer and (S)-enantiomer, and enantio-enriched stereomeric mixtures comprising of (R)- and (S)-enantiomers, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.

[0057] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the present disclosure embrace both solvated and unsolvated forms.

[0058] Generally, reference to or depiction of a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Compounds comprising radioisotopes such as tritium,14C,32P and35S are thus within the scope of the present technology. Procedures for inserting suchlabels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein.

[0059] The present disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0060] Certain isotopically-labeled disclosed compounds (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon- 14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0061] As used herein, singular articles such as “a,” “an” and “the” and similar referents in the context of describing the elements are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, including the upper and lower bounds of the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (i.e., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated.

[0062] In some embodiments, where the use of the term "about" is before a quantitative value, the present disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" refers to a ±10% variation from the nominal value unless otherwise indicated or inferred. Where a percentage is provided with respect to an amountof a component or material in a composition, the percentage should be understood to be a percentage based on weight, unless otherwise stated or understood from the context.

[0063] Where a molecular weight is provided and not an absolute value, for example, of a polymer, then the molecular weight should be understood to be an average molecule weight, unless otherwise stated or understood from the context.

[0064] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present disclosure remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0065] As used herein, the terms “active agent,” “drug,” “pharmacologically active agent” and “active pharmaceutical ingredient” are used interchangeably to refer to a compound or composition which, when administered to a subject, induces a desired pharmacologic or physiologic effect by local or systemic action or both.

[0066] The terms “individual,” “subject,” and “patient” are used interchangeably herein, and refer to an animal, including, but not limited to, human and non-human primates, including simians and humans; rodents, including rats and mice; bovines; equines; ovines; felines; canines; and the like. "Mammal" means a member or members of any mammalian species, and includes, by way of example, canines, felines, equines, bovines, ovines, rodentia, etc. and primates, i.e., non-human primates, and humans. Non-human animal models, i.e., mammals, non-human primates, murines, lagomorpha, etc. may be used for experimental investigations.

[0067] As used herein, the terms “treating,” “treatment,” and the like, refer to obtaining a desired pharmacologic and / or physiologic effect, such as reduction of tumor burden. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease. “Treatment,” as used herein, covers any treatment of a disease in a mammal, particularly in a human and includes: (a) preventing the disease or a symptom of a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it (i.e., including diseases that may be associated with or caused by a primary disease); (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease (i.e., reduction in of tumor burden).

[0068] As used herein, the terms “effective amount” and “therapeutically effective amount” are used interchangeably and refer to the amount of a compound that, when administered to a mammal or other subject for treating a disease, condition, or disorder, is sufficient to affect such treatment for the disease, condition, or disorder. The “effective amount” or "therapeuticallyeffective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated.

[0069] As used herein, the terms “pharmaceutically acceptable excipient,” “pharmaceutically acceptable diluent,” “pharmaceutically acceptable carrier,” and “pharmaceutically acceptable adjuvant” refer to an excipient, diluent, carrier, and adjuvant that are useful in preparing a pharmaceutical composition that are generally safe, non-toxic and neither biologically nor otherwise undesirable, and include an excipient, diluent, carrier, and adjuvant that are acceptable for veterinary use as well as human pharmaceutical use. The phrase “a pharmaceutically acceptable excipient, diluent, carrier and adjuvant” as used in the specification and claims includes both one and more than one such excipient, diluent, carrier, and adjuvant.

[0070] As used herein, the term “pharmaceutical composition” is meant to encompass a composition suitable for administration to a subject, such as a mammal, especially a human. In general a “pharmaceutical composition” is sterile, and free of contaminants that are capable of eliciting an undesirable response within the subject (i.e., the compound(s) in the pharmaceutical composition is pharmaceutical grade). Pharmaceutical compositions can be designed for administration to subjects or patients in need thereof via a number of different routes of administration including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intratracheal, intramuscular, subcutaneous, and the like.

[0071] As described herein, the text refers to various embodiments of the present compounds, compositions, and methods. The various embodiments described are meant to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather, it should be noted that the descriptions of various embodiments provided herein may be of overlapping scope. The embodiments discussed herein are merely illustrative and are not meant to limit the scope of the present technology. Compounds

[0072] In some embodiments, the present disclosure is directed to compounds that are useful as partial antagonist of IRE1α RNase (PAIR). In some embodiments, the present disclosure is directed to compounds that are useful as kinase inhibiting RNase attenuator (KIRA). The disclosed compounds find use in a variety of applications in which partial antagonism of IRE1α RNase and / or attenuation of RNase activity is desired.

[0073] In some embodiments, the compound disclosed herein is a KIRA and completely shuts down IRE1α. A KIRA stabilizes an ATP binding site conformation that almost completely disrupts the ability of IRE1α to form an RNase active back-to-back dimer.

[0074] In other embodiments, the compound disclosed herein is a PAIR which partially retain the RNase activity while inhibiting the kinase moiety of IRE1α. A PAIR preserves adaptive UPR but blocks terminal UPR.

[0075] For example, provided herein is a compound of Formula (I’):or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, wherein X1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl; Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl; L1is selected from the group consisting of -NRB-S(=O)2-, -S(=O)2-NRB-, -NRB-, - NRBC(=O)-, -C(=O)NRB-, -NRBC(=O)NRB-, -O-, and bond; R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1- C6haloalkyl; R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, C1-C6haloalkoxy, C3-C4cycloalkyl, andoxo, wherein the C1-C6alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl; R5is selected from the group consisting of C1-C6alkyl, C2-C4alkenyl, C2-C4alkynyl, C1- C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, phenyl, 4-12 membered monocyclic or bicyclic heterocyclyl, and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the C1-C6alkyl is optionally substituted with cyano or a C3-C8cycloalkyl further optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine, wherein the phenyl or 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; or R4and R5together with the atoms to which R4and R5are attached to and contiguous atoms, form a 5-6 membered heterocyclyl optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6haloalkyl, and oxo; n is integer 0-2; m is integer 0-4; and p is integer 0-4; provided that that i) when L1is -NH-S(=O)2-, -NH-C(=O)-, or -C(=O)-NH-, X1is N, X2is -O-, and ring A is N-containing 6-7 membered heterocyclyl optionally comprising an additional ring O atom, then R5is not phenyl substituted with -Cl; and ii) when L1is -NH-S(=O)2-, X1is N, X2is -O-, ring A is N-containing 6-membered heterocyclyl, m is 0 or 1, R3is F, ring B is naphthyl, p is 1 or 2, and each R4is methyl or F, then R5is not C1-C4alkyl or C2-C4haloalkyl.

[0076] In some embodiments, provided herein is a compound of Formula (I-I):or a pharmaceutically acceptable salt thereof, wherein X1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl; Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl; L1is selected from the group consisting of -NRB-S(=O)2-, -S(=O)2-NRB-, -NRB-, - NRBC(=O)-, -C(=O)NRB-, and bond; R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1- C6haloalkyl; R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, and C1-C6haloalkoxy, wherein the C1-C6alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl; R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, phenyl, 4-12 membered monocyclic or bicyclic heterocyclyl, and 5-12 membered monocyclic or bicyclic heteroaryl,wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy, wherein the phenyl or 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; n is integer 0-2; m is integer 0-4; and p is integer 0-4; provided that i) when L1is -NH-S(=O)2-, -NH-C(=O)-, or -C(=O)-NH-, X1is N, X2is -O- , and ring A is N-containing 6-7 membered heterocyclyl optionally comprising an additional ring O atom, then R5is not phenyl substituted with -Cl; and ii) when L1is -NH-S(=O)2-, X1is N, X2is -O-, ring A is N-containing 6-membered heterocyclyl, m is 0 or 1, R3is F, ring B is naphthyl, p is 1 or 2, and each R4is methyl or F, then R5is not C1-C4alkyl or C2-C4haloalkyl.

[0077] In some embodiments, provided herein is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein X1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl;Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl; L1is selected from the group consisting of -NRB-S(=O)2-, -S(=O)2-NRB-, -NRB-, - NRBC(=O)-, -C(=O)NRB-, and bond; R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1- C6haloalkyl; R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, and C1-C6haloalkoxy, wherein the C1-C6alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl; R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, phenyl, 4-12 membered monocyclic or bicyclic heterocyclyl, and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy, wherein the phenyl or 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; n is integer 0-2; m is integer 0-4; and p is integer 0-4; provided that when L1is -NH-S(=O)2- or -NH-C(=O)-, X1is N, X2is -O-, A is N-containing 6-membered heterocyclyl, and m is 0, then R5is not phenyl substituted with -Cl.

[0078] Also provided herein, in some embodiments, is a compound of Formula (II’):or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, wherein X1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl; Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl; L1is selected from the group consisting of -NRB-S(=O)2-, -S(=O)2-NRB-, -NRB-, - NRBC(=O)-, -C(=O)NRB-, -NRBC(=O)NRB-, -O-, and bond; R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1- C6haloalkyl; R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, C1-C6haloalkoxy, C3-C4cycloalkyl, and oxo, wherein the C1-C6alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl; when L1is selected from the group consisting of -S(=O)2-NRB-, -NRB-, -NRBC(=O)-, - C(=O)NRB-, -NRBC(=O)NRB-, and -O-, R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, and 4-12 membered monocyclic or bicyclic heterocyclyl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl further optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine; when L1is -NRB-S(=O)2-, R5is selected from the group consisting of C1-C6heteroalkyl, C3-C8cycloalkyl, and 4-12 membered monocyclic or bicyclic heterocyclyl, and C1-C6alkyl substituted with C3-C8cycloalkyl further optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine; and when L1is bond, R5is 4-12 membered monocyclic or bicyclic heterocyclyl optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine; or R4and R5together with the atoms to which R4and R5are attached to and contiguous atoms, form a 5-6 membered heterocyclyl optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6haloalkyl, and oxo; n is integer 0-2; m is integer 0-4; and p is integer 0-4.

[0079] Provided herein, in some embodiments, is a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein X1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl; Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl; L1is selected from the group consisting of -NRB-S(=O)2-, -S(=O)2-NRB-, -NRB-, - NRBC(=O)-, -C(=O)NRB-, and bond; R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1- C6haloalkyl; R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, and C1-C6haloalkoxy, wherein the C1-C6alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl; R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, and 4-12 membered monocyclic or bicyclic heterocyclyl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl,wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; n is integer 0-2; m is integer 0-4; and p is integer 0-4.

[0080] Also provided herein, in some embodiments, is a compound of Formula (III):or a pharmaceutically acceptable salt thereof, wherein X1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl; Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl; R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1- C6haloalkyl; R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy;R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, and C1-C6haloalkoxy, wherein the C1-C6alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl; R5is C3-C8cycloalkyl optionally substituted with 1-4 substituents selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; n is integer 0-2; m is integer 0-4; and p is integer 0-4.

[0081] Also provided herein, in some embodiments, is a compound of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein X1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl; Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl; R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy;R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1- C6haloalkyl; R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, and C1-C6haloalkoxy, wherein the C1- C6alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl; R5is C1-C4alkyl-C3-C6cycloalkyl or C1-C4haloalkyl; n is integer 0-2; m is integer 0-4; and p is integer 0-4, provided that when X1is N, X2is -O-, ring A is N-containing 6-membered heterocyclyl, m is 0 or 1, R3is F, ring B is naphthyl, p is 1 or 2, and each R4is methyl or F, then R5is not C2-C4haloalkyl.

[0082] In some embodiments, X1is N. In other embodiments, X1is CH or CF. In some embodiments, X1is CH. In some embodiments, X1is CF.

[0083] In some embodiments, X2is -O-. In other embodiments, X2is -NRB-, wherein RBis H or C1-C4alkyl. For example, in some embodiments, X2is -NH-. In some embodiments, X2is - C(RA)2-, wherein RAis each independently selected from the group consisting of H, halo, and C1- C4alkyl. For example, in some embodiments, X2is -CH2-.

[0084] In some embodiments, L1is selected from the group consisting of -NRB-S(=O)2-, - NRB-, -NRBC(=O)-, and -C(=O)NRB-. In some embodiments, L1is -NRB-S(=O)2-, such as -NH- S(=O)2-. In some embodiments, L1is -S(=O)2-NRB-, such as -S(=O)2-NH-. In some embodiments, L1is -NRB-, such as -NH-. In some embodiments, L1is -NRBC(=O)-, such as -NHC(=O)-. In some embodiments, L1is -C(=O)NRB-, such as -C(=O)NH-. In some embodiments, L1is bond. In some embodiments, L1is -NRBC(=O)NRB-, such as -NHC(=O)NH-. In some embodiments, L1is -O-.

[0085] In some embodiments, RBis H or C1-C4alkyl. In some embodiments, RBis H or methyl. In some embodiments, RBis H.

[0086] In some embodiments, L1is selected from the group consisting of -NRB-S(=O)2-, - S(=O)2-NRB-, -NRB-, -NRBC(=O)-, -C(=O)NRB-, -NRBC(=O)NRB-, and -O-, and R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H,phenyl, 4-12 membered monocyclic or bicyclic heterocyclyl, and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl further optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine, wherein the phenyl or 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; or L1 is bond, and R5is selected from the group consisting of 4-12 membered monocyclic or bicyclic heterocyclyl and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine, wherein the 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy.

[0087] In some embodiments, L1is selected from the group consisting of -NRB-S(=O)2-, - S(=O)2-NRB-, -NRB-, -NRBC(=O)-, -C(=O)NRB-, -NRBC(=O)NRB-, and -O-, and R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, phenyl, 4-12 membered monocyclic or bicyclic heterocyclyl, and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl further optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selectedfrom the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine, wherein the phenyl or 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; or L1is bond, and R5is selected from the group consisting of 4-12 membered monocyclic or bicyclic heterocyclyl and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine, wherein the 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy.

[0088] In some embodiments, L1is selected from the group consisting of -NRB-S(=O)2-, - S(=O)2-NRB-, -NRB-, -NRBC(=O)-, -C(=O)NRB-, -NRBC(=O)NRB-, and -O-, and R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, and 4-12 membered monocyclic or bicyclic heterocyclyl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl further optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 each independently substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine; or L1is bond, and R5is selected from the group consisting of 4-12 membered monocyclic or bicyclic heterocyclyl and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine,wherein the 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy.

[0089] In some embodiments, L1is selected from the group consisting of -NRB-S(=O)2-, - S(=O)2-NRB-, -NRB-, -NRBC(=O)-, -C(=O)NRB-, -NRBC(=O)NRB-, and -O-, and R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, and 4-12 membered monocyclic or bicyclic heterocyclyl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl further optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine; or L1is bond, and R5is selected from the group consisting of 4-12 membered monocyclic or bicyclic heterocyclyl and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine, wherein the 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy.

[0090] In some embodiments, L1is selected from the group consisting of -NRB-, - NRBC(=O)-, -C(=O)NRB-, -NRBC(=O)NRB-, and -O-, and R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, and 4-12 membered monocyclic or bicyclic heterocyclyl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl further optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selectedfrom the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine; or L1is -NRB-S(=O)2-, and R5is selected from the group consisting of C1-C6heteroalkyl, C3-C8cycloalkyl, 4-12 membered monocyclic or bicyclic heterocyclyl, and C1-C6alkyl substituted with C3-C8cycloalkyl further optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine; or L1is bond, and R5is 4-12 membered monocyclic or bicyclic heterocyclyl optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine.

[0091] In some embodiments, L1is selected from the group consisting of -NRB-S(=O)2-, - S(=O)2-NRB-, -NRB-, -NRBC(=O)-, and -C(=O)NRB-, and R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, phenyl, 4-12 membered monocyclic or bicyclic heterocyclyl, and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy, wherein the phenyl or 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; or L1is bond, and R5is selected from the group consisting of 4-12 membered monocyclic or bicyclic heterocyclyl and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy,wherein the 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy.

[0092] In some embodiments, L1is selected from the group consisting of -NRB-S(=O)2-, - S(=O)2-NRB-, -NRB-, -NRBC(=O)-, and -C(=O)NRB-, and R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, phenyl, 4-12 membered monocyclic or bicyclic heterocyclyl, and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy, wherein the phenyl or 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; or L1is bond, and R5is selected from the group consisting of 4-12 membered monocyclic or bicyclic heterocyclyl and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy, wherein the 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy.

[0093] In some embodiments, L1is selected from the group consisting of -NRB-S(=O)2-, - S(=O)2-NRB-, -NRB-, -NRBC(=O)-, and -C(=O)NRB-, and R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, and 4-12 membered monocyclic or bicyclic heterocyclyl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selectedfrom the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; or L1is bond, and R5is selected from the group consisting of 4-12 membered monocyclic or bicyclic heterocyclyl and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy, wherein the 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy.

[0094] In some embodiments, L1is selected from the group consisting of -NRB-S(=O)2-, - S(=O)2-NRB-, -NRB-, -NRBC(=O)-, and -C(=O)NRB-, and R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, and 4-12 membered monocyclic or bicyclic heterocyclyl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; or L1is bond, and R5is selected from the group consisting of 4-12 membered monocyclic or bicyclic heterocyclyl and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy, wherein the 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy.

[0095] In some embodiments, L1is selected from the group consisting of -NRB-, - NRBC(=O)-, and -C(=O)NRB-, and R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, and 4-12 membered monocyclic or bicyclic heterocyclyl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; or L1is -NRB-S(=O)2-, and R5is selected from the group consisting of C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, and 4-12 membered monocyclic or bicyclic heterocyclyl, and C1-C6alkyl substituted with C3-C8cycloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; or L1is bond, and R5is 4-12 membered monocyclic or bicyclic heterocyclyl optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy.

[0096] Provided herein, in some embodiments, is a compound represented by Formula I-A:or a pharmaceutically acceptable salt thereof.

[0097] Also provided herein, in some embodiments, is a compound represented by Formula I-B:or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the compound is represented by Formula I-C:or a pharmaceutically acceptable salt thereof.

[0099] Also provided herein, in some embodiments, is a compound represented by Formula I- D:or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, ring A is 4-12 membered monocyclic or bicyclic carbocyclyl. In other embodiments, ring A is 4-12 membered monocyclic or bicyclic heterocyclyl. In some embodiments, ring A is 4-8 membered monocyclic carbocyclyl or 4-8 membered monocyclic heterocyclyl. In some embodiments, ring A is 4-6 membered monocyclic carbocyclyl or 4-6 membered monocyclic heterocyclyl. For example, ring A is selected from the group consisting of cyclohexyl, piperidyl, azetidinyl, and tetrahydropyranyl. In some embodiments, ring A is 5-6 membered monocyclic carbocyclyl or 5-6 membered monocyclic heterocyclyl. In some embodiments, ring A is 6-membered monocyclic carbocyclyl or 6-membered monocyclic heterocyclyl. In some embodiments, ring A is cyclohexyl. In other embodiments, ring A is piperidyl.

[0101] In some embodiments, ring B is selected from the group consisting of phenyl, naphthyl, 5-10 membered monocyclic or bicyclic heteroaryl, partially unsaturated 5-10 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 5-10 membered monocyclic or bicyclic heterocyclyl. In some embodiments, ring B is selected from the group consisting of phenyl, naphthyl, 6-10 membered monocyclic or bicyclic heteroaryl, and partially unsaturated 6-10 membered monocyclic or bicyclic carbocyclyl. In some embodiments, ring B is selected from the group consisting of phenyl, naphthyl, 6-membered monocyclic heteroaryl, 10 membered bicyclic heteroaryl, and partially unsaturated 9-10 membered bicyclic carbocyclyl. For example, ring B ring B is selected from the group consisting of naphthyl, phenyl, pyridyl, indolyl, quinolinyl, indanyl, benzofuranyl, tetralinyl, indazolyl, benzothiophenyl, and indenyl. In some embodiments, ring B is phenyl, pyridyl, or naphthyl. In some embodiments, ring B is phenyl. In some embodiments, ring B is naphthyl. In some embodiments, ring B is pyridyl.

[0102] In some embodiments, Ring B is selected from the group consisting of

[0103] In some embodiments, Ring B is selected from the group consisting of

[0104] In some embodiments, R1is selected from the group consisting of halo, cyano, and C1- C4alkyl. In some embodiments, R1is halo or C1-C2alkyl. In some embodiments, R1is halo. In some embodiments, R1is C1-C2alkyl.

[0105] In some embodiments, R2is each independently selected from the group consisting of H, halo, and C1-C6alkyl. In some embodiments, R2is H or C1-C6alkyl. In some embodiments, R2is H or C1-C4alkyl. In some embodiments, R2is H or C1-C2alkyl. In some embodiments, R2is H or methyl. In some embodiments, R2is H. In other embodiments, R2is methyl.

[0106] In some embodiments, R3is selected from the group consisting of halo, C1-C6alkyl, C1-C6haloalkyl, amine, C1-C6alkylamine, and di-(C1-C6alkyl)amine. In some embodiments, R3is each independently selected from the group consisting of halo, C1-C6alkyl, and amine. In some embodiments, R3is each independently selected from the group consisting of fluoro, methyl, andamine. In some embodiments, R3is each independently fluoro or methyl. In some embodiments, R3is fluoro or amine. In some embodiments, R3is fluoro. In other embodiments, R3is amine. In some embodiments, R3is methyl.

[0107] In some embodiments, R4is each independently selected from the group consisting of halo, C1-C6alkyl, haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy. In some embodiments, R4is each independently selected from the group consisting of halo, C1-C6alkyl, and C1-C6alkoxy. In some embodiments, R4is each independently selected from the group consisting of halo, C1-C4alkyl, and C1-C4alkoxy. For example, R4is each independently selected from the group consisting of fluoro, chloro, methyl, and methoxy.

[0108] In some embodiments, R5is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, phenyl, 4-8 membered monocyclic or bicyclic heterocyclyl, and 5-8 membered monocyclic or bicyclic heteroaryl, wherein the C1-C6alkyl is optionally substituted with C3-C6cycloalkyl, wherein the C3-C8cycloalkyl or 4-8 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-3 substituents selected from the group consisting of oxo, halo, C1-C6alkyl, and C1-C6haloalkyl, wherein the phenyl or 5-8 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-3 substituents selected from the group consisting of halo and C1-C6alkyl. In some embodiments, R5is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, phenyl, 4-8 membered monocyclic or bicyclic heterocyclyl, and 5-8 membered monocyclic or bicyclic heteroaryl, wherein the C1-C6alkyl is optionally substituted with C3-C6cycloalkyl, wherein the C3-C8cycloalkyl or 4-8 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-3 substituents selected from the group consisting of oxo, halo, C1-C6alkyl, and C1-C6haloalkyl, wherein the phenyl or 5-8 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-3 substituents selected from the group consisting of halo and C1-C6alkyl.

[0109] In some embodiments, R5is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, phenyl, 4-8 membered monocyclic heterocyclyl, and 5-8 membered monocyclic heteroaryl, wherein the C1-C6alkyl is optionally substituted with C3-C6cycloalkyl, wherein the C3-C8cycloalkyl or 4-8 membered monocyclic heterocyclyl is optionally substituted with 1-3 substituents selected from the group consisting of oxo, halo, C1-C4alkyl, and C1-C4haloalkyl, wherein the phenyl or 5-8 membered monocyclic heteroaryl is optionally substituted with 1-3 substituents selected from the group consisting of halo and C1-C4alkyl.

[0110] In some embodiments, R5is selected from the group consisting of C1-C6alkyl optionally substituted with C3-C6cycloalkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 5-6 membered N- bound heterocyclyl, H, and phenyl, wherein the C3-C6cycloalkyl or phenyl is each optionallysubstituted with 1-2 halo or methyl or wherein the 5-6 membered N-bound heterocyclyl is optionally substituted with oxo and 1-2 halo or methyl. In some embodiments, wherein R5is selected from the group consisting of C3-C6alkyl, C1-C2alkyl substituted with C3-C4cycloalkyl, C2-C4haloalkyl, C3-C4cycloalkyl, 5-6 membered N-bound heterocyclyl, and phenyl, wherein the C3-C4cycloalkyl or phenyl is each optionally substituted with 1-2 halo or methyl or wherein the 5-6 membered N-bound heterocyclyl is optionally substituted with oxo and 1-2 halo or methyl. In some embodiments, R5is selected from the group consisting of C1-C2alkyl substituted with C3- C4cycloalkyl, C2-C4haloalkyl, C3-C4cycloalkyl, pyrrolidinone, and phenyl, wherein the C3-C4cycloalkyl or phenyl is each optionally substituted with 1-2 halo or methyl or wherein the pyrrolidinone is optionally substituted with 1-2 halo or methyl. In some embodiments, R5is selected from the group consisting of C1-C2alkyl substituted with C3-C4cycloalkyl, C2-C4haloalkyl, and C3-C4cycloalkyl, wherein the C3-C4cycloalkyl is each optionally substituted with methyl. In some embodiments, R5is C3-C6cycloalkyl optionally substituted with methyl, such as a C3-C4cycloalkyl substituted with methyl. In some embodiments, R5is C1-C2 alkyl substituted with C3-C4cycloalkyl or C1-C4haloalkyl.

[0111] In some embodiments, R5is selected from the group consisting of C1-C6alkyl optionally substituted with C3-C4cycloalkyl, C1-C4alkyl-C3-C4cycloalkyl optionally substituted with C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, H, and phenyl, wherein the C3-C6cycloalkyl or phenyl is each optionally substituted with 1-2 halo, amine, or methyl or wherein the 4-6 membered heterocyclyl is optionally substituted with 1-2 oxo, 1-2 halo, or methyl.

[0112] In some embodiments, R5is selected from the group consisting of C1-C6alkyl substituted with C3-C4cycloalkyl, C1-C4alkyl-C3-C4cycloalkyl optionally substituted with C1-C4alkyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, H, and phenyl, wherein the C3-C6cycloalkyl or phenyl is each optionally substituted with 1-2 halo, amine, or methyl or wherein the 4-6 membered heterocyclyl is optionally substituted with 1-2 oxo, 1-2 halo, or methyl.

[0113] In some embodiments, R5is selected from the group consisting of C1-C6alkyl substituted with C3-C4cycloalkyl, C1-C4alkyl-C3-C4cycloalkyl optionally substituted with C1-C4alkyl, C3-C6cycloalkyl, and 4-6 membered heterocyclyl, wherein the C3-C6cycloalkyl is each optionally substituted with 1-2 halo, amine, or methyl or wherein the 4-6 membered heterocyclyl is optionally substituted with 1-2 oxo, 1-2 halo, or methyl.

[0114] In some embodiments, L1is -NRBC(=O)-, such as -NHC(=O)-, and R5is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, and C3-C8cycloalkyl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl. In some embodiments, L1is -NRBC(=O)-, such as -NHC(=O)-, and R5is C1-C6haloalkyl or C3-C6cycloalkyl.

[0115] In some embodiments, L1is -C(=O)NRB-, such as -C(=O)NH-, and R5is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, and C3-C8cycloalkyl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl. In some embodiments, L1is -C(=O)NRB-, such as -C(=O)NH-, and R5is C1-C6haloalkyl or C3-C6cycloalkyl.

[0116] In some embodiments, L1is -NRB-, such as -NH-, and R5is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, and phenyl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl and wherein the C3-C8cycloalkyl is optionally substituted with amine. In some embodiments, L1is -NRB-, such as -NH-, and R5is selected from the group consisting of C1-C6alkyl-C3-C6cycloalkyl, C1-C6haloalkyl, and C3-C6cycloalkyl.

[0117] In some embodiments, L1is -S(=O)2NRB-, such as -S(=O)2NH-, and R5is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, and C3-C8cycloalkyl, wherein the C1-C6alkyl is optionally substituted with C3-C8 cycloalkyl. In some embodiments, L1 is -S(=O)2NRB-, such as -S(=O)2NH-, and R5is C1-C6haloalkyl or C3-C6cycloalkyl.

[0118] In some embodiments, L1is bond and R5is 4-12 membered monocyclic or bicyclic heterocyclyl or 5-12 membered monocyclic or bicyclic heteroaryl, wherein the 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-3 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, and C1-C6haloalkyl, and the 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, and C1- C6haloalkyl. In some embodiments, L1is bond and R5is 4-6 membered monocyclic heterocyclyl or 5-6 membered monocyclic heteroaryl, wherein the 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, and C1-C6haloalkyl, and the 5-6 membered monocyclic heteroaryl is optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, and C1-C6haloalkyl.

[0119] In some embodiments, L1-R5is selected from the group consisting of:.

[0120] In some embodiments, L1-R5is selected from the group consisting of:

[0121] In some embodiments, L1-R5is selected from the group consisting of:.

[0122] In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In other embodiments, n is 0.

[0123] In some embodiments, m is integer 0-2. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In other embodiments, m is 1. In other embodiments, m is 2.

[0124] In some embodiments, p is integer 0-3. In some embodiments, p is integer 0-2. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In other embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0125] Also provided herein is a compound selected from the group consisting of:,,,,,,,,,,,,,,,,and pharmaceutically acceptable salts, enantiomers, and stereoisomers thereof. Pharmaceutical Compositions

[0126] The compounds and pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof described herein can be useful as pharmaceutical compositions for administration to a subject in need thereof.

[0127] Accordingly, pharmaceutical compositions are presented that can comprise at least a compound described herein, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, and at least one pharmaceutically acceptable carriers, diluent, stabilizers, excipients,dispersing agents, suspending agents, or thickening agents. For example, a disclosed pharmaceutical compositions may include one or more of the disclosed compounds, or pharmaceutically acceptable salts, enantiomers, or stereoisomers thereof. Contemplated compositions may be formulated for oral administration to a subject in need thereof, formulated for parenteral administration to a subject in need thereof, formulated for intravenous administration to a subject in need thereof, formulated for subcutaneous administration to a subject in need thereof, or formulated for inhalation administration (e.g., oral or nasal respiratory route for local or systemic effect) to a subject in need thereof.

[0128] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. Methods of Use

[0129] As described above, embodiments of the present disclosure include the use of compounds and pharmaceutical compositions described herein to treat an IRE1α and / or IRE1β associated diseases and disorders in a subject in need thereof.

[0130] Such diseases and disorders include, for example, cancer, fibrosis, diabetes, neurological, neuropsychiatric, neurodegenerative or other diseases, disorders and conditions having some association with the central nervous system, dermatologic diseases and disorders, autoimmune diseases and disorders, and inflammatory diseases and disorders, or in the treatment and prevention of diseases and disorders where partial antagonism of IRE1α RNase and / or attenuation of RNase activity is desired. For example, organ cells in patients (such as patients that suffer diabetes, e.g., pancreatic β-cells in patients with diabetes) suffer from terminal UPR. The modulation of the UPR in these conditions could eventually protect such cells e.g., pancreatic E- cells from apoptosis and thereby delay disease progression.

[0131] In some embodiments, disclosed herein is a method of treating a inositol-requiring enzyme 1α (IRE1α) modulated disease or disorder in a subject in need thereof, the method comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a pharmaceutical composition described herein, to the subject.

[0132] In some embodiments, also provided herein is a method of treating a inositol-requiring enzyme 1β (IRE1β) modulated disease or disorder in a subject in need thereof, the method comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a pharmaceutical composition described herein, to the subject.

[0133] Furthermore, in some embodiments, provided herein is a method of treating a inositol- requiring enzyme 1β (IRE1β) and inositol-requiring enzyme 1α (IRE1α) modulated disease or disorder in a subject in need thereof, the method comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a pharmaceutical composition described herein, to the subject.

[0134] In some embodiments, provided herein is a method of treating diabetes mellitus in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein. Diabetes mellitus includes, but is not limited to, type 1 (autoimmune), type 2 (obesity-induced / insulin-resistant), monogenic (MODY) syndrome, Wolcott Rallisson syndrome, and Wolfram syndrome.

[0135] Also provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0136] Cancer includes carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non- Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma.

[0137] Exemplary cancers that may be treated with a compound, composition, or method provided herein include, but are not limited to, cancers of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, ovary, pancreas, rectum, stomach, and uterus. Additional examples include, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, non-small cell lung carcinoma, mesothelioma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme,ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulinoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, and prostate cancer.

[0138] In some embodiments, the cancer is metastatic or at risk of becoming metastatic, or may occur in a diffuse tissue, including cancers of the blood or bone marrow (e.g., leukemia). In some embodiments, the compounds and compositions of the disclosure can be used to overcome T-cell tolerance.

[0139] Modulating of IRE1α and / or IRE1β activity may also be useful for the treatment or prevention of neurological, neuropsychiatric, neurodegenerative or other diseases, disorders and conditions having some association with the central nervous system, including disorders associated with impairment of cognitive function and / or motor function. Many of these diseases, disorders and conditions include an immune and / or inflammatory component. In some embodiments, the disease or disorder is Parkinson's disease, dementia, Alzheimer's disease, lateral sclerosis, prion disorders, multiple sclerosis, Guillan-Barre syndrome, adrenoleukodystrophy, adrenomyeloneuropathy, optic neuritis, transverse myelitis, primary peripheral neuropathy, such as Charcot-Marie Tooth (CMT), and secondary peripheral neuropathy, such as diabetes mellitus (DM).

[0140] Embodiments of the present disclosure also contemplate the administration of the compounds or compositions described herein to a subject in need thereof for the treatment or prevention of any other diseases and disorders that may benefit from at least some level of IRE1α or IRE1β modulation. Such diseases and disorders include, for example, fibrosis (e.g., idiopathic pulmonary fibrosis, familial pulmonary fibrosis, scleroderma), dermatologic diseases and disorders (e.g., psoriasis), autoimmune diseases and disorders (e.g., rheumatoid arthritis, Grave's disease, Hashimoto's disease, Addison's disease, lupus, ankylosing spondylitis, sarcoidosis), inflammatory diseases and disorders such as gastro-intestinal tract inflammation (e.g., inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis) and inflammatory lung diseases such as chronic inflammatory lung disease (e.g., bronchial asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, and cystic fibrosis (CF)), metabolic diseases and disorders (e.g., development of insulitis diabetes), hepatic diseases and disorders (e.g., hepatic fibrosis, NASH, and NAFLD), ophthalmologic diseases and disorders (e.g., diabeticretinopathy), renal diseases and disorders (e.g., renal failure), demyelinating diseases or disorders, posterior eye indication, and peripheral neuropathy.

[0141] In some embodiments, provided herein is a method of treating a neurodegenerative disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0142] Examples of neurodegenerative diseases that may be treated with a compound, pharmaceutical composition, or method described herein include, but are not limited to, Alexander's disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, chronic fatigue syndrome, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Sträussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewy body dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple sclerosis, Multiple System Atrophy, myalgic encephalomyelitis, Narcolepsy, Neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick's disease, Primary lateral sclerosis, Prion diseases, Refsum's disease, Sandhoff s disease, Schilder's disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia, Schizophrenia, Spinocerebellar ataxia (multiple types with varying characteristics), Spinal muscular atrophy, Steele-Richardson-Olszewski disease, progressive supranuclear palsy, or Tabes dorsalis. In certain instances, the neurodegenerative disorder is amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Prion diseases, and frontotemporal dementia.

[0143] In some embodiments, the neurodegenerative disease or disorder is amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, prion disorders (e.g., bovine spongiform encephalopathy (BSE)), or frontotemporal dementia.

[0144] Also provided herein is a method of treating fibrosis in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein. Fibrosis includes, but is not limited to, idiopathic pulmonary fibrosis (IPF), familial pulmonary fibrosis (FPF), scleroderma (systemic sclerosis), renal fibrosis, and hepatic fibrosis.

[0145] In some embodiments, provided herein is a method of treating a dermatologic disease and disorder in a subject in need thereof, comprising administering to the subject an effectiveamount of a compound disclosed herein, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein. Dermatologic disease or disorder includes, but is not limited to, psoriasis.

[0146] In some embodiments, provided herein is a method of treating an autoimmune disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0147] Autoimmune disease or disorder refers to a disease or disorder in which a subject's immune system has an aberrant immune response against a substance that does not normally elicit an immune response in a healthy subject. Examples of autoimmune diseases and disorders that may be treated with a compound, pharmaceutical composition, or method described herein include, but are not limited to, Acute Disseminated Encephalomyelitis (ADEM), Acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM / Anti-TBM nephritis, Antiphospholipid syndrome (APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis, Autoimmune hyperlipidemia, Autoimmune immunodeficiency, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura (ATP), Autoimmune thyroid disease, Autoimmune urticaria, Axonal or neuronal neuropathies, Balo disease, Behcet's disease, Bullous pemphigoid, Cardiomyopathy, Castleman disease, Celiac disease, Chagas disease, Chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal ostomyelitis (CRMO), Churg-Strauss syndrome, Cicatricial pemphigoid / benign mucosal pemphigoid, Crohn's disease, Cogans syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST disease, Essential mixed cryoglobulinemia, Demyelinating neuropathies, Dermatitis herpetiformis, Dermatomyositis, Devic's disease (neuromyelitis optica), Discoid lupus, Dressier's syndrome, Endometriosis, Eosinophilic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Experimental allergic encephalomyelitis, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture's syndrome, Granulomatosis with Polyangiitis (GPA) (formerly called Wegener's Granulomatosis), Graves' disease, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura, Herpes gestationis, Hypogammaglobulinemia, Idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4- related sclerosing disease, Immunoregulatory lipoproteins, Inclusion body myositis, Interstitialcystitis, Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus (SLE), Lyme disease, chronic, Meniere's disease, Microscopic polyangiitis, Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica (Devic's), Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus), Paraneoplastic cerebellar degeneration, Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Parsonnage-Tumer syndrome, Pars planitis (peripheral uveitis), Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia, POEMS syndrome, Polyarteritis nodosa, Type I, II, & III autoimmune polyglandular syndromes, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Progesterone dermatitis, Primary biliary cirrhosis, Primary sclerosing cholangitis, Psoriasis, Psoriatic arthritis, Idiopathic pulmonary fibrosis, Pyoderma gangrenosum, Pure red cell aplasia, Raynauds phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Reiter's syndrome, Relapsing polychondritis, Restless legs syndrome, Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiff person syndrome, Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia, Takayasu's arteritis, Temporal arteritis / Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, Transverse myelitis, Type 1 diabetes, Ulcerative colitis, Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vesiculobullous dermatosis, Vitiligo, or Wegener's granulomatosis (i.e., Granulomatosis with Polyangiitis (GPA).

[0148] In some embodiments, the autoimmune disease or disorder is rheumatoid arthritis, Grave's disease, Hashimoto's disease, Addison's disease, lupus, ankylosing spondylitis, or sarcoidosis.

[0149] Also provided herein is a method of treating an inflammatory disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0150] Examples of inflammatory diseases and disorders include, for example, autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto'sthyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison's disease, Vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, ischemia reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, atopic dermatitis, and traumatic brain injury.

[0151] In some embodiments, the inflammatory disease or disorder is acute. In other embodiments, the inflammatory disease or disorder is chronic. In some embodiments, the inflammatory disease or disorder is a chronic inflammatory lung disease. Chronic inflammatory lung disease includes, but is not limited to, bronchial asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, and cystic fibrosis (CF). In some embodiments, the inflammatory disease or disorder is gastro-intestinal tract inflammation. Gastro-intestinal tract inflammation includes, but is not limited to, inflammatory bowel disease (IBD), Crohn's disease, and colitis.

[0152] Also provided herein is a method of treating a hepatic disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein. Hepatic disease or disorder includes, but is not limited to, hepatic fibrosis, non-alcoholic steatohepatitis (NASH), and non-alcoholic fatty liver disease (NAFLD).

[0153] In some embodiments, provided herein is a method of treating an ophthalmologic disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein. Ophthalmologic disease or disorder includes, but is not limited to diabetic retinopathy.

[0154] In some embodiments, provided herein is a method of treating a renal disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein. Renal disease or disorder includes, but is not limited to, renal failure.

[0155] Demyelinating disease or disorder refers to a disease or disorder of the nervous system in which the myelin sheath of neurons is damaged. In some embodiments, provided herein is a method of treating a demyelinating disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or apharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein. Demyelinating disease or disorder includes, but is not limited to, multiple sclerosis (MS), Guillan-Barre syndrome, adrenoleukodystrophy, adrenomyeloneuropathy, optic neuritis, and transverse myelitis.

[0156] Posterior eye indication refers to eye conditions caused by changes in the anterior hyaloid membrane of the eye and the optical structures behind it. In some embodiments, provided herein is a method of treating a posterior eye indication in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein. Posterior eye indication includes, but is not limited to, retinal degeneration, Stargardt's disease, wet age-related macular degeneration (AMD), and dry AMD. Anterior eye indication includes, but is not limited to, glaucoma and Fuch's dystrophy.

[0157] Peripheral neuropathy refers to a damaged neuron, a condition caused by trauma, injury, local compression, prolonged pressure, or inflammation of a nerve or group of nerves. In some embodiments, provided herein is a method of treating peripheral neuropathy in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein. Peripheral neuropathy can be primary, such as Charcot-Marie Tooth (CMT), or secondary, caused by diabetes mellitus. EXAMPLES

[0158] Below are examples of specific embodiments for carrying out the present disclosure. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present disclosure in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be allowed for. Chemical Synthesis

[0159] The following abbreviations and terms have the indicated meanings throughout: boc tert-butoxycarbonyl br. broad brine saturated solution of sodium chloride in water CDCl3 deuterated chloroform d doublet dd doublet of doubletsDCM dichloromethane DIPEA N,N-diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DMSO-d6 deuterated dimethyl sulfoxide ELS evaporative light scattering ESI electrospray ionisation EtOAc ethyl acetate EtOH ethanol Ex. example h hour(s) HPLC high-performance liquid chromatography LC / MS liquid chromatography–mass spectrometry m multiplet MeCN acetonitrile MeOH methanol MeOD deuterated methanol min minute(s) mL millilitre(s) NMR Nuclear Magnetic Resonance NMP N-methyl-2-pyrrolidone prep. preparative PMB para-methoxybenzyl q quartet RBF round bottom flask RT room temperature Rt retention time s singlet t triplet TBME tert-butyl methyl ether t-Bu tert-butyl THF tetrahydrofuran XantPhosPdG3 [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulfonateDBU 1,8-diazabicyclo[5.4.0]undec-7-ene DMAP N,N-dimethylpyridin-4-amine HCl hydrogen chloride IPA propan-2-ol NBS N-bromosuccinimide STAB sodium triacetoxyborohydride TFA trifluoroacetic acid Analytical LC / MS were carried out on the following systems:

[0160] LCMS Method A refers to a low pH analysis reverse phase system using a Waters UPLCTMBEHTMC18 column (2.1 mm × 50 mm, 1.7 μm; temperature: 40 °C), with an injection volume of 1 μL at a flow rate of 0.9 mL / min and a gradient of 5 – 100% B over 1.1 min, then 100% B for 0.25 min, where A = 0.1% formic acid in water, and B = 0.1% formic acid in acetonitrile. A second gradient of 100 – 5% B was then applied over 0.05 min and held for 0.1 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters SQD, SQD2 or a QDa detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0161] LCMS Method B refers to a low pH analysis reverse phase system using a Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 μm; temperature: 40 °C), with an injection volume of 1 μL at a flow rate of 0.6 mL / min and a gradient of 5 – 100% B over 5.3 min, then 100% B for 0.5 min, where A = 0.1% formic acid in water, and B = 0.1% formic acid in acetonitrile. A second gradient of 100 – 5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. ELS data was collected on a Waters ELS detector when reported. Mass spectra were obtained using a Waters SQD or QDa detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0162] LCMS Method C refers to a high pH analysis reverse phase system using a Waters UPLCTMBEHTMC18 column (2.1 mm × 30 mm, 1.7 μm; temperature; 55 °C), with an injection volume of 1 μL at a flow rate of 1.0 mL / min and a gradient of 1 –100% B over 1.10min, then 100% B for 0.25 min, where A = 2 mM ammonium bicarbonate in water, buffered to pH 10, and B = acetonitrile. A second gradient of 100 –1% B was then applied over 0.05 min and held for 0.40 min. UV spectra were recorded at 215nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters Quattro Premier XE, a QDa or a SQD2 detector; ionization mode:electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0163] LCMS Method D refers to a high pH analysis reverse phase system using a Phenomenex Kinetex® Evo C18 column (2.1 mm × 50 mm, 1.7 μm; temperature: 40 °C), with an injection volume of 1 μL at a flow rate of 1.0 mL / min and a gradient of 1 –100% B over 1.10min, then 100% B for 0.25 min, where A = 0.2% ammonium hydroxide in water and B = acetonitrile. A second gradient of 100 – 1% B was then applied over 0.05 min and held for 0.40 min. UV spectra were recorded at 215nm; spectrum range: 200 –400 nm. Mass spectra were obtained using a Waters QDa or a SQD2 detector; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0164] LCMS Method E refers to high pH reverse phase system using a Waters UPLCTMBEHTMC18 column (2.1 mm × 100 mm, 1.7 μm; temperature: 55 °C), with an injection volume of 1 μL and at a flow rate of 0.6 mL / min and a gradient of 5 – 100% B over 5.3 min, then 100% B for 0.5 min, where A = 2 mM ammonium bicarbonate in water, buffered to pH 10, and B = acetonitrile. A second gradient of 100 – 5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector or a Waters SQD2; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0165] LCMS Method F refers to high pH reverse phase system using a Phenomenex Kinetex® Evo C18 column (2.1 mm × 100 mm, 1.7 μm; temperature: 40°C), with an injection volume of 1 μL and at a flow rate of 0.6 mL / min and a gradient of 5 – 100% B over 5.30 min, then 100% B for 0.50 min, where A = 0.2% ammonium hydroxide in water and B = acetonitrile. A second gradient of 100 – 5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. Mass spectra were obtained using a Waters QDa or a SQD2; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0166] LCMS Method G refers to a low pH analysis reverse phase system using a Waters UPLCTMCORTECSTMC8 column (2.1 mm × 100 mm, 1.6 μm; temperature: 40 °C), with an injection volume of 1 μL at a flow rate of 0.6 mL / min and a gradient of 5 – 100% B over 5.30 min, then 100% B for 0.50 min, where A= 0.1% formic acid in water, and B = 0.1% formic acid in acetonitrile. A second gradient of 100 – 5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm; spectrum range: 200 – 400 nm. ELS data was collected using a Waters ELS detector when reported. Mass spectra were obtained using a Waters SQD2 orQDa; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software. Preparative HPLC methods were carried out as follows:

[0167] Preparative Method A refers to low pH reverse phase purification using a Waters Sunfire C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 10% B for 1.90 min then a gradient of 10 – 95% B over 14.1 min and held for 1.9 min, where A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile. A second gradient of 95 – 10% B was then applied over 0.3 min and held for a further 0.9 min. UV spectra were recorded at 215 nm using a Gilson detector.

[0168] Preparative Method B refers to low pH reverse phase purification using a Waters Sunfire C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 30% B for 1.9 min then a gradient of 30 – 95% B over 9.6 min and held for 2.0 min, where A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile. A second gradient of 95 – 30% B was then applied over 0.3 min and held for 1.3 min. UV spectra were recorded at 215 nm using a Gilson detector.

[0169] Preparative Method C refers to high pH reverse phase purification using a Waters XBridgeTMC18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 10% B for 2.0 min then a gradient of 10 – 95% B over 14.0 min and held for 2.0 min, where A = 0.2% ammonium hydroxide in water and B = 0.2% ammonium hydroxide in acetonitrile. A second gradient of 95 – 10% B was then applied over 0.2 min and held for 0.9 min. UV spectra were recorded at 215 nm.

[0170] Preparative Method D refers to high pH reverse phase purification using a Waters XBridgeTMC18 column (30 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 30% B for 2.0 min then a gradient of 30 – 95% B over 9.5 min and held for 2.0 min, where A = 0.2% ammonium hydroxide in water and B = 0.2% ammonium hydroxide in acetonitrile. A second gradient of 95 – 30% B was then applied over 0.3 min and held for 1.3 min. UV spectra were recorded at 215 nm.

[0171] Preparative Method E refers to low pH reverse phase purification using a Waters Sunfire C18 column (19 mm × 100 mm, 5 μm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 20 mL / min at 5% B for 1.90 min then a gradient of 5 – 95% B over 14.2 min and held for 1.9 min, where A = 0.1% formic acid in water; B = 0.1% formic acidin acetonitrile. A second gradient of 95 – 5% B was then applied over 0.1 min and held for a further 1.9 min. UV spectra were recorded at 215 nm using a Gilson detector. NMR conditions:

[0172] 1H NMR spectra were recorded on a Bruker Avance III HD 500 MHz or a Bruker Avance III HD 400 MHz spectrometer. Chemical shifts, δ, are quoted in parts per million (ppm) and are referenced to the residual solvent peak. Spectra were recorded at room temperature unless otherwise stated. Variable temperature (VT) experiments were carried out at the specified temperatures (such as 353 K). Coupling constants, J, are quoted to the nearest 0.1 Hz. General conditions:

[0173] Commercial anhydrous solvents were used in reactions where specified. HPLC grade solvents were used for all other reactions, work-up and chromatography.

[0174] Reported yields are corrected for LC / MS purity (determined by UV (215 nm) or ELS detection) unless otherwise stated.

[0175] Microwave experiments were carried out using a Biotage Initiator+.

[0176] Flash column chromatography was carried out on a Biotage Isolera 4 machine. Biotage Sfär KP-Sil Silica D Duo columns or Biotage Sfär KP-Amino D Duo (KP-NH) columns were used for normal phase chromatography and Biotage Sfär C18 Duo columns were used for reverse phase chromatography. Synthetic methods of exemplary compounds:

[0177] Table A provides corresponding example number for exemplary compounds of the disclosure. Table A. Corresponding example number for exemplary compounds of the disclosureScheme 1. Synthesis of Example 1. 2,2,2‐Trifluoro‐N‐(4‐{[5‐(2‐{[(trans)‐4‐ aminocyclohexyl]amino}pyrimidin‐4‐yl)‐1,3‐thiazol‐4‐yl]oxy}naphthalen‐1‐yl)ethane‐1‐ sulfonamide hydrochlorideIntermediate A. Synthesis of tert‐butyl N‐[(trans)‐4‐carbamimidamidocyclohexyl]carbamate

[0178] N-Ethyl-N-isopropyl-propan-2-amine (8.7 mL, 49.8 mmol) was added to a suspension of tert-butyl N-[(trans)-4-aminocyclohexyl]carbamate (10.00 g, 46.7 mmol) and 1H-pyrazole-1- carboximidamide hydrochloride (1:1) (6.84 g, 46.7 mmol) in acetonitrile (250 mL) and the reaction was stirred at 60oC for 24 h. The reaction was re-treated with 1H-pyrazole-1- carboximidamide hydrochloride (1:1) (1.03 g, 7.00 mmol) and N-ethyl-N-isopropyl-propan-2- amine (1.2 mL, 7.00 mmol) and stirred at 60oC for 20 h. The reaction was cooled to room temperature and filtered under vacuum. The collected solids were washed with acetonitrile (2 x 20 mL) and dried under vacuum at 40oC to afford the title compound as a powder. (10.68 g, 37.5 mmol, 80% yield). LC-MS (Method A): m / z (ESI+) = 257.3 [M+H]+, Rt = 0.52 min, ELS purity = 100%. 1H NMR (500 MHz, DMSO-d6) δ 7.85 – 6.40 (m, 5H), 3.29 – 3.08 (m, 2H), 1.96 – 1.70 (m, 4H), 1.43 – 1.33 (m, 9H), 1.27 – 1.10 (m, 4H).Scheme 1 Step 1. Synthesis of 1-(4-chlorothiazol-5-yl)ethanol

[0179] 4-Chlorothiazole-5-carbaldehyde (10.00 g, 67.8 mmol) was dissolved in 2- methyltetrahydrofuran (200 mL). The reaction was stirred at -40 °C in a 3 neck RBF for the dropwise addition of a solution of 3 M bromo(methyl)magnesium in diethyl ether (34 mL, 0.102 mol) in THF (30 mL) over 30 min. Upon complete addition the reaction was stirred for 30 min before being quenched with saturated aqueous ammonium chloride solution (50 mL). The reaction was stirred for 3 h while warming to room temperature. The reaction mixture was concentrated in vacuo to remove the organics and then diluted with saturated aqueous ammonium chloride solution (100 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous was further extracted with ethyl acetate (2 x 80 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane) to afford the title compound as an oil. (9.2 g, 55.7 mmol, 82% yield). LC-MS (Method C): m / z (ESI+) = 164.0 [M(35Cl)+], 165.9 [M(37Cl)+], Rt = 0.47 min, UV purity = 97%. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 5.96 (d, J = 3.8 Hz, 1H), 5.00 (qd, J = 6.4, 3.6 Hz, 1H), 1.38 (d, J = 6.4 Hz, 3H). Scheme 1 Step 2. Synthesis of 1-(4-chlorothiazol-5-yl)ethanone

[0180] Oven dried manganese dioxide (59.62 g, 685.78 mmol) was added to a solution of 1- (4-chlorothiazol-5-yl)ethanol (15.02 g, 91.44 mmol) in acetonitrile (anhydrous, 130 mL) and the reaction was stirred at room temperature overnight. The reaction mixture was filtered through celite, washed through with acetonitrile, and the filtrate was concentrated in vacuo. The material was purified by silica chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane) to afford the title compound as a solid. (9.23 g, 57.1 mmol, 62% yield). LC-MS (Method C): m / z (ESI+) =no ionisation, Rt = 0.48 min, UV purity = 99%. 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 2.64 (s, 3H). Scheme 1 Step 3. Synthesis of 1-[4-[(4-amino-1-naphthyl)oxy]thiazol-5-yl]ethanone

[0181] 4-Aminonaphthalen-1-ol;hydrochloride (5.91 g, 30.2 mmol) and cesium carbonate (29.52 g, 90.6 mmol) were sparged with nitrogen for 5 min. DMF (anhydrous, 200 mL) was added and the resulting suspension was stirred vigorously and sparged with nitrogen for another 5 min. 1- (4-Chlorothiazol-5-yl)ethanone (4.88 g, 30.2 mmol) was added in one portion as a solid and thereaction was vigorously stirred at room temperature and sparged with nitrogen for 10 min. The reaction was stirred at 50oC for 30 min, 80oC for 6.5 h, and then room temperature overnight. The reaction was filtered through glass fibre filter paper under vacuum, washed through with ethyl acetate, and the filtrate was concentrated in vacuo. The resulting material was suspended in DCM, filtered under vacuum and the filtrate was concentrated in vacuo. The material was purified by silica chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane followed by 0- 20% MeOH in ethyl acetate) to afford the title compound as a solid. (605 mg, 6% yield). LC-MS (Method B): m / z (ESI+) = 285.1 [M+H]+, Rt = 2.49 min. 1H NMR (500 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.19 – 8.06 (m, 1H), 7.87 – 7.75 (m, 1H), 7.51 – 7.37 (m, 2H), 7.08 (d, J = 8.2 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 5.73 (s, 2H), 2.68 (s, 3H). Scheme 1 Step 4. Synthesis of N'‐[4‐({5‐[(E)‐3‐(dimethylamino)prop‐2‐enoyl]‐1,3‐thiazol‐4‐ yl}oxy)naphthalen‐1‐yl]‐N,N‐dimethylmethanimidamide

[0182] 1-[4-[(4-Amino-1-naphthyl)oxy]thiazol-5-yl]ethanone (605 mg, 2.13 mmol) was dissolved in 1,1-dimethoxy-N,N-dimethylmethanamine (4 mL, 30.1 mmol) and stirred at 80oC for 6 h then room temperature overnight. The resulting suspension was filtered under vacuum and the solid was washed with diethyl ether (10 mL) and dried under vacuum at 40oC to afford the title compound as a solid. (655 mg, 1.64 mmol, 77% yield). LC-MS (Method B): m / z (ESI+) = 395.2 [M+H]+, Rt 1.60 min, UV purity = 99%. 1H NMR (500 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.44 – 8.34 (m, 1H), 8.05 – 7.98 (m, 1H), 7.80 (s, 1H), 7.77 – 7.70 (m, 1H), 7.57 – 7.46 (m, 2H), 6.96 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 6.02 (d, J = 12.3 Hz, 1H), 3.12 – 3.08 (m, 3H), 3.07 – 3.04 (m, 6H), 2.65 – 2.57 (m, 3H). Scheme 1 Step 5. Synthesis of tert‐butyl N‐[(trans)‐4‐[(4‐{4‐[(4‐ {[(dimethylamino)methylidene]amino}naphthalen‐1‐yl)oxy]‐1,3‐thiazol‐5‐yl}pyrimidin‐2‐ yl)amino]cyclohexyl]carbamate

[0183] N'‐[4‐({5‐[(E)‐3‐(Dimethylamino)prop‐2‐enoyl]‐1,3‐thiazol‐4‐yl}oxy)naphthalen‐1‐ yl]‐N,N‐dimethylmethanimidamide (0.7 g, 1.76 mmol) was dissolved in ethanol (8 mL). Potassium carbonate (1.46 g, 10.6 mmol) was added, followed by tert‐butyl N‐[(trans)‐4‐ carbamimidamidocyclohexyl]carbamate (Intermediate A) (0.68 g, 2.64 mmol) and the reaction was stirred at 80oC overnight. The reaction was cooled to room temperature, filtered under vacuum, and the solids were washed with MeOH (approx. 40 mL). The filtrate was concentrated in vacuo and the material was purified by silica chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane) to afford the title compound as a solid. (528 mg, 0.835 mmol, 47% yield). LC-MS (Method B): m / z (ESI+) = 588.4 [M+H]+, Rt = 2.49 min, UV purity = 93%. 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.44 – 8.37 (m, 1H), 8.35 – 8.27 (m, 1H), 7.94 – 7.87 (m, 1H), 7.81 (s, 1H), 7.55 – 7.46 (m, 2H), 7.29 – 7.23 (m, 1H), 7.18 – 7.06 (m, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.78 – 6.68 (m, 1H), 3.71 – 3.58 (m, 1H), 3.29 – 3.15 (m, 1H), 3.12 – 3.01 (m, 6H), 1.97 – 1.74 (m, 4H), 1.42 – 1.37 (m, 9H), 1.31 – 1.21 (m, 4H). Scheme 1 Step 6. Synthesis of tert‐butyl N‐[(trans)‐4‐[(4‐{4‐[(4‐aminonaphthalen‐1‐yl)oxy]‐ 1,3‐thiazol‐5‐yl}pyrimidin‐2‐yl)amino]cyclohexyl]carbamate

[0184] Ethane-1,2-diamine (240 μL, 3.59 mmol) was added to a solution of tert‐butyl N‐ [(trans)‐4‐[(4‐{4‐[(4‐{[(dimethylamino)methylidene]amino}naphthalen‐1‐yl)oxy]‐1,3‐thiazol‐5‐ yl}pyrimidin‐2‐yl)amino]cyclohexyl]carbamate (400 mg, 0.681 mmol) in ethanol (anhydrous, 4 mL). The reaction was sparged with nitrogen for 5 min and then stirred at 80oC overnight. The reaction was cooled to room temperature, filtered under vacuum and the resulting solid was washed with ethanol (5 mL) and dried under vacuum at 40oC to afford the title compound as a solid. (275 mg, 0.516 mmol, 76% yield). LC-MS (Method B): m / z (ESI+) = 533.4 [M+H]+, Rt = 3.37 min, UV purity = 100%. 1H NMR (500 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.37 – 8.25 (m, 1H), 8.15 – 8.07 (m, 1H), 7.82 – 7.75 (m, 1H), 7.47 – 7.39 (m, 2H), 7.34 – 7.25 (m, 1H), 7.15 – 7.01 (m, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.79 – 6.69 (m, 1H), 6.63 (d, J = 8.2 Hz, 1H), 5.68 (s, 2H), 3.72 – 3.58 (m, 1H), 3.25 – 3.16 (m, 1H), 2.05 – 1.72 (m, 4H), 1.44 – 1.37 (m, 9H), 1.34 – 1.21 (m, 4H). Scheme 1 Step 7. Synthesis of tert‐butyl N‐[(trans)‐4‐{[4‐(4‐{[4‐(2,2,2‐ trifluoroethanesulfonamido)naphthalen‐1‐yl]oxy}‐1,3‐thiazol‐5‐yl)pyrimidin‐2‐ yl]amino}cyclohexyl]carbamate

[0185] A solution of tert‐butyl N‐[(trans)‐4‐[(4‐{4‐[(4‐aminonaphthalen‐1‐yl)oxy]‐1,3‐ thiazol‐5‐yl}pyrimidin‐2‐yl)amino]cyclohexyl]carbamate (50 mg, 0.0939 mmol) in pyridine (anhydrous, 0.9 mL) was sparged with nitrogen for 3 min then stirred in an ice bath for the addition of 2,2,2-trifluoroethanesulfonyl chloride (11 μL, 0.0959 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature over 1 h. The reaction was cooled in an ice bath and retreated with 2,2,2-trifluoroethanesulfonyl chloride (11 μL, 0.0959 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature over 30 min and then stirred at room temperature overnight. The reaction was diluted with saturated aqueous sodiumbicarbonate solution (3 mL) and the product was extracted with ethyl acetate (3 x 3 mL). The combined organic layers were washed with water (1 mL), dried using magnesium sulfate, filtered, and concentrated in vacuo. The material was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) to afford the title compound as a solid. (22 mg, 0.0308 mmol, 33% yield). LC-MS (Method B): m / z (ESI+) = 679.4 [M+H]+, Rt = 3.98 min, UV purity = 95%. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.01 (s, 1H), 8.36 – 8.24 (m, 2H), 8.21 – 8.12 (m, 1H), 7.79 – 7.61 (m, 2H), 7.57 – 7.45 (m, 1H), 7.26 – 7.03 (m, 3H), 6.83 – 6.64 (m, 1H), 4.56 (q, J = 9.8 Hz, 2H), 3.76 – 3.54 (m, 1H), 3.26 – 3.10 (m, 1H), 2.10 – 1.70 (m, 4H), 1.38 (s, 9H), 1.33 – 1.13 (m, 4H). Scheme 1 Step 8. Synthesis of 2,2,2‐trifluoro‐N‐(4‐{[5‐(2‐{[(trans)‐4‐ aminocyclohexyl]amino}pyrimidin‐4‐yl)‐1,3‐thiazol‐4‐yl]oxy}naphthalen‐1‐yl)ethane‐1‐ sulfonamide hydrochloride

[0186] 4 M Hydrogen chloride in 1,4-dioxane (60 μL, 0.240 mmol) was added to a solution of tert‐butyl N‐[(trans)‐4‐{[4‐(4‐{[4‐(2,2,2‐trifluoroethanesulfonamido)naphthalen‐1‐yl]oxy}‐ 1,3‐thiazol‐5‐yl)pyrimidin‐2‐yl]amino}cyclohexyl]carbamate (22 mg, 0.0324 mmol) in 1,4- dioxane (anhydrous, 0.2 mL) and the reaction was stirred at room temperature overnight. The solvent was removed using a stream of nitrogen and the product was lyophilised overnight to afford the title compound as a solid. (18 mg, 0.0287 mmol, 89% yield). LC-MS (Method B): m / z (ESI+) = 579.3 [M+H]+, Rt = 2.09 min, UV purity = 97%. 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.06 (s, 1H), 8.33 (d, J = 5.5 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.07 – 7.87 (m, 3H), 7.77 – 7.60 (m, 3H), 7.54 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 5.5 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 4.57 (q, J = 9.8 Hz, 2H), 3.77 – 3.63 (m, 1H), 3.09 – 2.90 (m, 1H), 2.16 – 1.86 (m, 4H), 1.55 – 1.29 (m, 4H).

[0187] The compounds of the following tabulated Examples (Table 1) were prepared analogously to Scheme 1 Step 7 using tert‐butyl N‐[(trans)‐4‐[(4‐{4‐[(4‐aminonaphthalen‐1‐ yl)oxy]‐1,3‐thiazol‐5‐yl}pyrimidin‐2‐yl)amino]cyclohexyl]carbamate and the appropriate commercially available sulfonyl chloride. The boc protecting group was subsequently removed using 4 M hydrogen chloride in 1,4-dioxane analogously to Scheme 1 Step 8.Table 1: Exemplary compounds of the disclosureScheme 2. Synthesis of Example 2. 2,2,2‐Trifluoro‐N‐(3‐methyl‐4‐{[5‐(2‐{[(trans)‐4‐ aminocyclohexyl]amino}pyrimidin‐4‐yl)‐1,3‐thiazol‐4‐yl]oxy}naphthalen‐1‐yl)ethane‐1‐ sulfonamide hydrochlorideIntermediate B. Synthesis of 4-amino-2-methyl-naphthalen-1-ol

[0188] Sodium carbonate (4.1 g, 38.68 mmol) was added in four portions (vigorous effervescence) to a nitrogen flushed stirring solution of 4-aminobenzenesulfonic acid (14.5 g, 83.72 mmol) in water (90 mL) in a 250 mL 3 neck RBF. The reaction was stirred at room temperature for 5 min and then cooled to 0oC using an ice / brine bath.5 M Sodium nitrite solution (25 mL, 124.65 mmol) (8.6 g in 25 mL water) was added dropwise to the stirring solution over 15 min, keeping the internal temperature at approximately 0 °C throughout the addition, to afford a solution. The solution was stirred for 40 min maintaining the temperature below 5 °C. The reaction was then added dropwise over 15 min into an ice cooled stirring solution of 12 M hydrogen chloride (17 mL, 198 mmol), maintaining the temperature between 0 - 2 °C throughout the addition. The reaction was stirred in the ice bath for 20 min to afford the diazo compound as a suspension.

[0189] Nitrogen flushed 2-methylnaphthalen-1-ol (12 g, 75.85 mmol) was dissolved in a room temperature solution of sodium hydroxide (16.3 g, 407.53 mmol) in water (90 mL) and the reaction was stirred at room temperature under nitrogen for 10 min before cooling to 0oC.

[0190] The solution containing the diazo compound was added dropwise to a stirring solution containing the naphthyl compound over 30 min, keeping the temperature at 0 °C throughout the addition. The reaction was stirred for 40 min in the ice / brine bath under a constant flow of nitrogen and then allowed to warm to room temperature over 20 min.

[0191] The reaction was stirred at 80 °C for the addition of sodium dithionite (35 g, 201.03 mmol) in several small portions over 35 min. Upon complete addition the reaction was stirred at 80oC for 30 min.

[0192] The reaction was cooled to room temperature over 30 min and then filtered under vacuum under a cover of nitrogen. The resulting solid was washed with 10% aqueous sodium dithionite solution (150 mL), water (150 mL), and then dried under vacuum at 40oC to afford the title compound as a solid. The compound was stored under vacuum. (10.6 g, 58.14 mmol, 77% yield). LC-MS (Method A): m / z (ESI+) = 174.3 [M+H]+, Rt = 0.38 min, ELS purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 8.05 - 8.02 (m, 1H), 7.97 (s, 1H), 7.93 - 7.89 (m, 1H), 7.38 - 7.32 (m, 1H), 7.30 - 7.25 (m, 1H), 6.48 (s, 1H), 5.01 (br. s, 2H), 2.23 (s, 3H). Scheme 2 Step 1. Synthesis of 1-[4-[(4-amino-2-methyl-1-naphthyl)oxy]thiazol-5-yl]ethanone

[0193] 1-(4-Chlorothiazol-5-yl)ethanone (Scheme 1, Step 2) (5.00 g, 30.9 mmol), cesium carbonate (20.16 g, 61.9 mmol) and 4-amino-2-methyl-naphthalen-1-ol (Intermediate B) (90%, 6.00 g, 31.2 mmol) were thoroughly flushed with nitrogen for 15 min. DMF (anhydrous, 100 mL) was added and the reaction was stirred at room temperature and flushed with nitrogen for 5 min, then stirred at 80oC under nitrogen overnight. The reaction was cooled to room temperature and filtered through a pad of celite under vacuum, washing with ethyl acetate (approx. 200 mL). The filtrate was re-filtered under vacuum through glass fibre filter paper, repeating as necessary until a solution was obtained. The filtrate was concentrated in vacuo. The product was purified by silica chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane followed by 0-20% MeOH in ethyl acetate). The title product was obtained as a solid and used without further purification for the next step. LC-MS (Method B): m / z (ESI+) = 299.1 [M+H]+, Rt = 2.69 min.Scheme 2 Step 2. Synthesis of N'‐[4‐({5‐[(E)‐3‐(dimethylamino)prop‐2‐enoyl]‐1,3‐thiazol‐4‐ yl}oxy)‐3‐methylnaphthalen‐1‐yl]‐N,N‐dimethylmethanimidamide

[0194] 1-[4-[(4-Amino-2-methyl-1-naphthyl)oxy]thiazol-5-yl]ethanone (20%, 1.45 g, 0.972 mmol) was suspended in 1,1-dimethoxy-N,N-dimethylmethanamine (10 mL, 75.3 mmol) and stirred at 80oC overnight. The reaction was cooled to room temperature, concentrated in vacuo and the product was purified by silica chromatography (KP-NH column, eluting with a gradient of 0-100% ethyl acetate in heptane) to afford the title compound as a solid. (140 mg, 0.257 mmol, 26% yield). LC-MS (Method A): m / z (ESI+) = 409.6 [M+H]+, Rt = 0.60 min. UV purity = 75%. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.38 – 8.27 (m, 1H), 7.93 – 7.77 (m, 2H), 7.73 – 7.64 (m, 1H), 7.49 – 7.35 (m, 2H), 6.81 (s, 1H), 6.22 (d, J = 12.3 Hz, 1H), 3.16 (s, 3H), 3.07 (s, 6H), 2.80 (s, 3H), 2.25 (s, 3H). Scheme 2 Step 3. Synthesis of tert‐butyl N‐[(trans)‐4‐[(4‐{4‐[(4‐ {[(dimethylamino)methylidene]amino}‐2‐methylnaphthalen‐1‐yl)oxy]‐1,3‐thiazol‐5‐ yl}pyrimidin‐2‐yl)amino]cyclohexyl]carbamate

[0195] N'‐[4‐({5‐[(E)‐3‐(dimethylamino)prop‐2‐enoyl]‐1,3‐thiazol‐4‐yl}oxy)‐3‐ methylnaphthalen‐1‐yl]‐N,N‐dimethylmethanimidamide (25 mg, 0.0612 mmol) was dissolved in ethanol (0.5 mL). Potassium carbonate (51 mg, 0.367 mmol) and tert‐butyl N‐[(trans)‐4‐ carbamimidamidocyclohexyl]carbamate (Intermediate A) (24 mg, 0.0918 mmol) were added and the reaction was stirred at 80oC for 4 h. The reaction was cooled to room temperature, filtered under vacuum, and the solids were washed with MeOH (approx. 10 mL). The filtrate was concentrated in vacuo and the resulting residue was dissolved in DCM (2 mL). The organic layer was washed with water (4 x 2 mL), brine (2 mL), passed through a hydrophobic frit and concentrated in vacuo. The resulting oil was purified by silica chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane followed by 0-20% MeOH in ethyl acetate) to obtain the title compound as an oil. (27 mg, 0.0422 mmol, 69% yield).LC-MS (Method B): m / z (ESI+) = 602.4 [M+H]+, Rt = 2.50 min. UV purity = 94%.1H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.42 – 8.28 (m, 2H), 7.85 (s, 1H), 7.69 – 7.55 (m, 1H), 7.45 – 7.36 (m, 3H), 7.22 – 7.00 (m, 1H), 6.81 (s, 1H), 6.79 – 6.66 (m, 1H), 3.75 – 3.29 (m, 2H), 3.13 – 2.99 (m, 6H), 2.22 (s, 3H), 1.96 – 1.75 (m, 4H), 1.43 – 1.21 (m, 13H).Scheme 2 Step 4. Synthesis of tert‐butyl N‐[(trans)‐4‐[(4‐{4‐[(4‐amino‐2‐methylnaphthalen‐ 1‐yl)oxy]‐1,3‐thiazol‐5‐yl}pyrimidin‐2‐yl)amino]cyclohexyl]carbamate

[0196] Ethane-1,2-diamine (15 μL, 0.224 mmol) was added to a solution of tert‐butyl N‐ [(trans)‐4‐[(4‐{4‐[(4‐{[(dimethylamino)methylidene]amino}‐2‐methylnaphthalen‐1‐yl)oxy]‐1,3‐ thiazol‐5‐yl}pyrimidin‐2‐yl)amino]cyclohexyl]carbamate (25 mg, 0.0415 mmol) in ethanol (anhydrous, 0.4 mL). The reaction was sparged with nitrogen for 5 min at room temperature, stirred at 80oC overnight, and then stood at room temperature for 2 days. The reaction was concentrated in vacuo to afford an oil which was dissolved in DCM (2 mL) and washed with water (2 x 2 mL). The aqueous was extracted with DCM (2 x 1 mL) and the combined organic layers were passed through a hydrophobic frit and concentrated in vacuo to afford the title compound as an oil. (20 mg, 0.0311 mmol, 75% yield). LC-MS Method B: m / z (ESI+) = 547.3 [M+H]+, Rt = 3.47 min. UV purity = 96%. 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.39 – 8.29 (m, 1H), 8.06 (dd, J = 7.8, 1.7 Hz, 1H), 7.59 – 7.52 (m, 1H), 7.44 – 7.28 (m, 3H), 7.20 – 6.98 (m, 1H), 6.80 – 6.68 (m, 1H), 6.56 (s, 1H), 5.67 (s, 2H), 3.78 – 3.54 (m, 1H), 3.25 – 3.13 (m, 1H), 2.14 (s, 3H), 2.04 – 1.67 (m, 4H), 1.42 – 1.35 (m, 9H), 1.34 – 1.14 (m, 4H). NMR purity = 85%. Scheme 2 Step 5. Synthesis of tert‐butyl N‐[(trans)‐4‐{[4‐(4‐{[2‐methyl‐4‐(2,2,2‐ trifluoroethanesulfonamido)naphthalen‐1‐yl]oxy}‐1,3‐thiazol‐5‐yl)pyrimidin‐2- yl]amino}cyclohexyl]carbamate

[0197] A solution of tert‐butyl N‐[(trans)‐4‐[(4‐{4‐[(4‐amino‐2‐methylnaphthalen‐1‐yl)oxy]‐ 1,3‐thiazol‐5‐yl}pyrimidin‐2‐yl)amino]cyclohexyl]carbamate (85%, 20 mg, 0.0311 mmol) in pyridine (anhydrous, 0.4 mL) was sparged with nitrogen for 3 min then cooled in an ice bath for the addition of 2,2,2-trifluoroethanesulfonyl chloride (4.5 μL, 0.0407 mmol). The reaction was stirred in the ice bath for 10 min. The reaction was re-treated with 2,2,2-trifluoroethanesulfonyl chloride (3 μL, 0.0271 mmol) then stirred in the ice bath and allowed to equilibrate to room temperature over 40 min. The reaction was diluted with saturated aqueous sodium bicarbonate solution (2 mL) and the product was extracted with ethyl acetate (3 x 2 mL). The combined organic layers were washed with water (1 mL), dried using magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) to afford the title compound as a solid. (12 mg, 0.0166 mmol, 53% yield).LC-MS (Method B): m / z (ESI+) = 693.4 [M+H]+, Rt = 3.96 min. UV purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.42 – 8.33 (m, 1H), 8.25 – 8.19 (m, 1H), 8.13 (s, 1H), 7.78 – 7.72 (m, 1H), 7.60 – 7.45 (m, 3H), 7.43 – 7.33 (m, 1H), 7.24 – 7.05 (m, 1H), 6.80 – 6.70 (m, 1H), 4.65 – 4.44 (m, 2H), 3.75 – 3.57 (m, 1H), 3.25 – 3.16 (m, 1H), 2.27 (s, 3H), 2.06 – 1.76 (m, 4H), 1.39 (s, 9H), 1.35 – 1.19 (m, 4H). Scheme 2 Step 6. Synthesis of 2,2,2‐trifluoro‐N‐(3‐methyl‐4‐{[5‐(2‐{[(trans)‐4‐ aminocyclohexyl]amino}pyrimidin‐4‐yl)‐1,3‐thiazol‐4‐yl]oxy}naphthalen‐1‐yl)ethane‐1‐ sulfonamide hydrochloride

[0198] 4 M Hydrogen chloride in 1,4-dioxane (50 μL, 0.2 mmol) was added to a solution of tert‐butyl N‐[(trans)‐4‐{[4‐(4‐{[2‐methyl‐4‐(2,2,2‐trifluoroethanesulfonamido)naphthalen‐1‐ yl]oxy}‐1,3‐thiazol‐5‐yl)pyrimidin‐2-yl]amino}cyclohexyl]carbamate (10 mg, 0.0146 mmol) in 1,4-dioxane (anhydrous, 0.1 mL) and the reaction was stirred at room temperature overnight. The reaction was retreated with 4 M hydrogen chloride in 1,4-dioxane (50 μL, 0.2 mmol) followed by one drop of water and the reaction was stirred at room temperature for 30 min. The solvent was removed using a stream of nitrogen and the product was dried under vacuum at 40oC for 30 min and then lyophilised for 4 h to afford the title compound as a solid. (7.8 mg, 0.0124 mmol, 85% yield). LC-MS (Method B): m / z (ESI+) = 593.2 [M+H]+, Rt = 2.12 min. UV purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.92 – 8.84 (m, 1H), 8.41 (d, J = 5.6 Hz, 1H), 8.21 (d, J = 8.3 Hz, 1H), 8.07 – 7.88 (m, 3H), 7.80 – 7.74 (m, 1H), 7.73 – 7.44 (m, 5H), 4.65 (q, J = 9.8 Hz, 2H), 3.55 – 3.43 (m, 1H), 3.12 – 2.92 (m, 1H), 2.29 (s, 3H), 2.14 – 1.93 (m, 4H), 1.57 – 1.33 (m, 4H).Scheme 3. Synthesis of Example 3. 2,2,2-Trifluoro-N-[3-methyl-4-[5-[2-[[(3S)-3- piperidyl]amino]pyrimidin-4-yl]thiazol-4-yl]oxy-1- naphthyl]ethanesulfonamide;hydrochlorideIntermediate C. Synthesis of tert‐butyl (3S)‐3‐carbamimidamidopiperidine‐1‐carboxylate

[0199] N-ethyl-N-isopropyl-propan-2-amine (1.9 mL, 10.6 mmol) was added to a solution of tert-butyl (3S)-3-aminopiperidine-1-carboxylate (2.00 g, 9.99 mmol) and 1H-pyrazole-1- carboximidamide hydrochloride (1:1) (1.46 g, 9.99 mmol) in acetonitrile (50 mL) and the reaction was stirred at room temperature for 96 h. The reaction was concentrated in vacuo and the residue was re-dissolved in acetonitrile (40 mL). The acetonitrile layer was washed with heptane (3 x 50 mL) and then concentrated in vacuo to afford the title compound as an oil. (3.49 g, 10.1 mmol, 70% purity, quantitative recovery). LC-MS (Method A): m / z (ESI+) = 243.3 [M+H]+, Rt = 0.49 min. ELS purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 7.92 – 6.58 (m, 4H), 3.63 – 3.50 (m, 1H), 3.23 – 2.70 (m, 4H), 1.91 – 1.79 (m, 1H), 1.75 – 1.57 (m, 1H), 1.39 (m, 11H). NMR purity = 70%. Scheme 3 Step 1. Synthesis of tert‐butyl (3S)‐3‐[(4‐{4‐[(4‐ {[(dimethylamino)methylidene]amino}‐2‐methylnaphthalen‐1‐yl)oxy]‐1,3‐thiazol‐5‐ yl}pyrimidin‐2‐yl)amino]piperidine‐1‐carboxylate

[0200] N'‐[4‐({5‐[(E)‐3‐(dimethylamino)prop‐2‐enoyl]‐1,3‐thiazol‐4‐yl}oxy)‐3‐ methylnaphthalen‐1‐yl]‐N,N‐dimethylmethanimidamide (Scheme 2, Step 2) (140 mg, 0.343 mmol) was dissolved in ethanol (3 mL). Potassium carbonate (284 mg, 2.06 mmol) was added, followed by tert‐butyl (3S)‐3‐carbamimidamidopiperidine‐1‐carboxylate (Intermediate C) (166 mg, 0.685 mmol) and the reaction was stirred at 80oC overnight. The reaction was filtered undervacuum and the solids washed with MeOH (approx. 10 mL). The filtrate was concentrated in vacuo and the residue was dissolved in DCM (5 mL). The organic layer was washed with water (2 x 1 mL), passed through a hydrophobic frit, and concentrated in vacuo. The product was purified by silica chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane) to afford the title compound as a powder. (84 mg, 0.139 mmol, 40% yield). LC-MS (Method A): m / z (ESI+) = 588.4 [M+H]+, Rt = 0.78 min. UV purity = 97%. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.49 – 8.41 (m, 1H), 8.38 – 8.25 (m, 1H), 7.85 (s, 1H), 7.69 – 7.58 (m, 1H), 7.53 – 7.36 (m, 3H), 7.29 – 7.10 (m, 1H), 6.87 – 6.77 (m, 1H), 3.85 – 3.51 (m, 5H), 3.08 (s, 6H), 2.22 (s, 3H), 1.97 – 1.90 (m, 1H), 1.86 – 1.70 (m, 1H), 1.66 – 1.51 (m, 1H), 1.46 – 1.24 (m, 10H). Scheme 3 Step 2. Synthesis of tert-butyl (3S)-3-[[4-[4-[(4-amino-2-methyl-1- naphthyl)oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate

[0201] Ethane-1,2-diamine (54 μL, 0.808 mmol) was added to a solution of tert‐butyl (3S)‐3‐ [(4‐{4‐[(4‐{[(dimethylamino)methylidene]amino}‐2‐methylnaphthalen‐1‐yl)oxy]‐1,3‐thiazol‐5‐ yl}pyrimidin‐2‐yl)amino]piperidine‐1‐carboxylate (84 mg, 0.143 mmol) in ethanol (anhydrous, 1.2 mL) and the reaction was stirred at 80oC overnight. The reaction was concentrated in vacuo and the resulting residue was dissolved in DCM (2 mL) and washed with water (2 x 2 mL). The aqueous was extracted with DCM (2 x 1 mL) and the combined organic layers were washed with brine (1 mL), passed through a hydrophobic frit, concentrated in vacuo, and dried under vacuum at 40oC to afford the title compound as a powder. (74 mg, 0.129 mmol, 90% yield). LC-MS (Method B): m / z (ESI+) = 533.2 [M+H]+, Rt = 3.75 min. UV purity = 93%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 8.73 (s, 1H), 8.38 (d, J = 5.1 Hz, 1H), 8.10 – 8.00 (m, 1H), 7.65 - 7.58 (m, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.40 – 7.30 (m, 2H), 6.88 – 6.73 (m, 1H), 6.60 (s, 1H), 5.43 (s, 2H), 3.96 – 3.77 (m, 3H), 3.70 – 3.58 (m, 1H), 3.02 – 2.88 (m, 1H), 2.16 (s, 3H), 2.04 – 1.93 (m, 1H), 1.84 – 1.74 (m, 1H), 1.66 - 1.46 (m, 1H), 1.54 – 1.46 (m, 1H), 1.42 – 1.32 (m, 9H). Scheme 3 Step 3. Synthesis of tert-butyl (3S)-3-[[4-[4-[[2-methyl-4-(2,2,2- trifluoroethylsulfonylamino)-1-naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine- 1-carboxylate

[0202] A solution of tert-butyl (3S)-3-[[4-[4-[(4-amino-2-methyl-1-naphthyl)oxy]thiazol-5- yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (24 mg, 0.0451 mmol) in pyridine (anhydrous, 0.4 mL) was sparged with nitrogen for 3 min and then stirred in an ice bath for the addition of2,2,2-trifluoroethanesulfonyl chloride (6.5 μL, 0.059 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature for 1.25 h. The reaction was diluted with saturated aqueous sodium bicarbonate solution (2 mL) and the product was extracted with ethyl acetate (3 x 2 mL). The combined organics were washed with water (1 mL), dried using magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) to afford the title compound as a powder. (18 mg, 0.0265 mmol, 59% yield). LC-MS (Method B): m / z (ESI+) = 679.3 [M+H]+, Rt = 4.21 min. UV purity = 100%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 10.41 - 10.00 (br. s, 1H), 8.78 (s, 1H), 8.41 (d, J = 5.1 Hz, 1H), 8.24 (d, J = 8.3 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.63 – 7.51 (m, 3H), 7.46 (d, J = 5.2 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 4.50 (q, J = 9.8 Hz, 2H), 3.94 – 3.75 (m, 2H), 3.71 – 3.54 (m, 1H), 3.05 – 2.94 (m, 2H), 2.30 (s, 3H), 2.03 – 1.91 (m, 1H), 1.85 – 1.71 (m, 1H), 1.67 – 1.55 (m, 1H), 1.51 – 1.43 (m, 1H), 1.37 (s, 9H). Scheme 3 Step 4. Synthesis of 2,2,2-trifluoro-N-[3-methyl-4-[5-[2-[[(3S)-3- piperidyl]amino]pyrimidin-4-yl]thiazol-4-yl]oxy-1- naphthyl]ethanesulfonamide;hydrochloride

[0203] 4 M Hydrogen chloride in 1,4-dioxane (85 μL, 0.34 mmol) was added to a solution of tert-butyl (3S)-3-[[4-[4-[[2-methyl-4-(2,2,2-trifluoroethylsulfonylamino)-1- naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (17 mg, 0.025 mmol) in 1,4-dioxane (anhydrous, 0.15 mL) and the reaction was stirred at room temperature for 30 min before a drop of water was added. The reaction was stirred for 1.25 h, concentrated under a stream of nitrogen, dried under vacuum at 40oC for 1 h and then lyophilised over the weekend to afford the title compound as a powder. (13 mg, 0.0215 mmol, 86% yield). LC-MS (Method B): m / z (ESI+) = 579.2 [M+H]+, Rt = 2.10 min. UV purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.07 – 8.93 (m, 2H), 8.90 – 8.78 (m, 1H), 8.46 (d, J = 5.3 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.85 – 7.70 (m, 1H), 7.67 – 7.44 (m, 5H), 4.65 (q, J = 9.8 Hz, 2H), 4.29 – 4.09 (m, 1H), 3.44 – 3.31 (m, 1H), 3.27 – 3.13 (m, 1H), 2.98 – 2.76 (m, 2H), 2.29 (s, 3H), 2.08 – 1.86 (m, 2H), 1.81 – 1.52 (m, 2H).Scheme 4. Synthesis of Example 4. 2,2,2-Trifluoro-N-[4-[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]thiazol-4-yl]oxy-3-methyl-1-naphthyl]ethanesulfonamideSynthesis of Intermediate D. tert-Butyl (3S,5S)-3-fluoro-5-guanidino-piperidine-1- carboxylate;hydrochloride

[0204] 1H-Pyrazole-1-carboximidamide hydrochloride (1:1) (5.04 g, 34.36 mmol) and N- ethyl-N-isopropyl-propan-2-amine (6.4 mL, 36.64 mmol) were added to a solution of tert-butyl (3S,5S)-3-amino-5-fluoro-piperidine-1-carboxylate (5.00 g, 22.91 mmol) in acetonitrile (90 mL) and the reaction was stirred at 50oC overnight. The reaction was retreated with 1H-pyrazole-1- carboximidamide hydrochloride (1:1) (1.68 g, 11.46 mmol) and N-ethyl-N-isopropyl-propan-2- amine (2 mL, 11.45 mmol), stirred at 50oC for 5 h and then stirred at room temperature for 60 h. The reaction was filtered under vacuum to afford the title compound as a powder. (4.21 g, 13.5 mmol, 59% yield). LC-MS (Method B): m / z (ESI+) = 261.2 [M+H]+, Rt = 1.24 min. ELS purity = 100%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 8.04 – 7.04 (m, 5H), 5.03 – 4.81 (m, 1H), 3.95 – 3.76 (m, 3H), 3.34 – 3.16 (m, 1H), 2.93 – 2.80 (m, 1H), 2.26 – 2.11 (m, 1H), 1.86 – 1.66 (m, 1H), 1.42 (s, 9H). NMR purity = 95%. Scheme 4 Step 1. Synthesis of tert‐butyl (3S,5S)‐3‐[(4‐{4‐[(4‐ {[(dimethylamino)methylidene]amino}‐2‐methylnaphthalen‐1‐yl)oxy]‐1,3‐thiazol‐5‐ yl}pyrimidin‐2‐yl)amino]‐5‐fluoropiperidine‐1‐carboxylate

[0205] N'‐[4‐({5‐[(E)‐3‐(dimethylamino)prop‐2‐enoyl]‐1,3‐thiazol‐4‐yl}oxy)‐3‐ methylnaphthalen‐1‐yl]‐N,N‐dimethylmethanimidamide (Scheme 2, Step 2) (88%, 84 mg, 0.181 mmol) was dissolved in ethanol (1.5 mL). Potassium carbonate (150 mg, 1.09 mmol) and tert-butyl (3S,5S)-3-fluoro-5-guanidino-piperidine-1-carboxylate;hydrochloride (Intermediate D) (90 mg, 0.303 mmol) were added and the reaction was stirred at 80oC for 24 h. The reaction was filtered under vacuum and the solids washed with MeOH (approx. 10 mL). The filtrate was concentrated in vacuo and the residue was dissolved in DCM (5 mL). The organic layer was washed with water (2 x 1 mL), passed through a hydrophobic frit, and concentrated in vacuo. The product was purified by silica chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane) to afford the title compound as a powder. (47 mg, 0.0753 mmol, 42% yield). LC-MS (Method B): m / z (ESI+) = 606.3 [M+H]+, Rt = 2.48 min. UV purity = 97%. 1H NMR (400 MHz, DMSO-d6, 353K) δ 8.76 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.38 – 8.30 (m, 1H), 7.83 (s, 1H), 7.69 – 7.60 (m, 1H), 7.50 (d, J = 5.2 Hz, 1H), 7.44 – 7.32 (m, 2H), 7.03 (d, J = 7.7 Hz, 1H), 6.81 (s, 1H), 5.09 – 4.85 (m, 1H), 4.22 – 4.10 (m, 1H), 4.09 – 3.91 (m, 2H), 3.33 – 3.16 (m, 1H), 3.08 (obscured s, 6H), 2.99 – 2.87 (m, 1H), 2.30 – 2.19 (m, 4H), 1.94 – 1.77 (m, 1H), 1.46 – 1.34 (m, 9H). Scheme 4 Step 2. Synthesis of tert-butyl (3S,5S)-3-[[4-[4-[(4-amino-2-methyl-1- naphthyl)oxy]thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate

[0206] Ethane-1,2-diamine (30 μL, 0.449 mmol) was added to a solution of tert‐butyl (3S,5S)‐ 3‐[(4‐{4‐[(4‐{[(dimethylamino)methylidene]amino}‐2‐methylnaphthalen‐1‐yl)oxy]‐1,3‐thiazol‐ 5‐yl}pyrimidin‐2‐yl)amino]‐5‐fluoropiperidine‐1‐carboxylate (45 mg, 0.0743 mmol) in ethanol (anhydrous, 0.75 mL) and the reaction was stirred at 80oC overnight. The reaction was retreated with ethane-1,2-diamine (15 μL, 0.225 mmol) and stirred at 80oC for 4.5 h. The reaction was concentrated in vacuo and the resulting residue was dissolved in DCM (2 mL) and washed with water (2 x 2 mL). The aqueous was extracted with DCM (2 x 1 mL) and the combined organic layers were washed with brine (1 mL), passed through a hydrophobic frit, concentrated in vacuo, and dried under vacuum at 40oC to afford the title compound as a powder. (37 mg, 0.0645 mmol, 87% yield). LC-MS (Method B): m / z (ESI+) = 551.2 [M+H]+, Rt = 3.58 min. UV purity = 96%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 8.74 (s, 1H), 8.40 (d, J = 5.2 Hz, 1H), 8.08 – 8.00 (m, 1H), 7.65 – 7.57 (m, 1H), 7.49 (d, J = 5.2 Hz, 1H), 7.40 – 7.28 (m, 2H), 7.05 – 6.96 (m, 1H), 6.60 (s, 1H), 5.43 (s, 2H), 5.08 – 4.85 (m, 1H), 4.22 – 4.12 (m, 1H), 4.11 – 3.89 (m, 2H), 3.26 – 3.17 (m, 1H), 3.10 – 2.84 (m, 1H), 2.29 – 2.20 (m, 1H), 2.19 – 2.08 (m, 3H), 2.00 – 1.76 (m, 1H), 1.39 (s, 9H).Scheme 4 Step 3. Synthesis of tert-butyl (3S,5S)-3-fluoro-5-[[4-[4-[[2-methyl-4-(2,2,2- trifluoroethylsulfonylamino)-1-naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine- 1-carboxylate

[0207] A solution of tert-butyl (3S,5S)-3-[[4-[4-[(4-amino-2-methyl-1-naphthyl)oxy]thiazol- 5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate (96%, 37 mg, 0.0645 mmol) in pyridine (anhydrous, 0.5 mL) was sparged with nitrogen and stirred in an ice bath for the addition of 2,2,2-trifluoroethanesulfonyl chloride (9 μL, 0.0841 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature for 2.5 h. The reaction was cooled in an ice bath, retreated with 2,2,2-trifluoroethanesulfonyl chloride (5 μL, 0.0425 mmol), and allowed to equilibrate to room temperature for 2 h. The reaction was cooled in an ice bath, retreated with 2,2,2-trifluoroethanesulfonyl chloride (9 μL, 0.0841 mmol) and allowed to equilibrate to room temperature for 2.5 h. The reaction was stood at room temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate solution (2 mL), diluted with ethyl acetate (2 mL) and the layers were separated. The aqueous was extracted with ethyl acetate (2 x 2 mL) and the combined organics were washed with washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) to afford the title compound as a solid. (17.6 mg, 88% purity, 0.022 mmol, 35% yield). LC-MS (Method B): m / z (ESI+) = 697.3 [M+H]+, Rt = 4.02 min. Scheme 4 Step 4. Synthesis of 2,2,2-trifluoro-N-[4-[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]thiazol-4-yl]oxy-3-methyl-1-naphthyl]ethanesulfonamide

[0208] 4 M Hydrogen chloride in 1,4-dioxane (85 μL, 0.34 mmol) was added to a solution of tert-butyl (3S,5S)-3-fluoro-5-[[4-[4-[[2-methyl-4-(2,2,2-trifluoroethylsulfonylamino)-1- naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (88%, 17.1 mg, 0.022 mmol) in 1,4-dioxane (anhydrous, 170 μL) and the reaction was stirred at room temperature for 2 h. The reaction was retreated with 1,4-dioxane (anhydrous, 170 μL) and 4 M hydrogen chloride in 1,4-dioxane (85 μL, 0.34 mmol) and stirred at room temperature for 2 h. The solvent was removed under a stream of nitrogen and the residue was dried under vacuum at 40oC. The product was purified by high pH preparative HPLC (Preparative Method C) to afford the title compound as a powder. (9.6 mg, 0.0161 mmol, 72% yield). LC-MS (Method B): m / z (ESI+) = 597.1 [M+H]+, Rt = 2.20 min. UV purity = 100%.1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.41 (d, J = 5.1 Hz, 1H), 8.30 – 8.23 (m, 1H), 7.72 – 7.65 (m, 1H), 7.51 – 7.42 (m, 3H), 7.37 (s, 1H), 7.30 – 7.20 (m, 1H), 5.02 – 4.82 (m, 1H), 4.37 – 4.12 (m, 3H), 3.19 – 3.02 (m, 2H), 2.94 – 2.76 (m, 1H), 2.63 – 2.55 (m, 1H), 2.28 – 2.15 (m, 4H), 1.95 – 1.75 (m, 1H). Scheme 5. Synthesis of Example 5. 2,2,2-Trifluoro-N-[2-fluoro-3-methyl-4-[5-[2-[[(3S)-3- piperidyl]amino]pyrimidin-4-yl]thiazol-4-yl]oxy-1- naphthyl]ethanesulfonamide;hydrochlorideScheme 5 Step 1. Synthesis of tert-butyl (3S)-3-[[4-[4-[(4-amino-3-fluoro-2-methyl-1- naphthyl)oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate

[0209] A stirred solution of tert-butyl (3S)-3-[[4-[4-[(4-amino-2-methyl-1- naphthyl)oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (140 mg, 0.263 mmol) (Scheme 3, Step 2) in THF (anhydrous, 1.4 mL) was cooled to 5-10oC and sparged with nitrogen for 5 min. A solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (83 mg, 0.263 mmol) in THF (anhydrous, 1.4 mL) was added slowly dropwise over 10 min. The reaction was allowed to equilibrate to room temperature and stirred overnight. The reaction was quenched with saturated aqueous sodium thiosulfate solution (3 mL) and the product was extracted with ethyl acetate (2 x 2 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (3 mL), brine (3 mL), dried using magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by low pH reverse phase chromatography (eluting with a gradient of 10- 100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)). The product containing fractions were combined, the MeCN was removed in vacuo, the aqueous mixture was treated with saturated aqueous sodium bicarbonate solution (2 mL) and extracted with DCM (3 x 15 mL). The combined organic layers were washed with brine (5 mL), passed through a hydrophobic frit, andconcentrated in vacuo. The resulting residue was re-purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)). The product containing fractions were combined, the MeCN was removed in vacuo, the aqueous mixture was treated with saturated aqueous sodium bicarbonate solution (2 mL) and extracted with DCM (3 x 15 mL). The combined organic layers were washed with brine (5 mL), passed through a hydrophobic frit, and concentrated in vacuo. The resulting residue was re-purified by silica chromatography (KP-NH column, eluting in a gradient of 0-100% ethyl acetate in heptane) to afford the title compound as a powder. (25 mg, 0.0445 mmol, 17% yield). LC-MS (Method B): m / z (ESI+) = 551.2 [M+H]+, Rt = 4.18 min. UV purity = 100%. 1H NMR (400 MHz, DMSO-d6, 353K) δ 8.75 (s, 1H), 8.40 (d, J = 5.2 Hz, 1H), 8.21 – 8.11 (m, 1H), 7.71 – 7.59 (m, 1H), 7.50 – 7.28 (m, 3H), 6.85 (d, J = 7.2 Hz, 1H), 5.35 (s, 2H), 3.93 – 3.76 (m, 2H), 3.71 – 3.58 (m, 1H), 3.04 – 2.95 (m, 2H), 2.19 (d, J = 2.1 Hz, 3H), 2.05 – 1.90 (m, 1H), 1.84 – 1.73 (m, 1H), 1.70 – 1.56 (m, 1H), 1.52 – 1.42 (m, 1H), 1.37 (s, 9H). Scheme 5 Step 2. Synthesis of tert-butyl (3S)-3-[[4-[4-[[3-fluoro-2-methyl-4-(2,2,2- trifluoroethylsulfonylamino)-1-naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine- 1-carboxylate

[0210] A solution of tert-butyl (3S)-3-[[4-[4-[(4-amino-3-fluoro-2-methyl-1- naphthyl)oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (22 mg, 0.04 mmol) in pyridine (anhydrous, 0.4 mL) was stirred in an ice bath for the addition of 2,2,2- trifluoroethanesulfonyl chloride (5.5 μL, 0.0497 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature for 30 min. The reaction was diluted with saturated aqueous sodium bicarbonate solution (1 mL) and the product was extracted with ethyl acetate (2 x 2 mL). The combined organic layers were washed with brine (1 mL), dried using magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) to afford the title compound as a powder. (25 mg, 0.0352 mmol, 88% yield). LC-MS (Method B): m / z (ESI+) = 697.3 [M+H]+, Rt = 4.28 min. UV purity = 98%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 10.43 - 9.94 (br. s, 1H), 8.80 (s, 1H), 8.42 (d, J = 5.1 Hz, 1H), 8.22 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.70 – 7.61 (m, 1H), 7.56 – 7.47 (m, 1H), 7.44 (d, J = 5.1 Hz, 1H), 6.95 – 6.86 (m, 1H), 4.50 (q, J = 9.7 Hz, 2H), 3.94 – 3.78 (m, 2H), 3.71 – 3.59 (m, 1H), 3.05 – 2.94 (m, 2H), 2.25 (d, J = 1.9 Hz, 3H), 2.03 – 1.93 (m, 1H), 1.84 – 1.72 (m, 1H), 1.68 – 1.56 (m, 1H), 1.52 – 1.42 (m, 1H), 1.37 (s, 9H).Scheme 5 Step 3. Synthesis of 2,2,2-trifluoro-N-[2-fluoro-3-methyl-4-[5-[2-[[(3S)-3- piperidyl]amino]pyrimidin-4-yl]thiazol-4-yl]oxy-1- naphthyl]ethanesulfonamide;hydrochloride

[0211] 4 M Hydrogen chloride in 1,4-dioxane (90 μL, 0.36 mmol) and water (5 μL) were added to a solution of tert-butyl (3S)-3-[[4-[4-[[3-fluoro-2-methyl-4-(2,2,2- trifluoroethylsulfonylamino)-1-naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1- carboxylate (24 mg, 0.0344 mmol) in 1,4-dioxane (0.2 mL) and the reaction was stirred at room temperature for 2.5 h. The solvent was removed under a stream of nitrogen and the resulting residue was dried under vacuum at 40oC for 1 h, then lyophilised overnight to afford the title compound as a powder. (20 mg, 0.0316 mmol, 92% yield). LC-MS (Method B): m / z (ESI+) = 597.2 [M+H]+, Rt = 2.29 min. UV purity = 98%. 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.06 – 8.74 (m, 3H), 8.46 (d, J = 5.3 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.72 – 7.63 (m, 1H), 7.62 – 7.44 (m, 3H), 4.61 (q, J = 9.7 Hz, 2H), 4.25 – 4.07 (m, 1H), 3.43 – 3.33 (m, 1H), 3.25 – 3.12 (m, 1H), 2.97 – 2.76 (m, 2H), 2.24 (d, J = 1.8 Hz, 3H), 2.08 – 1.85 (m, 2H), 1.81 – 1.53 (m, 2H).Scheme 6. Synthesis of Example 6. 2,2,2-Trifluoro-N-[3-methyl-4-[2-methyl-5-[2-[[(3S)-3- piperidyl]amino]pyrimidin-4-yl]thiazol-4-yl]oxy-1- naphthyl]ethanesulfonamide;hydrochloride.Scheme 6 Step 1. Synthesis of 1-(4-chloro-2-methyl-thiazol-5-yl)ethanol

[0212] To a 3-neck 1 L RBF under an atmosphere of nitrogen was added 2,4-dichlorothiazole- 5-carbaldehyde (18.00 g, 98.88 mmol) and THF (anhydrous, 200 mL). The stirring solution was cooled in a brine / ice bath to -11 °C for the dropwise addition of 2 M trimethylaluminum in toluene (100 mL, 200 mmol) over 1 h. Upon complete addition the reaction was allowed to warm to room temperature over 10 min before stirring at 40 °C for 22 h. The reaction was cooled to room temperature, palladium - triphenylphosphane (1:4) (5.14 g, 4.45 mmol) was added, and the reaction was stirred at 60 °C for 2 h. The completed reaction was cooled to room temperature, then cooled further to -7 °C and diluted with ethyl acetate (50 mL). The solution was cautiously quenched with the slow addition of ice-cold water (100 mL) over 1 h (maximum temperature = 5 °C, gas evolution observed). Upon complete addition the solution was warmed to room temperature over 30 min. The reaction was diluted with ethyl acetate (100 mL) and the organic layer was decanted and filtered through glass fibre filter paper. The slurry remaining in the flask was diluted with water (100 mL) and ethyl acetate (100 mL) and filtered through glass fibre filter paper. The collected precipitate was washed with ethyl acetate (100 mL). The combined filtrate was transferred into a separating funnel and the layers were separated. The organic layer was washed with water (100 mL) and brine (100 mL). The combined aqueous layers were extractedwith ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica chromatography (eluting with a gradient of 10-40% ethyl acetate in heptane) to afford the title compound as an oil. (13.3 g, 74.1 mmol, 75% yield). LC-MS (Method B): m / z (ESI+) = 178.1 [M(35Cl)+], 180.1 [M(37Cl)+], Rt = 1.72 min. UV purity = 99%. 1H NMR (400 MHz, DMSO-d6) δ 5.85 (d, J = 3.2 Hz, 1H), 4.93 (qd, J = 6.4, 3.0 Hz, 1H), 2.59 (s, 3H), 1.35 (d, J = 6.4 Hz, 3H). Scheme 6 Step 2. Synthesis of 1-(4-chloro-2-methyl-thiazol-5-yl)ethanone

[0213] Manganese dioxide (49.73 g, 572.03 mmol) was added to a solution of 1-(4-chloro-2- methyl-thiazol-5-yl)ethanol (13.83 g, 76.27 mmol) in DCM (150 mL) and the reaction was stirred under nitrogen at room temperature for 18 h. The reaction mixture was filtered through celite and the filter cake washed with DCM (3 x 100 mL). The filtrate was partially concentrated in vacuo to approx. 150 mL and then re-treated with manganese dioxide (49.73 g, 572.03 mmol) and stirred at room temperature for 5 h. The reaction was filtered through a pad of celite and the filter cake was washed with DCM (3 x 100 mL). The filtrate was concentrated in vacuo to afford an oil which was purified by silica chromatography (eluting with a gradient of 5- 30% ethyl acetate in heptane) to afford the title compound as an oil which solidified upon standing at room temperature. (12.3 g, 68.63 mmol, 90% yield). LC-MS (Method A): m / z (ESI+) = 176.1 [M(35Cl)+], 178.1 [M(37Cl)+], Rt = 0.62 min. UV purity = 100%. 1H NMR (400 MHz, CDCl3) δ 2.69 (s, 3H), 2.66 (s, 3H). Scheme 6 Step 3. Synthesis of 1-[4-[(4-amino-2-methyl-1-naphthyl)oxy]-2-methyl-thiazol-5- yl]ethanone

[0214] A mixture of 1-(4-chloro-2-methyl-thiazol-5-yl)ethanone (292 mg, 1.5 mmol), 4- amino-2-methyl-naphthalen-1-ol (Intermediate B) (260 mg, 1.5 mmol) and cesium carbonate (976 mg, 3.0 mmol) in DMF (anhydrous, 6 mL) was stirred at 80 °C under a nitrogen atmosphere for 2.5 h. The reaction was cooled to room temperature and filtered through a pad of celite. The filter cake was washed with ethyl acetate (approx. 100 mL) and the filtrate was concentrated in vacuo to afford an oil. The oil was purified by silica chromatography (KP-NH column, eluting with a gradient of 0-60% ethyl acetate in heptane) to afford the title compound as a powder. (118 mg, 0.303 mmol, 20% yield).LC-MS (Method A): m / z (ESI+) = 313.1 [M+H]+, Rt = 0.77 min. UV purity = 80%. 1H NMR (400 MHz, CDCl3) δ 7.84 – 7.74 (m, 2H), 7.48 – 7.40 (m, 2H), 6.66 (s, 1H), 4.09 (s, 2H), 2.77 (s, 3H), 2.43 (s, 3H), 2.27 (s, 3H). Scheme 6 Step 4. Synthesis of N'‐[4‐({5‐[(E)‐3‐(dimethylamino)prop‐2‐enoyl]‐2‐methyl‐1,3‐ thiazol‐4‐yl}oxy)‐3‐methylnaphthalen‐1‐yl]‐N,N‐dimethylmethanimidamide

[0215] A solution of 1-[4-[(4-amino-2-methyl-1-naphthyl)oxy]-2-methyl-thiazol-5- yl]ethanone (85%, 169 mg, 0.46 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (2 mL, 15.06 mmol) was stirred at 80 °C for 2.5 h under nitrogen and then stood at room temperature overnight. The reaction was stirred at 80 °C under nitrogen for a further 5.5 h and then cooled to room temperature. The reaction mixture was concentrated in vacuo and purified by silica chromatography (KP-NH column, eluting with a gradient of 0-100% ethyl acetate in heptane) to afford the title compound as a solid. (107 mg, 0.233 mmol, 51% yield). LC-MS (Method B): m / z (ESI+) = 423.3 [M+H]+, Rt = 1.64 min. UV purity = 92%. 1H NMR (400 MHz, DMSO-d6) δ 8.37 – 8.32 (m, 1H), 7.86 (s, 1H), 7.78 (d, J = 12.4 Hz, 1H), 7.74 – 7.70 (m, 1H), 7.46 (ddd, J = 8.3, 6.8, 1.5 Hz, 1H), 7.40 (ddd, J = 8.1, 6.7, 1.4 Hz, 1H), 6.81 (s, 1H), 6.18 (d, J = 12.4 Hz, 1H), 3.15 (s, 3H), 3.08 (s, 6H), 2.77 (s, 3H), 2.37 (s, 3H), 2.26 (s, 3H). Scheme 6 Step 5. Synthesis of tert‐butyl (3S)‐3‐[(4‐{4‐[(4‐ {[(dimethylamino)methylidene]amino}‐2‐methylnaphthalen‐1‐yl)oxy]‐2‐methyl‐1,3‐thiazol‐ 5‐yl}pyrimidin‐2‐yl)amino]piperidine‐1‐carboxylate

[0216] N'‐[4‐({5‐[(E)‐3‐(Dimethylamino)prop‐2‐enoyl]‐2‐methyl‐1,3‐thiazol‐4‐yl}oxy)‐3‐ methylnaphthalen‐1‐yl]‐N,N‐dimethylmethanimidamide (92%, 107 mg, 0.23 mmol), tert‐butyl (3S)‐3‐carbamimidamidopiperidine‐1‐carboxylate (Intermediate C) (147 mg, 0.61 mmol) and potassium carbonate (194 mg, 1.4 mmol) were suspended in ethanol (2.2 mL) and the reaction was stirred at 80 °C for 18.5 h. The reaction was cooled to room temperature, filtered under vacuum, and the solids were washed with MeOH (10 mL). The filtrate was concentrated in vacuo and re- dissolved in DCM (3 mL). The organic layer was washed with water (2 x 1 mL), brine (2 mL), passed through a hydrophobic frit and concentrated in vacuo. The product was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)). Product containing fractions were combined and concentrated in vacuo to remove the MeCN. The aqueous was treated with saturated sodium hydrogen carbonate solution and extracted with DCM (3 x 10 mL). The organics were combined, washed with brine,passed through a hydrophobic frit, and concentrated in vacuo to afford the title compound as a solid. (22 mg, 0.0359 mmol, 15% yield). LC-MS (Method A): m / z (ESI+) = 602.3 [M+H]+, Rt = 0.84 min. UV purity = 99%. 1H NMR (400 MHz, DMSO-d6) δ 8.39 – 8.31 (m, 2H), 7.87 (s, 1H), 7.67 – 7.60 (m, 1H), 7.46 – 7.35 (m, 3H), 7.22 – 7.08 (m, 1H), 6.82 (s, 1H), 3.83 – 3.69 (m, 2H), 3.63 – 3.50 (m, 1H), 3.28 – 3.13 (m, 2H), 3.08 (s, 6H), 2.42 (s, 3H), 2.23 (s, 3H), 1.98 – 1.71 (m, 2H), 1.69 – 1.49 (m, 2H), 1.48 – 1.20 (m, 9H). Scheme 6 Step 6. Synthesis of tert-butyl (3S)-3-[[4-[4-[(4-amino-2-methyl-1-naphthyl)oxy]-2- methyl-thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate

[0217] Ethane-1,2-diamine (14 μL, 0.209 mmol) was added to a solution of tert‐butyl (3S)‐3‐ [(4‐{4‐[(4‐{[(dimethylamino)methylidene]amino}‐2‐methylnaphthalen‐1‐yl)oxy]‐2‐methyl‐1,3‐ thiazol‐5‐yl}pyrimidin‐2‐yl)amino]piperidine‐1‐carboxylate (22 mg, 0.0359 mmol) in ethanol (anhydrous, 0.3 mL). The reaction was purged with nitrogen and stirred at 80 °C for 16.5 h. The reaction was concentrated in vacuo to afford an oil which was redissolved in DCM (1 mL) and washed with water (2 x 1 mL). The aqueous was extracted with DCM (2 x 2 mL) and the combined organic layers were passed through a hydrophobic frit and concentrated in vacuo to afford the title compound as a solid. (19 mg, 0.0344 mmol, 96% yield). LC-MS (Method B): m / z (ESI+) = 547.3 [M+H]+, Rt = 3.71 min. UV purity = 100%. 1H NMR (400 MHz, DMSO-d6, 353K) δ 8.33 (d, J = 5.2 Hz, 1H), 8.08 – 8.02 (m, 1H), 7.65 – 7.60 (m, 1H), 7.42 – 7.30 (m, 3H), 6.77 – 6.71 (m, 1H), 6.59 (s, 1H), 5.42 (s, 2H), 3.94 – 3.75 (m, 2H), 3.70 – 3.60 (m, 1H), 3.04 – 2.96 (m, 2H), 2.42 (s, 3H), 2.17 (s, 3H), 2.02 – 1.92 (m, 1H), 1.84 – 1.73 (m, 1H), 1.69 – 1.55 (m, 1H), 1.52 – 1.42 (m, 1H), 1.38 (s, 9H). Scheme 6 Step 7. Synthesis of tert-butyl (3S)-3-[[4-[2-methyl-4-[[2-methyl-4-(2,2,2- trifluoroethylsulfonylamino)-1-naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine- 1-carboxylate

[0218] A solution of tert-butyl (3S)-3-[[4-[4-[(4-amino-2-methyl-1-naphthyl)oxy]-2-methyl- thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (18.2 mg, 0.03 mmol) in pyridine (anhydrous, 0.3 mL) was sparged with nitrogen and stirred in an ice bath for the addition of 2,2,2- trifluoroethanesulfonyl chloride (4 μL, 0.04 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature for 3 h. The reaction was retreated with 2,2,2- trifluoroethanesulfonyl chloride (4 μL, 0.04 mmol) and stirred at room temperature for 64 h. The reaction was diluted with saturated aqueous sodium bicarbonate solution (1 mL), extracted withethyl acetate (2 x 2 mL), the organics were combined, washed with brine (2 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)). Product containing fractions were combined, concentrated in vacuo to remove the MeCN, treated with saturated aqueous sodium bicarbonate solution, the aqueous was extracted with DCM (2 x 2 mL), the organics combined, passed through a hydrophobic frit, and concentrated in vacuo to afford the title compound as a solid. (8.6 mg, 0.0124 mmol, 37% yield). LC-MS (Method B): m / z (ESI+) = 693.3 [M+H]+, Rt = 4.20 min. UV purity = 100%. 1H NMR (400 MHz, DMSO-d6, 353K) δ 10.22 – 10.14 (m, 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.24 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.60 – 7.48 (m, 3H), 7.38 (d, J = 5.2 Hz, 1H), 6.86 – 6.75 (m, 1H), 4.49 (q, J = 9.8 Hz, 2H), 3.93 – 3.76 (m, 2H), 3.70 – 3.60 (m, 1H), 3.04 – 2.95 (m, 2H), 2.44 (s, 3H), 2.30 (s, 3H), 2.00 – 1.94 (m, 1H), 1.82 – 1.73 (m, 1H), 1.68 – 1.57 (m, 1H), 1.50 – 1.41 (m, 1H), 1.38 (s, 9H). Scheme 6 Step 8. Synthesis of 2,2,2-trifluoro-N-[3-methyl-4-[2-methyl-5-[2-[[(3S)-3- piperidyl]amino]pyrimidin-4-yl]thiazol-4-yl]oxy-1- naphthyl]ethanesulfonamide;hydrochloride

[0219] 2 M Hydrogen chloride in 1,4-dioxane (0.1 mL) was added to a solution of tert-butyl (3S)-3-[[4-[2-methyl-4-[[2-methyl-4-(2,2,2-trifluoroethylsulfonylamino)-1- naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (8.6 mg, 0.01 mmol) in 1,4-dioxane (anhydrous, 0.3 mL)) and the reaction was stirred at room temperature for 1.5 h. The reaction was retreated with 2 M hydrogen chloride in 1,4-dioxane (0.1 mL) and stirred for a further 30 min. The solvent was removed under a stream of nitrogen and the product was lyophilised overnight to afford the title compound as a powder. (7.6 mg, 0.0121 mmol, 97% yield). LC-MS (Method B): m / z (ESI+) = 593.2 [M+H]+, Rt = 2.17 min. UV purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.94 – 8.80 (m, 2H), 8.40 (d, J = 5.4 Hz, 1H), 8.23 – 8.19 (m, 1H), 7.82 – 7.75 (m, 1H), 7.70 – 7.33 (m, 5H), 4.66 (q, J = 9.8 Hz, 2H), 4.19 – 4.09 (m, 1H), 3.42 – 3.34 (m, 1H), 3.24 – 3.15 (m, 1H), 2.93 – 2.81 (m, 2H), 2.45 (s, 3H), 2.29 (s, 3H), 2.06 – 1.86 (m, 2H), 1.78 – 1.55 (m, 2H).Scheme 7. Synthesis of Example 7. 2,2,2-Trifluoro-N-[4-[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4- yl]oxyphenyl]ethanesulfonamide;hydrochlorideScheme 7 Step 1. Synthesis of tert-butyl N-[4-(5-acetyl-2-methyl-thiazol-4- yl)oxyphenyl]carbamate

[0220] 1-(4-Chloro-2-methyl-thiazol-5-yl)ethanone (Scheme 6 Step 2) (1.3 g, 7.4 mmol), tert- butyl (4-hydroxyphenyl)carbamate (1.55 g, 7.41 mmol) and cesium carbonate (4.82 g, 14.79 mmol) were suspended in DMF (anhydrous, 40 mL). The reaction was sparged with nitrogen at room temperature for 15 min then stirred at 50oC overnight. The reaction was cooled to room temperature, filtered through glass fibre filter paper under vacuum, and the solids were washed with ethyl acetate (approx. 60 mL). Water (160 mL), brine (100 mL) and ethyl acetate (100 mL) were added to the filtrate and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried using magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by silica chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane) followed by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+0.1% formic acid) in water (+0.1% formic acid)). Product containing fractions were combined and concentrated in vacuo to remove the MeCN and the resulting aqueous suspension was filtered under vacuum to afford the title compound as a solid. (254 mg, 0.729 mmol, 10% yield).LC-MS (Method A): m / z (ESI+) = 349.1 [M+H]+, Rt = 1.00 min. UV purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 7.54 – 7.37 (m, 2H), 7.18 – 7.04 (m, 2H), 2.55 (s, 3H), 2.53 – 2.49 (m, 3H), 1.48 (s, 9H). Scheme 7 Step 2. Synthesis of 1-[4-(4-aminophenoxy)-2-methyl-thiazol-5-yl]ethanone

[0221] 4 M Hydrogen chloride in 1,4-dioxane (1.5 mL, 6.0 mmol) was added to a solution of tert-butyl N-[4-(5-acetyl-2-methyl-thiazol-4-yl)oxyphenyl]carbamate (490 mg, 1.41 mmol) in 1,4-dioxane (5 mL) and the reaction was stirred at room temperature overnight. The reaction was treated with 5 drops of water, followed by 4 M hydrogen chloride in 1,4-dioxane (1.5 mL, 6.0 mmol) and stirred at room temperature for 2 h. The reaction was retreated with 4 M hydrogen chloride in 1,4-dioxane (1.5 mL, 6.0 mmol) and stirred at room temperature for 2 h. The reaction was concentrated in vacuo and the resulting solid was vigorously stirred in DCM (5 mL) and saturated aqueous sodium bicarbonate solution (5 mL) for 10 min. The organic layer was separated using a hydrophobic frit and the aqueous layer was extracted with DCM (2 x 3 mL). The combined organic layers were passed through a hydrophobic frit and concentrated in vacuo to afford the title compound as an oil. (350 mg, 1.34 mmol, 95% yield). LC-MS (Method A): m / z (ESI+) = 249.1 [M+H]+, Rt = 0.50 min. UV purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 6.94 – 6.81 (m, 2H), 6.60 – 6.49 (m, 2H), 5.02 (s, 2H), 2.53 (s, 3H), 2.52 – 2.47 (m, 3H). Scheme 7 Step 3. Synthesis of N'‐[4‐({5‐[(E)‐3‐(dimethylamino)prop‐2‐enoyl]‐2‐methyl‐1,3‐ thiazol‐4‐yl}oxy)phenyl]‐N,N‐dimethylmethanimidamide

[0222] 1-[4-(4-Aminophenoxy)-2-methyl-thiazol-5-yl]ethanone (350 mg, 1.41 mmol) was dissolved in 1,1-dimethoxy-N,N-dimethylmethanamine (0.75 mL, 5.65 mmol) and stirred at 80oC overnight. The reaction was cooled to room temperature and concentrated in vacuo. The residue was triturated in diethyl ether (5 mL) and filtered under vacuum to afford the title compound as a solid. (465 mg, 1.025 mmol, 72% yield). LC-MS (Method A): m / z (ESI+) = 359.1 [M+H]+, Rt = 0.59 min. UV purity = 79%. 1H NMR (400 MHz, DMSO-d6) δ 7.76 – 7.61 (m, 2H), 6.96 – 6.80 (m, 4H), 5.89 – 5.73 (m, 1H), 3.03 - 2.77 (m, 12H), 2.61 – 2.52 (m, 3H).Scheme 7 Step 4. Synthesis of tert‐butyl (3S,5S)‐3‐({4‐[4‐(4‐ {[(dimethylamino)methylidene]amino}phenoxy)‐2‐methyl‐1,3‐thiazol‐5‐yl]pyrimidin‐2‐ yl}amino)‐5‐fluoropiperidine‐1‐carboxylate

[0223] N'‐[4‐({5‐[(E)‐3‐(Dimethylamino)prop‐2‐enoyl]‐2‐methyl‐1,3‐thiazol‐4‐ yl}oxy)phenyl]‐N,N‐dimethylmethanimidamide (80%, 90 mg, 0.201 mmol), tert-butyl (3S,5S)-3- fluoro-5-guanidino-piperidine-1-carboxylate;hydrochloride (Intermediate D) (85 mg, 0.27 mmol) and potassium carbonate (166 mg, 1.2 mmol) were suspended in ethanol (1.5 mL) and the reaction was stirred at 80oC for 5 h. The reaction was cooled to room temperature, filtered under vacuum, and the solids were washed with MeOH (approx. 8 mL). The filtrate was concentrated in vacuo and the residue was dissolved in DCM (3 mL). The organic layer was washed with water (2 x 1 mL), passed through a hydrophobic frit, and concentrated in vacuo. The resulting residue was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)). Product containing fractions were combined and concentrated in vacuo. The resulting residue was dissolved in DCM (2 mL), washed with saturated aqueous sodium bicarbonate solution (1 mL), passed through a hydrophobic frit, concentrated in vacuo, and dried under vacuum at 40oC to afford the title compound as an oil. (44 mg, 0.0752 mmol, 37% yield). LC-MS (Method B): m / z (ESI+) = 556.2 [M+H]+, Rt = 2.27 min. UV purity = 95%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 8.29 (d, J = 5.2 Hz, 1H), 7.68 (s, 1H), 7.15 (d, J = 5.2 Hz, 1H), 7.00 – 6.85 (m, 5H), 5.07 – 4.80 (m, 1H), 4.20 – 3.88 (m, 3H), 3.23 – 3.13 (m, 1H), 3.00 – 2.80 (m, 7H), 2.58 (s, 3H), 2.25 – 2.11 (m, 1H), 1.96 – 1.74 (m, 1H), 1.39 (s, 9H). Scheme 7 Step 5. Synthesis of tert-butyl (3S,5S)-3-[[4-[4-(4-aminophenoxy)-2-methyl-thiazol- 5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate

[0224] Ethane-1,2-diamine (80 μL, 1.20 mmol) was added to a solution of tert‐butyl (3S,5S)‐ 3‐({4‐[4‐(4‐{[(dimethylamino)methylidene]amino}phenoxy)‐2‐methyl‐1,3‐thiazol‐5‐ yl]pyrimidin‐2‐yl}amino)‐5‐fluoropiperidine‐1‐carboxylate (107 mg, 0.193 mmol) in ethanol(anhydrous, 1.5 mL) and the reaction was stirred at 80 oC overnight. The reaction was concentratedin vacuo and the resulting oil was dissolved in DCM (2 mL) and washed with water (2 x 2 mL). The combined aqueous layers were extracted with DCM (2 x 1 mL). The combined organics were washed with water (2 mL), brine (2 mL), passed through a hydrophobic frit, and concentrated in vacuo to afford the title compound as a solid. (80 mg, 0.150 mmol, 78% yield). LC-MS (Method B): m / z (ESI+) = 501.2 [M+H]+, Rt = 2.53 min. UV purity = 94%.1H NMR (400 MHz, DMSO-d6, 353 K) δ 8.28 (d, J = 5.2 Hz, 1H), 7.16 (d, J = 5.2 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.86 – 6.76 (m, 2H), 6.64 – 6.53 (m, 2H), 5.09 – 4.85 (m, 1H), 4.75 (s, 2H), 4.19 – 3.84 (m, 3H), 3.24 – 3.14 (m, 1H), 2.96 – 2.79 (m, 1H), 2.56 (s, 3H), 2.27 – 2.14 (m, 1H), 1.98 – 1.72 (m, 1H), 1.39 (s, 9H). Scheme 7 Step 6. Synthesis of tert-butyl (3S,5S)-3-fluoro-5-[[4-[2-methyl-4-[4-(2,2,2- trifluoroethylsulfonylamino)phenoxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1- carboxylate

[0225] A solution of tert-butyl (3S,5S)-3-[[4-[4-(4-aminophenoxy)-2-methyl-thiazol-5- yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate (30 mg, 0.0599 mmol) in pyridine (anhydrous, 0.4 mL) was stirred in an ice bath for the addition of 2,2,2-trifluoroethanesulfonyl chloride (8 μL, 0.0724 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature for 50 min. The reaction was diluted with saturated aqueous sodium bicarbonate solution (1 mL) and the product was extracted with ethyl acetate (2 x 2 mL). The combined organic layers were washed with brine (1 mL), dried using magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) to afford the title compound as a solid. (27 mg, 0.0413 mmol, 69% yield). LC-MS (Method B): m / z (ESI+) = 647.3 [M+H]+, Rt = 3.71 min. UV purity = 99%. 1H NMR (400 MHz, DMSO-d6, 353K) δ 10.60 - 9.90 (m, 1H), 8.30 (d, J = 5.1 Hz, 1H), 7.33 – 7.20 (m, 2H), 7.18 – 7.08 (m, 3H), 6.99 (d, J = 7.6 Hz, 1H), 5.07 – 4.81 (m, 1H), 4.37 (q, J = 9.9 Hz, 2H), 4.20 – 3.86 (m, 3H), 3.28 – 3.15 (m, 1H), 2.93 – 2.81 (m, 1H), 2.60 (s, 3H), 2.26 – 2.12 (m, 1H), 1.97 – 1.73 (m, 1H), 1.39 (s, 9H). Scheme 7 Step 7. Synthesis of 2,2,2-trifluoro-N-[4-[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4- yl]oxyphenyl]ethanesulfonamide;hydrochloride

[0226] 4 M Hydrogen chloride in 1,4-dioxane (50 μL, 0.2 mmol) was added to a solution of tert-butyl (3S,5S)-3-fluoro-5-[[4-[2-methyl-4-[4-(2,2,2- trifluoroethylsulfonylamino)phenoxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1- carboxylate (24 mg, 0.0371 mmol) in 1,4-dioxane (0.2 mL). Water (5 μL) was added and the reaction was stirred at room temperature for 2 h. The reaction was retreated with 4 M hydrogen chloride in 1,4-dioxane (50 μL, 0.2 mmol) and stirred at room temperature for another 1.5 h. The reaction was concentrated in vacuo and the product was dried under vacuum at 40oC for 30 minand then lyophilised overnight to afford the title compound as a solid. (17 mg, 0.0295 mmol, 79% yield). LC-MS (Method B): m / z (ESI+) = 547.1 [M+H]+, Rt = 1.89 min. UV purity = 100%. 1H NMR (400 MHz, MeOD) δ 8.31 – 8.24 (m, 1H), 7.71 – 7.59 (m, 1H), 7.39 – 7.32 (m, 2H), 7.29 – 7.19 (m, 2H), 5.38 – 5.16 (m, 1H), 4.78 – 4.64 (m, 1H), 4.15 (q, J = 9.4 Hz, 2H), 3.77 – 3.37 (m, 3H), 3.18 – 3.04 (m, 1H), 2.71 – 2.53 (m, 4H), 2.18 – 1.95 (m, 1H). Scheme 8. Synthesis of Example 8. 4 4-[4-(4-Aminophenoxy)-2-methyl-thiazol-5-yl]-N- [(3S,5S)-5-fluoro-3-piperidyl]pyrimidin-2-amine;hydrochlorideScheme 8 Step 1. Synthesis of 4-[4-(4-aminophenoxy)-2-methyl-thiazol-5-yl]-N-[(3S,5S)-5- fluoro-3-piperidyl]pyrimidin-2-amine;hydrochloride

[0227] 4 M Hydrogen chloride in 1,4-dioxane (30 μL, 0.12 mmol) was added to a solution of tert-butyl (3S,5S)-3-[[4-[4-(4-aminophenoxy)-2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5- fluoro-piperidine-1-carboxylate (Scheme 7 Step 5) (94%, 10 mg, 0.0188 mmol) in 1,4-dioxane (0.1 mL). Water (10 μL) was added and the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo and the product was dried under vacuum at 40oC for 30 min and then lyophilised overnight to afford the title compound as a solid. (5.7 mg, 0.0129 mmol, 69% yield). LC-MS (Method B): m / z (ESI+) = 401.1 [M+H]+, Rt = 1.07 min. UV purity = 99%. 1H NMR (400 MHz, MeOD) δ 8.30 (d, J = 6.5 Hz, 1H), 7.77 – 7.30 (m, 5H), 5.38 – 5.17 (m, 1H), 4.76 – 4.60 (m, 1H), 3.76 – 3.61 (m, 2H), 3.48 – 3.35 (m, 1H), 3.20 – 3.00 (m, 1H), 2.72 – 2.52 (m, 4H), 2.21 – 1.94 (m, 1H).Scheme 9. Synthesis of Example 9. 2,2,2-Trifluoro-N-[4-[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]oxy-1- naphthyl]ethanesulfonamide;hydrochlorideScheme 9 Step 1. Synthesis of (E)-1-(4-chloro-2-methyl-thiazol-5-yl)-3- (dimethylamino)prop-2-en-1-one

[0228] 1-(4-Chloro-2-methyl-thiazol-5-yl)ethanone (Scheme 6, Step 2) (8.00 g, 44.64 mmol) was dissolved in 1,1-dimethoxy-N,N-dimethylmethanamine (8 mL, 60.2 mmol) and stirred at 80 °C for 3 h. The reaction was stood at room temperature overnight and the resulting suspension was filtered under vacuum, and washed with TBME (50 mL), to afford the title compound as a powder. (7.90 g, 27.4 mmol, 61% yield). LC-MS (Method A): m / z (ESI+) = 231.2 [M(35Cl)+], 233.2 [M(37Cl)+], Rt = 0.63 min, UV purity = 94%. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 12.1 Hz, 1H), 5.80 (d, J = 12.1 Hz, 1H), 3.17 (s, 3H), 2.90 (s, 3H), 2.62 (s, 3H). Scheme 9 Step 2. Synthesis of tert-butyl (3S,5S)-3-[[4-(4-chloro-2-methyl-thiazol-5- yl)pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate

[0229] (E)-1-(4-chloro-2-methyl-thiazol-5-yl)-3-(dimethylamino)prop-2-en-1-one (79%, 1.5 g, 5.14 mmol) and tert-butyl (3S,5S)-3-fluoro-5-guanidino-piperidine-1- carboxylate;hydrochloride (Intermediate D) (2.3 g, 7.75 mmol) were suspended in ethanol (40 mL) and purged with nitrogen for 5 min. Potassium carbonate (4.3 g, 31.11 mmol) was added and the reaction was purged with nitrogen for 1 min then stirred at 80 °C for 20 h. The reaction was filtered under vacuum, the solids were washed with methanol (approx.50 mL), and the filtrate wasconcentrated in vacuo. The resulting residue was dissolved in DCM (20 mL), washed with water (2 x 20 mL), brine (20 mL) and concentrated in vacuo. The product was purified by silica chromatography (KP-NH column, eluting with a gradient of 0-100% ethyl acetate in heptane) to afford the title compound as a powder. (1.98 g, 4.34 mmol, 85% yield). LC-MS (Method B): m / z (ESI+) = 428.1 [M(35Cl)+], 430.1 [M(37Cl)+], Rt = 3.69 min, UV purity = 94%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 8.43 (d, J = 5.2 Hz, 1H), 7.32 (d, J = 5.1 Hz, 1H), 7.24 – 7.02 (m, 1H), 5.10 – 4.83 (m, 1H), 4.17 – 3.87 (m, 3H), 3.25 – 3.11 (m, 1H), 2.98 – 2.80 (m, 1H), 2.70 – 2.63 (m, 3H), 2.27 – 2.12 (m, 1H), 1.99 – 1.74 (m, 1H), 1.38 (s, 9H). Scheme 9 Step 3. Synthesis of tert-butyl (3S,5S)-3-[[4-[4-[(4-amino-1-naphthyl)oxy]-2- methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate

[0230] The following procedure was carried out for reactions A to E. 4-Aminonaphthalen-1- ol hydrochloride (1:1) (151 mg, 0.772 mmol) and cesium carbonate (837 mg, 2.57 mmol) were flushed with nitrogen for 2 min. NMP (anhydrous, 1 mL) was added and the suspension was stirred under a flow of nitrogen for 15 min before a solution of tert-butyl (3S,5S)-3-[[4-(4-chloro-2- methyl-thiazol-5-yl)pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate (250 mg, 0.514 mmol) in NMP (anhydrous, 3 mL) was added via syringe to the reaction. The reaction was sparged with nitrogen for a further 10 min and then stirred at 130 °C under microwave irradiation for 2 h. Reactions A to E were combined and filtered through celite which was washed with ethyl acetate (170 mL). The filtrate was washed with water / brine (150 mL, 2:1), brine (3 x 100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting foam was purified by silica chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane followed by 0- 20% MeOH in ethyl acetate) followed by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)). The product containing fractions were combined and concentrated in vacuo to remove the MeCN. The remaining aqueous was treated with saturated aqueous sodium bicarbonate solution, extracted with DCM (3 x 50 mL), the organics were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a foam. (413 mg, 0.750 mmol, 29% yield). LC-MS (Method B): m / z (ESI+) = 551.5 [M+H]+, Rt = 3.50 min. UV purity = 100%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 8.31 (d, J = 5.2 Hz, 1H), 8.15 – 8.09 (m, 1H), 7.91 – 7.85 (m, 1H), 7.51 – 7.41 (m, 2H), 7.31 (d, J = 5.2 Hz, 1H), 6.97 – 6.92 (m, 2H), 6.67 (d, J = 8.2Hz, 1H), 5.43 (s, 2H), 5.06 – 4.87 (m, 1H), 4.22 – 3.93 (m, 3H), 3.25 – 3.14 (m, 1H), 2.97 – 2.87 (m, 1H), 2.50 (s, 3H), 2.23 (m, 1H), 1.99 – 1.78 (m, 1H), 1.41 (s, 9H). Scheme 9 Step 4. Synthesis of tert-butyl (3S,5S)-3-fluoro-5-[[4-[2-methyl-4-[[4-(2,2,2- trifluoroethylsulfonylamino)-1-naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine- 1-carboxylate

[0231] A solution of tert-butyl (3S,5S)-3-[[4-[4-[(4-amino-1-naphthyl)oxy]-2-methyl-thiazol- 5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate (29 mg, 0.05 mmol) in pyridine (anhydrous, 0.5 mL) was stirred in an ice bath under nitrogen for the addition of 2,2,2- trifluoroethanesulfonyl chloride (8 μL, 0.07 mmol). The reaction was stirred and allowed to equilibrate to room temperature for 1.5 h. The reaction was retreated with 2,2,2- trifluoroethanesulfonyl chloride (8 μL, 0.07 mmol) and stirred at room temperature for 67 h. The reaction was retreated with 2,2,2-trifluoroethanesulfonyl chloride (8 μL, 0.07 mmol) and stirred for a further 3 h at room temperature. The reaction was diluted with saturated aqueous sodium bicarbonate solution (1 mL), the aqueous was extracted with ethyl acetate (2 x 2 mL), the organics were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was purified by low pH reverse phase chromatography (eluting with a gradient of 10- 100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) to afford the title compound as a solid. (12 mg, 0.0177 mmol, 29% yield). LC-MS (Method B): m / z (ESI+) = 697.3 [M+H]+, Rt = 4.04 min. UV purity = 100%. 1H NMR (400 MHz, DMSO-d6, 353K) δ 10.39 – 9.95 (m, 1H), 8.33 – 8.27 (m, 2H), 8.22 – 8.17 (m, 1H), 7.74 – 7.63 (m, 2H), 7.53 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 5.2 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 7.06 – 7.00 (m, 1H), 5.05 – 4.88 (m, 1H), 4.46 (q, J = 9.8 Hz, 2H), 4.19 – 3.92 (m, 3H), 3.22 – 3.16 (m, 1H), 2.96 – 2.85 (m, 1H), 2.57 (s, 3H), 2.28 – 2.16 (m, 1H), 1.97 – 1.77 (m, 1H), 1.40 (s, 9H). Scheme 9 Step 5. Synthesis of 2,2,2-trifluoro-N-[4-[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]oxy-1- naphthyl]ethanesulfonamide;hydrochloride

[0232] 4 M Hydrogen chloride in 1,4-dioxane (100 μL, 0.4 mmol) was added to a solution of tert-butyl (3S,5S)-3-fluoro-5-[[4-[2-methyl-4-[[4-(2,2,2-trifluoroethylsulfonylamino)-1- naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (12 mg, 0.02 mmol) in 1,4-dioxane (100 μL). Water (10 μL) was added and the reaction was stirred at room temperature for 1.5 h. The solvent was removed under a stream of nitrogen, dried under vacuum at 40oC for 1h and then lyophilised overnight to afford the title compound as a powder. (8.5 mg, 0.0129 mmol, 75% yield). LC-MS (Method B): m / z (ESI+) = 597.2 [M+H]+, Rt = 2.14 min. UV purity = 96%. 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.76 – 9.52 (m, 1H), 9.33 – 9.01 (m, 1H), 8.34 (d, J = 5.3 Hz, 1H), 8.30 – 8.24 (m, 1H), 8.17 – 8.13 (m, 1H), 7.75 – 7.52 (m, 4H), 7.26 (d, J = 5.3 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 5.32 – 5.13 (m, 1H), 4.58 (q, J = 9.8 Hz, 2H), 4.46 – 4.32 (m, 1H), 3.31 – 3.09 (m, 3H), 2.92 – 2.76 (m, 1H), 2.57 (s, 3H), 2.42 – 2.24 (m, 1H), 2.00 – 1.78 (m, 1H).

[0233] The compounds of the following tabulated Examples (Table 2) were prepared analogously to Scheme 9 Step 4 using tert-butyl (3S,5S)-3-[[4-[4-[(4-amino-1-naphthyl)oxy]-2- methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate and the appropriate commercially available sulfonyl chloride. The boc protecting group was then removed using 4 M hydrogen chloride in 1,4-dioxane analogously to Scheme 9 Step 5.

[0234] The Step 5 boc deprotection of Example 9.15 was performed using TFA / DCM at 0 °C and was followed by an aqueous work up to afford the free base.

[0235] Table 2: Exemplary compounds of the disclosureScheme 10. Synthesis of Example 10. N-[4-[5-[2-[[(3S)-5,5-Difluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]oxy-1-naphthyl]-2,2,2-trifluoro- ethanesulfonamide;hydrochlorideIntermediate E. Synthesis of tert-butyl (5S)-3,3-difluoro-5-guanidino-piperidine-1- carboxylate;hydrochloride

[0236] N-ethyl-N-isopropyl-propan-2-amine (1.2 mL, 6.87 mmol) was added to a solution of tert-butyl (5S)-5-amino-3,3-difluoropiperidine-1-carboxylate (1.00 g, 4.23 mmol) and 1H- pyrazole-1-carboximidamide hydrochloride (1:1) (0.93 g, 6.34 mmol) in acetonitrile (anhydrous, 20 mL). The reaction was stirred at 50oC for 41 h. The reaction was cooled to room temperature, retreated with 1H-pyrazole-1-carboximidamide hydrochloride (1:1) (0.31 g, 2.12 mmol) and N- ethyl-N-isopropyl-propan-2-amine (0.4 mL, 2.26 mmol) and stirred at 50oC for 21 h. The reaction was filtered under vacuum. Heptane (30 mL) was added to the filtrate and the layers were separated. The MeCN layer was treated with 70:30 diethyl ether:heptane solution (30 mL) and the mixture was swirled at room temperature. The resulting suspension was filtered under vacuum and the filtrate was concentrated in vacuo to afford an oil. The oil was dissolved in MeCN (10 mL) and treated with a solution of 70:30 heptane:diethyl ether (10 mL). The resulting suspension was stood at room temperature overnight and then filtered under vacuum. The filtrate was concentrated in vacuo and redissolved in MeCN (20 mL). The MeCN was washed with 70:30 heptane:diethyl ether (2 x 20 mL, then 10 mL) and then concentrated in vacuo to afford the title compound as an oil. (1.9 g, 3.32 mmol, 78% yield). LC-MS (Method B): m / z (ESI+) = 279.2 [M+H]+, Rt = 1.34 min, ELS purity = 88%.1H NMR (400 MHz, MeOD) δ 4.13 – 3.37 (m, 5H), 2.54 – 2.36 (m, 1H), 2.26 – 2.08 (m, 1H), 1.48 (s, 9H). NMR purity estimated at 55%. Scheme 10 Step 1. Synthesis of tert-butyl (5S)-5-[[4-(4-chloro-2-methyl-thiazol-5- yl)pyrimidin-2-yl]amino]-3,3-difluoro-piperidine-1-carboxylate

[0237] (E)-1-(4-Chloro-2-methyl-thiazol-5-yl)-3-(dimethylamino)prop-2-en-1-one (Scheme 9 Step 1) (190 mg, 0.824 mmol), tert-butyl (5S)-3,3-difluoro-5-guanidino-piperidine-1- carboxylate;hydrochloride (Intermediate E) (55%, 500 mg, 0.874 mmol) and potassium carbonate (690 mg, 4.99 mmol) were suspended in ethanol (7 mL) and the reaction was stirred at 80oC overnight. The reaction was cooled to room temperature, filtered under vacuum, and the solids washed with methanol (approx. 5 mL). The filtrate was concentrated in vacuo and the resulting residue was dissolved in DCM (5 mL). The organic layer was washed with water (3 mL) and concentrated in vacuo. The resulting material was purified by silica chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane) to obtain the title compound as a solid. (255 mg, 0.560 mmol, 68% yield). LC-MS (Method A): m / z (ESI+) = 446.1 [M(35Cl)+], 448.1 [M(37Cl)+], Rt = 1.08 min, UV purity = 98%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 8.46 (d, J = 5.1 Hz, 1H), 7.37 (d, J = 5.1 Hz, 1H), 7.06 (d, J = 7.1 Hz, 1H), 4.16 – 3.96 (m, 3H), 3.45 – 3.22 (m, 1H), 3.03 – 2.90 (m, 1H), 2.67 (s, 3H), 2.46 – 2.38 (m, 1H), 2.24 – 2.01 (m, 1H), 1.40 (s, 9H). Scheme 10 Step 2. Synthesis of tert-butyl (5S)-5-[[4-[4-[(4-amino-1-naphthyl)oxy]-2-methyl- thiazol-5-yl]pyrimidin-2-yl]amino]-3,3-difluoro-piperidine-1-carboxylate

[0238] 4-Aminonaphthalen-1-ol hydrochloride (1:1) (168 mg, 0.86 mmol) and cesium carbonate (930 mg, 2.85 mmol) were flushed with nitrogen for 2 min. NMP (anhydrous, 1 mL) was added and the reaction was stirred under a flow of nitrogen for 5 min. A solution of tert-butyl (5S)-5-[[4-(4-chloro-2-methyl-thiazol-5-yl)pyrimidin-2-yl]amino]-3,3-difluoro-piperidine-1- carboxylate (255 mg, 0.57 mmol) in NMP (anhydrous, 3 mL) was added to the reaction and it was stirred under a flow of nitrogen for another 3 min. The reaction was stirred at 130 °C under microwave irradiation for 4 h. The reaction was filtered through a 2.5 g prepacked celite cartridge eluting in ethyl acetate (approx. 30 mL). The organic layer was washed with water (2 x 10 mL). The combined aqueous layers were extracted with ethyl acetate (2 x 20 mL) and then the combined organic layers were washed with water (10 mL), brine (10 mL), dried using magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by silica chromatography (elutingwith a gradient of 0-100% ethyl acetate in heptane followed by 0-20% MeOH in ethyl acetate) followed by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)). Product containing fractions were combined, concentrated in vacuo to remove the MeCN and treated with saturated aqueous sodium bicarbonate solution (3 mL). The product was extracted with DCM (2 x 20 mL) and the combined organic layers were passed through a hydrophobic frit and concentrated in vacuo. The resulting solid was repurified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)). Product containing fractions were combined, concentrated in vacuo to remove the MeCN and treated with saturated aqueous sodium bicarbonate solution (3 mL). The product was extracted with DCM (2 x 20 mL) and the combined organic layers were passed through a hydrophobic frit and concentrated in vacuo to afford the title compound as a solid. (90 mg, 0.147 mmol, 26% yield). LC-MS (Method B): m / z (ESI+) = 569.2 [M+H]+, Rt = 3.87 min, UV purity = 93%. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 5.3 Hz, 1H), 8.17 – 8.07 (m, 1H), 7.84 – 7.73 (m, 1H), 7.50 – 7.41 (m, 2H), 7.38 – 7.11 (m, 2H), 6.99 (d, J = 8.1 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 5.69 (s, 2H), 4.32 – 3.92 (m, 3H), 3.45 – 3.38 (m, 1H), 3.11 – 2.68 (m, 1H), 2.47 – 2.40 (m, 4H), 2.21 – 1.97 (m, 1H), 1.53 – 1.18 (m, 9H). Scheme 10 Step 3. Synthesis of tert-butyl (5S)-3,3-difluoro-5-[[4-[2-methyl-4-[[4-(2,2,2- trifluoroethylsulfonylamino)-1-naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine- 1-carboxylate

[0239] A solution of tert-butyl (5S)-5-[[4-[4-[(4-amino-1-naphthyl)oxy]-2-methyl-thiazol-5- yl]pyrimidin-2-yl]amino]-3,3-difluoro-piperidine-1-carboxylate (30 mg, 0.0528 mmol) in pyridine (anhydrous, 0.3 mL) was stirred in an ice bath for the addition of 2,2,2- trifluoroethanesulfonyl chloride (6 μL, 0.0543 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature over 45 min. The reaction was diluted with saturated aqueous sodium bicarbonate solution (1 mL) and the product was extracted with ethyl acetate (2 x 2 mL). The combined organic layers were washed with brine (1 mL), dried using magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) to afford the title compound as a solid. (27 mg, 0.0378 mmol, 72% yield). LC-MS (Method B): m / z (ESI+) = 715.3 [M+H]+, Rt = 4.28 min, UV purity = 100%.1H NMR (400 MHz, DMSO-d6) δ 10.80 – 10.05 (m, 1H), 8.43 – 8.26 (m, 2H), 8.21 – 8.08 (m, 1H), 7.78 – 7.61 (m, 2H), 7.60 – 7.48 (m, 1H), 7.46 – 7.02 (m, 3H), 4.56 (q, J = 9.7 Hz, 2H), 4.32 – 3.88 (m, 3H), 3.33 – 3.21 (m, 1H), 3.08 – 2.73 (m, 1H), 2.56 (s, 3H), 2.52 – 2.40 (m, 1H), 2.21 – 1.98 (m, 1H), 1.55 – 1.21 (m, 9H). Scheme 10 Step 4. Synthesis of N-[4-[5-[2-[[(3S)-5,5-difluoro-3-piperidyl]amino]pyrimidin- 4-yl]-2-methyl-thiazol-4-yl]oxy-1-naphthyl]-2,2,2-trifluoro- ethanesulfonamide;hydrochloride

[0240] 4 M Hydrogen chloride in 1,4-dioxane (50 μL, 0.2 mmol) was added to a solution of tert-butyl (5S)-3,3-difluoro-5-[[4-[2-methyl-4-[[4-(2,2,2-trifluoroethylsulfonylamino)-1- naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (25 mg, 0.0350 mmol) in 1,4-dioxane (0.15 mL).5 μL water was added and the reaction was stirred at room temperature for 3 h. The reaction was concentrated in vacuo and the resulting residue dried under vacuum at 40oC for 30 min before being lyophilised for 60 h to afford the title compound as a solid. (21 mg, 0.0319 mmol, 91% yield). LC-MS (Method B): m / z (ESI+) = 615.5 [M+H]+, Rt = 2.36 min, UV purity = 99%. 1H NMR (400 MHz, MeOD) δ 8.38 – 8.25 (m, 2H), 8.13 (d, J = 8.4 Hz, 1H), 7.79 – 7.56 (m, 4H), 7.23 (d, J = 8.2 Hz, 1H), 4.71 – 4.59 (m, 1H), 4.22 (q, J = 9.4 Hz, 2H), 3.88 – 3.74 (m, 1H), 3.74 – 3.52 (m, 2H), 3.28 – 3.19 (m, 1H), 2.87 – 2.71 (m, 1H), 2.60 (s, 3H), 2.45 – 2.28 (m, 1H).

[0241] The compounds of the following tabulated Examples (Table 3) were prepared analogously to Scheme 10 Step 3 using tert-butyl (5S)-5-[[4-[4-[(4-amino-1-naphthyl)oxy]-2- methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-3,3-difluoro-piperidine-1-carboxylate and the appropriate commercially available sulfonyl chloride. The boc protecting group was then removed using 4 M hydrogen chloride in 1,4-dioxane analogously to Scheme 10 Step 4. Table 3: Exemplary compounds of the disclosureScheme 11. Synthesis of Example 11. N-[4-[5-[2-[[(3S)-5,5-difluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]oxy-1-naphthyl]-3,3,3-trifluoro- propanamide;hydrochlorideScheme 11 Step 1. Synthesis of tert-butyl (5S)-3,3-difluoro-5-[[4-[2-methyl-4-[[4-(3,3,3- trifluoropropanoylamino)-1-naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1- carboxylate

[0242] A solution of tert-butyl (5S)-5-[[4-[4-[(4-amino-1-naphthyl)oxy]-2-methyl-thiazol-5- yl]pyrimidin-2-yl]amino]-3,3-difluoro-piperidine-1-carboxylate (Scheme 10 Step 2) (15 mg, 0.0264 mmol) in DCM (0.15 mL) was stirred in an ice bath for the sequential addition of N-ethyl- N-isopropyl-propan-2-amine (12 μL, 0.0687 mmol) and 3,3,3-trifluoropropanoyl chloride (3 μL, 0.0273 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature for 1 h. The reaction was cooled in an ice bath and retreated with 3,3,3- trifluoropropanoyl chloride (3 μL, 0.0273 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature for 1 h. The reaction was diluted with DCM (2 mL) and saturated aqueous sodium bicarbonate solution (1 mL). The organic layer was separated using a hydrophobic frit and concentrated in vacuo. The resulting material was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) to afford the title compound as a solid. (7.5 mg, 0.011 mmol, 41% yield). LC-MS (Method B): m / z (ESI+) = 679.3 [M+H]+, Rt = 4.19 min, UV purity = 98%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 10.09 (s, 1H), 8.32 (d, J = 5.2 Hz, 1H), 8.22 – 8.15 (m, 1H), 8.15 – 8.04 (m, 1H), 7.75 – 7.52 (m, 3H), 7.26 (d, J = 5.2 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.97 – 6.83 (m, 1H), 4.18 – 3.98 (m, 3H), 3.64 (q, J = 11.2 Hz, 2H), 3.46 – 3.29 (obscured m, 1H), 3.24 – 2.95 (obscured m, 1H), 2.56 (s, 3H), 2.51 – 2.39 (m, 1H), 2.28 – 2.04 (obscured m, 1H), 1.41 (s, 9H).Scheme 11 Step 2. Synthesis of N-[4-[5-[2-[[(3S)-5,5-difluoro-3-piperidyl]amino]pyrimidin- 4-yl]-2-methyl-thiazol-4-yl]oxy-1-naphthyl]-3,3,3-trifluoro-propanamide;hydrochloride

[0243] 4 M Hydrogen chloride in 1,4-dioxane (50 μL, 0.2 mmol) was added to a solution of tert-butyl (5S)-3,3-difluoro-5-[[4-[2-methyl-4-[[4-(3,3,3-trifluoropropanoylamino)-1- naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (15 mg, 0.0221 mmol) in 1,4-dioxane (0.15 mL).5 μL water was added and the reaction was stirred at room temperature for 2 h. The reaction was retreated with 4 M hydrogen chloride in 1,4-dioxane (50 μL, 0.2 mmol) and stirred at room temperature for 2 h. The reaction was retreated with 4 M hydrogen chloride in 1,4-dioxane (50 μL, 0.2 mmol) and stirred at room temperature for 15 min. The reaction was concentrated in vacuo and the product was lyophilised for 60 h to afford the title compound as a solid. (8.4 mg, 0.0137 mmol, 62% yield). LC-MS (Method B): m / z (ESI+) = 579.2 [M+H]+, Rt = 2.29 min, UV purity = 100%. 1H NMR (400 MHz, MeOD) δ 8.30 (d, J = 5.8 Hz, 1H), 8.18 (d, J = 8.3 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.72 – 7.57 (m, 3H), 7.55 – 7.49 (m, 1H), 7.18 – 7.09 (m, 1H), 4.65 – 4.52 (m, 1H), 3.84 – 3.72 (m, 1H), 3.71 – 3.50 (m, 4H), 3.25 – 3.15 (m, 1H), 2.80 – 2.67 (m, 1H), 2.59 (s, 3H), 2.42 – 2.23 (m, 1H). Scheme 12. Synthesis of Example 12. 2,2,2-Trifluoro-N-[5-[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]oxy-6-methoxy-2- pyridyl]ethanesulfonamide;hydrochlorideScheme 12 Step 1. Synthesis of 1-[4-[(6-bromo-2-methoxy-3-pyridyl)oxy]-2-methyl-thiazol- 5-yl]ethanone

[0244] 1-(4-Chloro-2-methyl-thiazol-5-yl)ethanone (Scheme 6 Step 2) (2.3 g, 11.79 mmol), 6-bromo-2-methoxypyridin-3-ol (2.41 g, 11.79 mmol) and cesium carbonate (7.68 g, 23.57 mmol)were suspended in DMF (anhydrous, 50 mL). The suspension was sparged with nitrogen for 5 min then stirred at 60 °C for 6 h. The reaction was cooled to room temperature and diluted with water (75 mL). The aqueous was extracted with ethyl acetate (4 x 100 mL), the organics were combined, washed with brine (3 x 100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The product was purified by silica chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane) followed by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) to afford the title compound as a solid. (658 mg, 1.90 mmol, 16% yield). LC-MS (Method B): m / z (ESI+) = 343.1 [M(79Br)+], 345.1 [M(81Br)+], Rt = 3.64 min, UV purity = 99%. 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 3.94 (s, 3H), 2.62 (s, 3H), 2.54 (s, 3H). Scheme 12 Step 2. Synthesis of (E)-1-[4-[(6-bromo-2-methoxy-3-pyridyl)oxy]-2-methyl- thiazol-5-yl]-3-(dimethylamino)prop-2-en-1-one

[0245] A solution of 1-[4-[(6-bromo-2-methoxy-3-pyridyl)oxy]-2-methyl-thiazol-5- yl]ethanone (653 mg, 1.90 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (2 mL, 15.06 mmol) was stirred at 60 °C for 6 h. The reaction was stood at room temperature for 40 h. The reaction was stirred at 60 °C for a further 2 h and then stirred at 80oC overnight. The reaction was concentrated in vacuo to afford the title compound as a solid which was carried forward to the next step. (764 mg, 1.076 mmol, 57% yield). LC-MS (Method B): m / z (ESI+) = 398.1 [M(79Br)+], 400.1 [M(81Br)+], Rt = 3.27 min. Scheme 12 Step 3. Synthesis of tert-butyl (3S,5S)-3-[[4-[4-[(6-bromo-2-methoxy-3- pyridyl)oxy]-2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1- carboxylate

[0246] A suspension of (E)-1-[4-[(6-bromo-2-methoxy-3-pyridyl)oxy]-2-methyl-thiazol-5- yl]-3-(dimethylamino)prop-2-en-1-one (57%, 764 mg, 1.08 mmol), tert-butyl (3S,5S)-3-fluoro-5- guanidino-piperidine-1-carboxylate;hydrochloride (Intermediate D) (281 mg, 1.08 mmol) and potassium carbonate (600 mg, 4.34 mmol) in ethanol (5 mL) was stirred at 80 °C for 22 h. The reaction was filtered under vacuum and the solids were washed with MeOH (approx.10 mL). The filtrate was concentrated in vacuo and the residue redissolved in DCM (10 mL) and washed with water (15 mL). The aqueous layer was extracted with DCM (3 x 15 mL) and the combined organics were passed through a hydrophobic frit and concentrated in vacuo. The resulting material waspurified by silica chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane) to afford the title compound as a solid. (345 mg, 0.556 mmol, 52% yield). LC-MS (Method B): m / z (ESI+) = 595.4 [M(79Br)+], 597.4 [M(81Br)+], Rt = 4.36 min, UV purity = 96%. 1H NMR (400 MHz, DMSO-d6, 353K) δ 8.32 (d, J = 5.2 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.18 – 7.12 (m, 1H), 7.00 – 6.90 (m, 1H), 5.04 – 4.85 (m, 1H), 4.18 – 3.93 (m, 3H), 3.92 – 3.86 (m, 3H), 3.30 – 3.09 (m, 1H), 2.98 – 2.82 (m, 1H), 2.55 (s, 3H), 2.28 – 2.14 (m, 1H), 1.97 – 1.73 (m, 1H), 1.39 (s, 9H). Scheme 12 Step 4. Synthesis of tert-butyl (3S,5S)-3-fluoro-5-[[4-[4-[[2-methoxy-6-(2,2,2- trifluoroethylsulfonylamino)-3-pyridyl]oxy]-2-methyl-thiazol-5-yl]pyrimidin-2- yl]amino]piperidine-1-carboxylate

[0247] A suspension of 2,2,2-trifluoroethane-1-sulfonamide (190 mg, 1.11 mmol), copper(I) iodide (11 mg, 0.058 mmol), cesium carbonate (540 mg, 1.66 mmol) and tert-butyl (3S,5S)-3-[[4- [4-[(6-bromo-2-methoxy-3-pyridyl)oxy]-2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro- piperidine-1-carboxylate (330 mg, 0.55 mmol) in 1,4-dioxane (anhydrous, 3 mL) was sparged with nitrogen for 2 min. N,N'-dimethylethane-1,2-diamine (185 μL, 1.72 mmol) was added and the reaction was stirred at 80 °C for 23 h. The reaction was diluted with saturated aqueous sodium bicarbonate solution (7 mL) and extracted with ethyl acetate (3 x 15 mL). The organics were combined, washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The material was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)). The resulting solid was re-purified by low pH preparative HPLC (Preparative Method E) to afford the title compound as a powder. (20 mg, 0.0295 mmol, 5% yield). LC-MS (Method B): m / z (ESI+) = 678.5 [M+H]+, Rt = 3.70 min, UV purity = 99%. 1H NMR (400 MHz, DMSO-d6, 353K) δ 11.18 – 10.84 (m, 1H), 8.32 (d, J = 5.2 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 5.2 Hz, 1H), 6.99 – 6.90 (m, 1H), 6.58 (d, J = 8.3 Hz, 1H), 5.06 – 4.87 (m, 1H), 4.78 – 4.65 (m, 2H), 4.20 – 3.93 (m, 3H), 3.87 (s, 3H), 3.22 – 3.09 (m, 1H), 2.96 – 2.82 (m, 1H), 2.55 (s, 3H), 2.29 – 2.16 (m, 1H), 1.97 – 1.77 (m, 1H), 1.40 (s, 9H).Scheme 12 Step 5. Synthesis of 2,2,2-trifluoro-N-[5-[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]oxy-6-methoxy-2- pyridyl]ethanesulfonamide;hydrochloride

[0248] 4 M Hydrogen chloride in 1,4-dioxane (220 μL, 0.88 mmol) was added to a solution of tert-butyl (3S,5S)-3-fluoro-5-[[4-[4-[[2-methoxy-6-(2,2,2-trifluoroethylsulfonylamino)-3- pyridyl]oxy]-2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (20 mg, 0.0292 mmol) in 1,4-dioxane (200 μL). Water (10 μL) was added and the reaction was stirred at room temperature for 4.5 h. The solvent was removed under a stream of nitrogen and the product was lyophilised overnight to afford the title compound as a powder. (16.9 mg, 0.0275 mmol, 94% yield). LC-MS (Method B): m / z (ESI+) = 578.3 [M+H]+, Rt = 1.98 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 9.40 – 8.99 (m, 2H), 8.35 (d, J = 5.3 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.56 – 7.36 (m, 1H), 7.23 (d, J = 5.3 Hz, 1H), 6.56 (d, J = 8.3 Hz, 1H), 5.32 – 5.12 (m, 1H), 4.95 –4.82 (m, 2H), 4.53 – 4.26 (m, 1H), 3.88 – 3.79 (m, 3H), 3.54 – 3.48 (m, 1H), 3.32 – 3.08 (m, 2H), 2.90 – 2.75 (m, 1H), 2.55 (s, 3H), 2.37 – 2.25 (m, 1H), 1.98 – 1.73 (m, 1H).

[0249] The compounds of the following tabulated Examples (Table 4) were prepared analogously to Scheme 12 Step 4 using tert-butyl (3S,5S)-3-[[4-[4-[(6-bromo-2-methoxy-3- pyridyl)oxy]-2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate and the appropriate commercially available sulfonamide. The boc protecting group was then removed using 4 M hydrogen chloride in 1,4-dioxane analogously to Scheme 12 Step 5. Table 4: Exemplary compounds of the disclosureScheme 13. Synthesis of Example 13. 2,2,2-Trifluoro-N-[4-[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]oxy-2,5-dimethyl- phenyl]ethanesulfonamide;hydrochlorideScheme 13 Step 1. Synthesis of 1-[4-(4-amino-2,5-dimethyl-phenoxy)-2-methyl-thiazol-5- yl]ethanone

[0250] 1-(4-Chloro-2-methyl-thiazol-5-yl)ethanone (Scheme 6 Step 2) (1.00 g, 5.69 mmol), 4-amino-2,5-dimethylphenol (0.78 g, 5.69 mmol) and cesium carbonate (3.71 g, 11.39 mmol) were suspended in DMF (anhydrous, 15 mL). The reaction was heated at 80oC for 30 min and then retreated with 1-(4-chloro-2-methyl-thiazol-5-yl)ethanone (Scheme 6 Step 2) (0.2 g, 1.14 mmol). The reaction was heated at 80oC for 30 min and then retreated with 1-(4-chloro-2-methyl-thiazol- 5-yl)ethanone (Scheme 6 Step 2) (0.2 g, 1.14 mmol). The reaction was cooled to room temperature and concentrated in vacuo. The resulting gum was purified by silica chromatography (eluting witha gradient of 0-100% ethyl acetate in heptane) to afford the title product as a solid. (240 mg, 0.773 mmol, 14% yield). LC-MS (Method A): m / z (ESI+) = 277.1 [M+H]+, Rt = 0.64 min, UV purity = 89%. 1H NMR (400 MHz, DMSO-d6) δ 6.72 (s, 1H), 6.48 (s, 1H), 4.72 (s, 2H), 2.53 (s, 3H), 2.52 (s, 3H), 2.05 – 1.96 (m, 6H). Scheme 13 Step 2. Synthesis of N'‐[4‐({5‐[(E)‐3‐(dimethylamino)prop‐2‐enoyl]‐2‐methyl‐1,3‐ thiazol‐4‐yl}oxy)‐2,5‐dimethylphenyl]‐N,N‐dimethylmethanimidamide

[0251] 1-[4-(4-Amino-2,5-dimethyl-phenoxy)-2-methyl-thiazol-5-yl]ethanone (89%, 255 mg, 0.82 mmol) was dissolved in 1,1-dimethoxy-N,N-dimethylmethanamine (330 μL, 2.48 mmol) and stirred at 80oC overnight. The reaction was concentrated in vacuo and purified by silica chromatography (eluting with a gradient of 0-10% MeOH in DCM) to afford the title compound. (151 mg, 0.277 mmol, 34% yield). LC-MS (Method A): m / z (ESI+) = 387.2 [M+H]+, Rt = 0.55 min, UV purity = 71%. Scheme 13 Step 3. Synthesis of tert‐butyl (3S,5S)‐3‐({4‐[4‐(4‐ {[(dimethylamino)methylidene]amino}‐2,5‐dimethylphenoxy)‐2‐methyl‐1,3‐thiazol‐5‐ yl]pyrimidin‐2‐yl}amino)‐5‐fluoropiperidine‐1‐carboxylate

[0252] N'‐[4‐({5‐[(E)‐3‐(dimethylamino)prop‐2‐enoyl]‐2‐methyl‐1,3‐thiazol‐4‐yl}oxy)‐2,5‐ dimethylphenyl]‐N,N‐dimethylmethanimidamide (71%, 148 mg, 0.272 mmol), tert-butyl (3S,5S)- 3-fluoro-5-guanidino-piperidine-1-carboxylate;hydrochloride (Intermediate D) (170 mg, 0.54 mmol) and potassium carbonate (226 mg, 1.64 mmol) were suspended in ethanol (1.5 mL) and the reaction was stirred at 80oC overnight. The reaction was cooled to room temperature, filtered under vacuum, and the solids were washed with ethanol (3 mL). The filtrate was concentrated in vacuo and purified by silica chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane) to afford the title compound as a gum. (96 mg, 0.127 mmol, 47% yield). LC-MS (Method B): m / z (ESI+) = 584.3 [M+H]+, Rt = 2.43 min, UV purity = 77% 1H NMR (400 MHz, DMSO-d6, 353 K) δ 8.30 (d, J = 5.2 Hz, 1H), 7.59 (s, 1H), 7.20 (d, J = 5.2 Hz, 1H), 6.98 – 6.90 (m, 1H), 6.74 (s, 1H), 6.67 (s, 1H), 5.07 – 4.86 (m, 1H), 4.20 – 3.90 (m, 3H), 3.23 – 3.12 (m, 1H), 2.97 (s, 6H), 2.93 – 2.83 (m, 1H), 2.54 (s, 3H), 2.28 – 2.16 (m, 1H), 2.12 (s, 6H), 1.88 – 1.77 (m, 1H), 1.39 (s, 9H).Scheme 13 Step 4. Synthesis of tert-butyl (3S,5S)-3-[[4-[4-(4-amino-2,5-dimethyl-phenoxy)- 2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate

[0253] Ethane-1,2-diamine (53 μL, 0.792 mmol) was added to a solution of tert‐butyl (3S,5S)‐ 3‐({4‐[4‐(4‐{[(dimethylamino)methylidene]amino}‐2,5‐dimethylphenoxy)‐2‐methyl‐1,3‐thiazol‐ 5‐yl]pyrimidin‐2‐yl}amino)‐5‐fluoropiperidine‐1‐carboxylate (77%, 96 mg, 0.127 mmol) in ethanol (anhydrous, 1 mL) and the reaction was stirred at 80oC for 3 h. The solvent was removed under a stream of nitrogen, water (3 mL) was added, and the product was extracted with DCM (3 x 3 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to afford the title compound as a solid. (68 mg, 0.104 mmol, 82% yield). LC-MS (Method B): m / z (ESI+) = 529.3 [M+H]+, Rt = 2.91 min, UV purity = 81%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 8.29 (d, J = 5.2 Hz, 1H), 7.21 (d, J = 5.3 Hz, 1H), 7.00 – 6.84 (m, 1H), 6.63 (s, 1H), 6.51 (s, 1H), 5.08 – 4.83 (m, 1H), 4.52 – 4.37 (m, 2H), 4.22 – 3.85 (m, 5H), 2.53 (s, 3H), 2.27 – 2.13 (m, 2H), 2.07 – 1.99 (m, 6H), 1.39 (s, 9H). Scheme 13 Step 5. Synthesis of tert-butyl (3S,5S)-3-[[4-[4-[2,5-dimethyl-4-(2,2,2- trifluoroethylsulfonylamino)phenoxy]-2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5- fluoro-piperidine-1-carboxylate

[0254] A solution of tert-butyl (3S,5S)-3-[[4-[4-(4-amino-2,5-dimethyl-phenoxy)-2-methyl- thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate (81%, 32 mg, 0.0490 mmol) in pyridine (anhydrous, 0.4 mL) was stirred in an ice bath for the addition of 2,2,2- trifluoroethanesulfonyl chloride (7 μL, 0.06 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature over 1 h. The reaction was cooled in an ice bath for the addition of 2,2,2-trifluoroethanesulfonyl chloride (2 μL, 0.0147 mmol) and the reaction was stirred in the ice bath and allowed to equilibrate to room temperature over 1 h. The reaction was diluted with saturated aqueous sodium bicarbonate solution (2 mL) and the product was extracted with ethyl acetate (2 x 3 mL). The organics were dried using sodium sulfate, filtered, and concentrated in vacuo. The material was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) to afford the title compound as a solid. (15 mg, 0.0222 mmol, 45% yield). LC-MS (Method A): m / z (ESI+) = 675.3 [M+H]+, Rt = 1.02 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6, 353K) δ 9.59 (s, 1H), 8.30 (d, J = 5.1 Hz, 1H), 7.23 (s, 1H), 7.15 (d, J = 5.2 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 6.87 (s, 1H), 5.07 – 4.87 (m, 1H), 4.43 – 4.31 (m,2H), 4.18 – 3.93 (m, 3H), 3.27 – 3.14 (m, 1H), 2.96 – 2.85 (m, 1H), 2.57 (s, 3H), 2.27 – 2.17 (m, 7H), 2.01 – 1.68 (m, 1H), 1.39 (s, 9H). Scheme 13 Step 6. Synthesis of 2,2,2-trifluoro-N-[4-[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]oxy-2,5-dimethyl- phenyl]ethanesulfonamide;hydrochloride

[0255] 4 M Hydrogen chloride in 1,4-dioxane (33 μL, 0.132 mmol) was added to a solution of tert-butyl (3S,5S)-3-[[4-[4-[2,5-dimethyl-4-(2,2,2-trifluoroethylsulfonylamino)phenoxy]-2- methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate (16.6 mg, 0.02 mmol) in 1,4-dioxane (0.15 mL). Water (5 μL) was added and the reaction was stirred at room temperature for 1.5 h.2 drops of water were added and the reaction was stirred at room temperature for 3.5 h. 2 drops of water were added and the reaction was stirred at room temperature for 4.5 h. 4 M Hydrogen chloride in 1,4-dioxane (33 μL, 0.132 mmol) was added and the reaction was stirred at room temperature for 1 h. The solvent was removed under a stream of nitrogen and the residue was dried under vacuum at 40oC. The solid was dissolved in 1,4-dioxane (0.15 mL), 4 M Hydrogen chloride in 1,4-dioxane (15 μL, 0.066 mmol) was added and the reaction was stirred at room temperature for 2 h. The solvent was removed under a stream of nitrogen and the residue was dried under vacuum at 40oC and then lyophilised overnight to afford the title compound as a powder. (15 mg, 0.025 mmol, 100% yield). LC-MS (Method B): m / z (ESI+) = 575.2 [M+H]+, Rt = 2.17 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 9.60 – 9.45 (m, 1H), 9.26 – 9.02 (m, 1H), 8.35 (d, J = 5.3 Hz, 1H), 7.63 – 7.39 (m, 1H), 7.25 (s, 1H), 7.21 (d, J = 5.3 Hz, 1H), 6.91 (s, 1H), 5.30 – 5.13 (m, 1H), 4.57 – 4.31 (m, 3H), 3.46 – 3.11 (m, 3H), 2.89 – 2.76 (m, 1H), 2.58 (s, 3H), 2.39 – 2.26 (m, 1H), 2.23 (s, 3H), 2.18 (s, 3H), 1.97 – 1.78 (m, 1H).Scheme 14. Synthesis of Example 14. 2,2,2-Trifluoro-N-[4-[[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]amino]-1- naphthyl]ethanesulfonamide;dihydrochlorideScheme 14 Step 1. Synthesis of tert-butyl (3S,5S)-3-[[4-[4-[(4-amino-1-naphthyl)amino]-2- methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate

[0256] tert-Butyl (3S,5S)-3-[[4-(4-chloro-2-methyl-thiazol-5-yl)pyrimidin-2-yl]amino]-5- fluoro-piperidine-1-carboxylate (Scheme 9 Step 2) (200 mg, 0.467 mmol), naphthalene-1,4- diamine (150 mg, 0.948 mmol), cesium carbonate (610 mg, 1.87 mmol) and XantPhosPdG3 (45 mg, 0.0475 mmol) were suspended in 1,4-dioxane (anhydrous, 3 mL). The reaction was sparged with nitrogen and stirred at 120oC for 1.5 h.

[0257] The reaction was cooled to room temperature, diluted with ethyl acetate (5 mL) and filtered through a celite pad which was washed with additional ethyl acetate (approx. 10mL). The filtrate was washed with water (3 x 5 mL), brine (5 mL), dried using magnesium sulfate, filtered, and concentrated in vacuo. The material was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)). Product containing fractions were combined and concentrated in vacuo to remove the organics. The aqueous was treated with saturated aqueous sodium bicarbonate solution (5 mL) and extracted using DCM (4 x 5 mL). The combined organics were washed with brine (5 mL), dried using magnesium sulfate, filtered, and concentrated in vacuo. The resulting material was re-purified bysilica chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane) to afford the title compound as a solid. (88 mg, 0.157 mmol, 34% yield). LC-MS (Method B): m / z (ESI+) = 550.3 [M+H]+, Rt = 2.91 min, UV purity = 95%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 9.90 (s, 1H), 8.16 (d, J = 5.4 Hz, 1H), 8.11 – 8.04 (m, 1H), 7.90 – 7.83 (m, 1H), 7.45 – 7.36 (m, 2H), 7.28 (d, J = 7.9 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.43 (d, J = 5.4 Hz, 1H), 5.42 (s, 2H), 5.00 – 4.79 (m, 1H), 4.20 – 4.09 (m, 1H), 4.02 – 3.79 (m, 2H), 3.41 – 3.14 (m, 1H), 2.99 – 2.80 (m, 1H), 2.48 (s, 3H), 2.26 – 2.11 (m, 1H), 1.90 – 1.67 (m, 1H), 1.36 (s, 9H). Scheme 14 Step 2. Synthesis of tert-butyl (3S,5S)-3-fluoro-5-[[4-[2-methyl-4-[[4-(2,2,2- trifluoroethylsulfonylamino)-1-naphthyl]amino]thiazol-5-yl]pyrimidin-2- yl]amino]piperidine-1-carboxylate

[0258] A solution of tert-butyl (3S,5S)-3-[[4-[4-[(4-amino-1-naphthyl)amino]-2-methyl- thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate (32 mg, 0.06 mmol) in pyridine (anhydrous, 0.23 mL) was stirred in an ice bath and sparged with nitrogen before the addition of 2,2,2-trifluoroethanesulfonyl chloride (7 μL, 0.06 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature for 1 h. The reaction was retreated with 2,2,2-trifluoroethanesulfonyl chloride (3 μL, 0.0271 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (2 mL) and the product was extracted with ethyl acetate (3 x 3 mL). The combined organic layers were washed with brine (5 mL), dried using magnesium sulfate, filtered, and concentrated in vacuo. The material was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) to afford the title compound as a powder. (12 mg, 0.0171 mmol, 31% yield). LC-MS (Method B): m / z (ESI+) = 696.4 [M+H]+, Rt = 4.05 min, UV purity = 99%. 1H NMR (500 MHz, DMSO-d6) δ 11.00 – 10.44 (m, 1H), 10.34 – 10.18 (m, 1H), 8.31 – 8.18 (m, 2H), 8.12 (d, J = 8.4 Hz, 1H), 7.91 – 7.69 (m, 1H), 7.68 – 7.46 (m, 3H), 7.35 – 7.15 (m, 1H), 6.56 (d, J = 5.4 Hz, 1H), 5.04 – 4.79 (m, 1H), 4.60 – 4.42 (m, 2H), 4.31 – 3.94 (m, 2H), 3.84 – 3.58 (m, 1H), 3.24 – 2.95 (m, 2H), 2.61 (s, 3H), 2.30 – 2.12 (m, 1H), 2.00 – 1.58 (m, 1H), 1.51 – 1.07 (m, 9H).Scheme 14 Step 3. Synthesis of 2,2,2-trifluoro-N-[4-[[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]amino]-1- naphthyl]ethanesulfonamide;dihydrochloride

[0259] 4 M Hydrogen chloride in 1,4-dioxane (59 μL, 0.236 mmol) was added to a stirring solution of tert-butyl (3S,5S)-3-fluoro-5-[[4-[2-methyl-4-[[4-(2,2,2-trifluoroethylsulfonylamino)- 1-naphthyl]amino]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (12 mg, 0.02 mmol) in 1,4-dioxane (anhydrous, 100 μL). A drop of water was added and the reaction was stirred at room temperature for 30 min. The reaction was retreated with 4 M hydrogen chloride in 1,4- dioxane (59 μL, 0.236 mmol) and stirred at room temperature for 1 h. The reaction was concentrated in vacuo and the product was lyophilised overnight to afford the title compound as a powder. (12 mg, 0.0179 mmol, quantitative yield). LC-MS (Method B): m / z (ESI+) = 596.2 [M+H]+, Rt = 2.41 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 10.78 – 10.29 (m, 1H), 10.20 – 10.09 (m, 1H), 10.04 – 9.71 (m, 1H), 9.25 – 8.86 (m, 2H), 8.36 – 8.09 (m, 2H), 7.79 (d, J = 8.0 Hz, 1H), 7.70 – 7.55 (m, 2H), 7.54 – 7.34 (m, 1H), 6.66 (d, J = 5.6 Hz, 1H), 5.30 – 5.09 (m, 1H), 4.57 – 4.39 (m, 2H), 3.67 – 3.51 (m, 3H), 3.22 – 3.11 (m, 1H), 2.94 – 2.83 (m, 1H), 2.63 (s, 3H), 2.45 – 2.29 (m, 1H), 2.04 – 1.80 (m, 1H).Scheme 15. Synthesis of Example 15. 2,2,2-Trifluoro-N-[4-[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]oxy-3-methyl-1- isoquinolyl]ethanesulfonamide;hydrochlorideScheme 15 Step 1. Synthesis of ethyl 2-(1,3-dioxoisoindolin-2-yl)propanoate

[0260] Ethyl alaninate hydrochloride (1:1) (5.19 g, 33.79 mmol), triethylamine (4.7 mL, 33.7 mmol) and toluene (anhydrous, 48 mL) were stirred at room temperature for 20 min. Isobenzofuran-1,3-dione (5.00 g, 33.76 mmol) was added and the reaction was stirred at 130 °C for 1.5 h under Dean Stark conditions. The reaction was cooled to room temperature over 1.5 h. The resulting suspension was filtered under vacuum, and the solids were washed with ethyl acetate (3 x 25 mL). The organic filtrate was washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The product was purified by silica chromatography (eluting with a gradient of 0-60% ethyl acetate in heptane) to afford the title compound as an oil. (3.49 g, 14.127 mmol, 42% yield). LC-MS (Method A): m / z (ESI+) = no ionisation [M+H]+, Rt = 0.79 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 7.96 – 7.83 (m, 4H), 4.98 (q, J = 7.2 Hz, 1H), 4.18 – 4.03 (m, 2H), 1.54 (d, J = 7.2 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H).Scheme 15 Step 2. Synthesis of 4-hydroxy-3-methyl-2H-isoquinolin-1-one

[0261] Under nitrogen, a solution of ethyl 2-(1,3-dioxoisoindolin-2-yl)propanoate (3.49 g, 14.1 mmol) in ethanol (anhydrous, 20 mL) was added dropwise over 20 min to a stirred solution of 21% sodium ethoxide in ethanol (15.8 mL, 42.32 mmol) at 95 °C and the reaction was stirred for 2 h. The reaction was cooled to room temperature and poured into an ice cooled stirred solution of 1M aqueous HCl (150 mL). The reaction was stirred in the ice bath for 30 min and the resulting suspension was filtered under vacuum. The solid was collected and dried under vacuum at 40oC to afford the title compound as a solid. (1.82 g, 10.384 mmol, 74% yield). LC-MS (Method A): m / z (ESI+) = 176.0 [M+H]+, Rt = 0.43 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.16 – 8.10 (m, 1H), 8.02 (s, 1H), 7.87 – 7.79 (m, 1H), 7.74 – 7.67 (m, 1H), 7.47 – 7.38 (m, 1H), 2.18 (s, 3H). Scheme 15 Step 3. Synthesis of 1-bromo-3-methyl-isoquinolin-4-ol

[0262] A mixture of 4-hydroxy-3-methyl-2H-isoquinolin-1-one (750 mg, 4.28 mmol) and phosphoryl bromide (1.84 g, 6.42 mmol) in toluene (anhydrous, 15 mL) was sparged with nitrogen before DMF (anhydrous, 5 mL) was added. The reaction was stirred at 90 °C under microwave irradiation for 30 min. The reaction was quenched by the slow dropwise addition of the reaction solution into room temperature water (50 mL). The aqueous was extracted with 20% MeOH in ethyl acetate (50 mL) and ethyl acetate (2 x 80 mL). The organics were combined, washed with brine (2 x 100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was sonicated in heptane, filtered under vacuum, and the collected solids were dried under vacuum at 40oC to afford the title compound as a solid. (911 mg, 3.406 mmol, 80% yield). LC-MS (Method A): m / z (ESI+) = 238.0 [M(79Br)+], 240.0 [M(81Br)+], Rt = 0.85 min, UV purity = 89%. 1H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.24 – 8.20 (m, 1H), 8.08 – 8.02 (m, 1H), 7.85 – 7.77 (m, 1H), 7.75 – 7.68 (m, 1H), 2.52 (s, 3H). Scheme 15 Step 4. Synthesis of 1-[4-[(1-bromo-3-methyl-4-isoquinolyl)oxy]-2-methyl- thiazol-5-yl]ethanone

[0263] 1-Bromo-3-methyl-isoquinolin-4-ol (911 mg, 3.41 mmol), 1-(4-chloro-2-methyl- thiazol-5-yl)ethanone (Scheme 6 Step 2) (597 mg, 3.40 mmol), and cesium carbonate (2.77 g, 8.51 mmol) were suspended in DMF (anhydrous, 17 mL), sparged with nitrogen, and stirred at 80 °C for 4 h. The reaction was cooled to room temperature and retreated with 1-(4-chloro-2-methyl-thiazol-5-yl)ethanone (Scheme 6 Step 2) (298 mg, 1.70 mmol). The reaction was sparged with nitrogen and stirred at 80 °C for 3 h and then overnight at room temperature. The reaction was re- treated with 1-(4-chloro-2-methyl-thiazol-5-yl)ethanone (Scheme 6 Step 2) (298 mg, 1.70 mmol). The reaction was sparged with nitrogen and stirred at 80 °C for 24 h. The reaction was cooled to room temperature and diluted with water (40 mL), ethyl acetate (50 mL) and brine (10 mL). The layers were separated and the aqueous was extracted with ethyl acetate (3 x 50 mL). The organics were combined, washed with brine (2 x 100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting gum was triturated in heptane (50 mL) and concentrated in vacuo. The resulting residue was purified by silica chromatography (eluting with a gradient of 0- 50% ethyl acetate in heptane) followed by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+0.1% formic acid) in water (+0.1% formic acid)) to afford the title compound as a solid. (154 mg, 0.362 mmol, 11% yield). LC-MS (Method A): m / z (ESI+) = 377.0 [M(79Br)+], 379.0 [M(81Br)+], Rt = 1.00 min, UV purity = 89%. 1H NMR (500 MHz, DMSO-d6) δ 8.25 – 8.22 (m, 1H), 8.02 – 7.99 (m, 1H), 7.93 – 7.88 (m, 1H), 7.86 – 7.81 (m, 1H), 2.70 (s, 3H), 2.46 (s, 3H), 2.43 (s, 3H). Scheme 15 Step 5. Synthesis of (E)-1-[4-[(1-bromo-3-methyl-4-isoquinolyl)oxy]-2-methyl- thiazol-5-yl]-3-(dimethylamino)prop-2-en-1-one

[0264] 1-[4-[(1-Bromo-3-methyl-4-isoquinolyl)oxy]-2-methyl-thiazol-5-yl]ethanone (153 mg, 0.361 mmol) was dissolved in 1,1-dimethoxy-N,N-dimethylmethanamine (0.5 mL, 3.76 mmol) and stirred at 80 °C for 22.5 h. The reaction was cooled to room temperature and diluted with water (approx. 3 mL). The resulting suspension was filtered under vacuum, washed with water (2 x 5 mL) and dried under vacuum at 40oC to afford the title compound as a powder. (153 mg, 0.134 mmol, 37% yield). LC-MS (Method A): m / z (ESI+) = 432.0 [M(79Br)+], 434.0 [M(81Br)+], Rt = 0.98 min, UV purity = 38%. Scheme 15 Step 6. Synthesis of tert-butyl (3S,5S)-3-[[4-[4-[(1-bromo-3-methyl-4- isoquinolyl)oxy]-2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1- carboxylate

[0265] A suspension of (E)-1-[4-[(1-bromo-3-methyl-4-isoquinolyl)oxy]-2-methyl-thiazol-5- yl]-3-(dimethylamino)prop-2-en-1-one (38%, 162 mg, 0.142 mmol), (E)-1-[4-[(1-bromo-3- methyl-4-isoquinolyl)oxy]-2-methyl-thiazol-5-yl]-3-(dimethylamino)prop-2-en-1-one (68%, 25.7mg, 0.04 mmol), potassium carbonate (101 mg, 0.731 mmol) and tert-butyl (3S,5S)-3-fluoro-5- guanidino-piperidine-1-carboxylate;hydrochloride (Intermediate D) (58 mg, 0.186 mmol) in ethanol (1.2 mL) was stirred at 80 °C for 20 h. The reaction was cooled to room temperature, filtered under vacuum, and the solids were washed with MeOH (approx. 30 mL). The filtrate was concentrated in vacuo and purified by silica chromatography (eluting with 0-100% ethyl acetate in heptane) to afford the title compound as a solid. (50 mg, 0.0679 mmol, 37% yield). LC-MS (Method B): m / z (ESI+) = 629.2 [M(79Br)+], 631.2 [M(81Br)+], Rt = 4.73 min, UV purity = 85%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 8.39 (d, J = 5.2 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.90 - 7.86 (m, 2H), 7.85 - 7.79 (m, 1H), 7.40 (d, J = 5.2 Hz, 1H), 7.09 - 7.02 (m, 1H), 5.08 - 4.89 (m, 1H), 4.19 - 3.94 (m, 3H), 3.31 - 3.13 (m, 1H), 2.98 - 2.89 (m, 1H), 2.47 - 2.44 (m, 6H), 2.31 - 2.17 (m, 1H), 1.99 - 1.79 (m, 1H), 1.40 (s, 9H). Scheme 15 Step 7. Synthesis of tert-butyl (3S,5S)-3-fluoro-5-[[4-[2-methyl-4-[[3-methyl-1- (2,2,2-trifluoroethylsulfonylamino)-4-isoquinolyl]oxy]thiazol-5-yl]pyrimidin-2- yl]amino]piperidine-1-carboxylate

[0266] A suspension of tert-butyl (3S,5S)-3-[[4-[4-[(1-bromo-3-methyl-4-isoquinolyl)oxy]-2- methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate (85%, 50 mg, 0.0675 mmol), tert-butyl (3S,5S)-3-[[4-[4-[(1-bromo-3-methyl-4-isoquinolyl)oxy]-2-methyl- thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate (95%, 10 mg, 0.0151 mmol), 2,2,2-trifluoroethane-1-sulfonamide (29 mg, 0.169 mmol), copper(I) iodide (2 mg, 0.01 mmol) and cesium carbonate (81 mg, 0.249 mmol) in 1,4-dioxane (anhydrous, 0.6 mL) was sparged with nitrogen for 2 min before the addition of N,N'-dimethylethane-1,2-diamine (27 μL, 0.251 mmol). The reaction was stirred at 80 °C for 3.5 h. The reaction was cooled to room temperature and retreated with 2,2,2-trifluoroethane-1-sulfonamide (29 mg, 0.169 mmol), copper(I) iodide (2 mg, 0.01 mmol) and cesium carbonate (81 mg, 0.249 mmol). The reaction was sparged with nitrogen for 2 min before the addition of N,N'-dimethylethane-1,2-diamine (27 μL, 0.251 mmol). The reaction was stirred at 90 °C for 2.5 h. The reaction was cooled to room temperature and filtered through celite, which was washed with MeOH (approx.1 mL). The filtrate was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)). Product containing fractions were combined and concentrated in vacuo. The concentrate was treated with saturated aqueous sodium bicarbonate solution and extracted with DCM (2 x 10 mL). The organics were combined, passedthrough a hydrophobic frit, and concentrated in vacuo to afford the title compound as a solid. (33 mg, 0.0457 mmol, 55% yield). LC-MS (Method B): m / z (ESI+) = 712.4 [M+H]+, Rt = 4.11 min, UV purity = 98%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 11.73 – 11.24 (m, 1H), 8.51 – 8.43 (m, 1H), 8.39 (d, J = 5.2 Hz, 1H), 7.90 – 7.80 (m, 1H), 7.71 – 7.62 (m, 2H), 7.37 (d, J = 5.2 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 5.07 – 4.89 (m, 1H), 4.86 – 4.25 (m, 2H), 4.22 – 3.94 (m, 3H), 3.27 – 3.17 (m, 1H), 3.01 – 2.86 (m, 1H), 2.48 (s, 3H), 2.39 (s, 3H), 2.27 – 2.18 (m, 1H), 1.99 – 1.78 (m, 1H), 1.40 (s, 9H). Scheme 15 Step 8. Synthesis of 2,2,2-trifluoro-N-[4-[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]oxy-3-methyl-1- isoquinolyl]ethanesulfonamide;hydrochloride

[0267] 4 M Hydrogen chloride in 1,4-dioxane (0.1 mL, 0.4 mmol) was added to a solution of tert-butyl (3S,5S)-3-fluoro-5-[[4-[2-methyl-4-[[3-methyl-1-(2,2,2-trifluoroethylsulfonylamino)- 4-isoquinolyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (33 mg, 0.0457 mmol). Water (10 μL) was added and the reaction was stirred at room temperature for 1 h. The reaction was retreated with 4 M hydrogen chloride in dioxane (0.1 mL, 0.4 mmol) and stirred at room temperature for 67.5 h. The solvent was removed under a stream of air and the product was lyophilised overnight to afford the title compound as a powder. (18 mg, 0.0282 mmol, 62% yield). LC-MS (Method B): m / z (ESI+) = 612.3 [M+H]+, Rt = 2.15 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 9.61 - 9.40 (m, 1H), 9.18 - 9.02 (m, 1H), 8.50 - 8.44 (m, 1H), 8.42 (d, J = 5.3 Hz, 1H), 7.91 - 7.83 (m, 1H), 7.73 - 7.62 (m, 2H), 7.43 (d, J = 5.2 Hz, 1H), 7.31 - 7.24 (m, 1H), 5.32 - 5.16 (m, 1H), 4.80 - 4.37 (m, 3H), 3.58 - 3.40 (m, 3H), 2.99 - 2.86 (m, 1H), 2.49 - 2.48 (m, 3H), 2.44 - 2.36 (m, 4H), 2.07 - 1.87 (m, 1H). Scheme 16 Synthesis of Example 16. N-[(3S,5S)-5-Fluoro-3-piperidyl]-4-[2-methyl-4-[[4- (3,3,3-trifluoropropylamino)-1-naphthyl]oxy]thiazol-5-yl]pyrimidin-2-amine;hydrochlorideScheme 16 Step 1. Synthesis of tert-butyl (3S,5S)-3-fluoro-5-[[4-[2-methyl-4-[[4-(3,3,3- trifluoropropylamino)-1-naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1- carboxylate

[0268] A mixture of tert-butyl (3S,5S)-3-[[4-[4-[(4-amino-1-naphthyl)oxy]-2-methyl-thiazol- 5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate (100 mg, 0.182 mmol) (Scheme 9 Step 3) and 3,3,3-trifluoropropanal (19 μL, 0.220 mmol) in DCM (1.9 mL) was stirred at room temperature for 3 h before the addition of sodium triacetoxyborohydride (190 mg, 0.896 mmol). The reaction was stirred at room temperature for 5 h before the addition of acetic acid (13 μL, 0.227 mmol). The reaction was stirred at room temperature for 16.5 h. The reaction mixture was diluted with DCM and water before being neutralised with saturated aqueous sodium bicarbonate solution. The organic layer was passed through a hydrophobic frit and concentrated in vacuo. The material was purified by low pH reverse phase chromatography (eluting with a gradient of 10- 100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) followed by low pH preparative HPLC (Preparative Method B) to afford the title compound as a glassy solid. (44 mg, 0.068 mmol, 38% yield). LC-MS (Method B): m / z (ESI+) = 647.5 [M+H]+, Rt = 4.51 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 8.30 (d, J = 5.2 Hz, 1H), 8.20 – 8.13 (m, 1H), 7.98 – 7.89 (m, 1H), 7.55 – 7.46 (m, 2H), 7.30 (d, J = 5.3 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 6.52 (d, J = 8.2 Hz, 1H), 6.01 (t, J = 5.7 Hz, 1H), 5.08 – 4.85 (m, 1H), 4.20 – 3.90 (m, 3H), 3.55 – 3.46 (m, 2H), 3.24 – 3.15 (m, 1H), 3.09 – 2.83 (m, 1H), 2.79 – 2.62 (m, 2H), 2.49 (s, 3H), 2.28 – 2.16 (m, 1H), 1.97 – 1.77 (m, 1H), 1.40 (s, 9H). Scheme 16 Step 2. Synthesis of N-[(3S,5S)-5-fluoro-3-piperidyl]-4-[2-methyl-4-[[4-(3,3,3- trifluoropropylamino)-1-naphthyl]oxy]thiazol-5-yl]pyrimidin-2-amine;hydrochloride

[0269] 4 M Hydrogen chloride in 1,4-dioxane (240 μL, 0.96 mmol) was added to a solution of tert-butyl (3S,5S)-3-fluoro-5-[[4-[2-methyl-4-[[4-(3,3,3-trifluoropropylamino)-1- naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (44 mg, 0.0680 mmol) in 1,4-dioxane (400 μL). A drop of water was added and the reaction was stirred at room temperature for 16 h. The solvent was concentrated in vacuo and the product was lyophilised overnight to afford the title compound as a solid. (36 mg, 0.0609 mmol, 90% yield). LC-MS (Method B): m / z (ESI+) = 547.3 [M+H]+, Rt = 2.49 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6, 353K) δ 10.16 – 9.77 (m, 1H), 9.32 – 8.97 (m, 1H), 8.40 – 8.28 (m, 1H), 8.25 – 8.12 (m, 1H), 7.97 – 7.83 (m, 1H), 7.72 – 7.21 (m, 4H), 7.11 – 7.00 (m, 1H), 6.53(d, J = 8.4 Hz, 1H), 5.35 – 5.09 (m, 1H), 4.51 – 4.38 (m, 1H), 3.55 – 3.47 (m, 2H), 3.47 – 3.35 (m, 2H), 3.32 – 3.08 (m, 1H), 3.02 – 2.84 (m, 1H), 2.81 – 2.61 (m, 2H), 2.49 (s, 3H), 2.40 – 2.31 (m, 1H), 2.09 – 1.84 (m, 1H).

[0270] The compounds of the following tabulated Examples (Table 5) were prepared analogously to Scheme 16 Step 1 using tert-butyl (3S,5S)-3-[[4-[4-[(4-amino-1-naphthyl)oxy]-2- methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate (Scheme 9 step 3) and the appropriate commercially available aldehyde. The boc protecting group was removed using 4 M hydrogen chloride in 1,4-dioxane analogously to Scheme 16 Step 2. Table 5: Exemplary compounds of the disclosureScheme 17. Synthesis of Example 17. 4-[4-[(4-Anilino-1-naphthyl)oxy]-2-methyl-thiazol-5- yl]-N-[(3S,5S)-5-fluoro-3-piperidyl]pyrimidin-2-amine;hydrochlorideScheme 17 Step 1. Synthesis of tert-butyl (3S,5S)-3-[[4-[4-[(4-anilino-1-naphthyl)oxy]-2- methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate

[0271] tert-Butyl (3S,5S)-3-[[4-[4-[(4-amino-1-naphthyl)oxy]-2-methyl-thiazol-5- yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate (60 mg, 0.11 mmol) (Scheme 9 Step 3), cesium carbonate (140 mg, 0.43 mmol) and XantPhosPdG3 (11 mg, 0.0116 mmol) were suspended in 1,4-dioxane (anhydrous, 0.6 mL) and sparged with nitrogen before the addition of bromobenzene (14 μL, 0.134 mmol). The reaction stirred at 80oC for 2 h. The reaction was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water (3 x 5 mL), brine (5 mL), dried using magnesium sulfate, filtered, and concentrated in vacuo. The resulting product was purified by low pH preparative HPLC (Preparative Method B) to afford the title compound as a glassy solid. (48 mg, 0.0758 mmol, 70% yield). LC-MS (Method B): m / z (ESI+) = 627.5 [M+H]+, Rt = 4.75 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 5.2 Hz, 1H), 8.24 – 8.17 (m, 1H), 8.16 (s, 1H), 8.07 – 7.98 (m, 1H), 7.64 – 7.53 (m, 2H), 7.43 – 7.24 (m, 3H), 7.24 – 7.15 (m, 2H), 7.09 (d, J = 8.2 Hz, 1H), 7.02 – 6.94 (m, 2H), 6.83 – 6.74 (m, 1H), 5.11 – 4.82 (m, 1H), 4.28 – 3.80 (m, 3H), 3.22 – 2.87 (m, 2H), 2.53 (s, 3H), 2.30 – 2.10 (m, 1H), 1.99 – 1.65 (m, 1H), 1.52 – 1.26 (m, 9H). Scheme 17 Step 2. Synthesis of 4-[4-[(4-anilino-1-naphthyl)oxy]-2-methyl-thiazol-5-yl]-N- [(3S,5S)-5-fluoro-3-piperidyl]pyrimidin-2-amine;hydrochloride

[0272] 4 M Hydrogen chloride in 1,4-dioxane (170 μL, 0.68 mmol) was added to a solution of tert-butyl (3S,5S)-3-[[4-[4-[(4-anilino-1-naphthyl)oxy]-2-methyl-thiazol-5-yl]pyrimidin-2- yl]amino]-5-fluoro-piperidine-1-carboxylate (48 mg, 0.0758 mmol) in 1,4-dioxane (450 μL). A drop of water was added and the reaction was stirred at room temperature for 16 h. The reaction was concentrated in vacuo, and the product was lyophilised overnight to afford the title compound as a powder. (33 mg, 0.0585 mmol, 77% yield). LC-MS (Method B): m / z (ESI+) = 527.3 [M+H]+, Rt = 2.66 min, UV purity = 99%.1H NMR (400 MHz, MeOD) δ 8.30 (d, J = 6.4 Hz, 1H), 8.25 – 8.18 (m, 1H), 8.01 – 7.93 (m, 1H), 7.81 – 7.68 (m, 1H), 7.57 – 7.50 (m, 2H), 7.32 (d, J = 8.2 Hz, 1H), 7.25 – 7.13 (m, 3H), 7.05 – 6.99 (m, 2H), 6.88 – 6.80 (m, 1H), 5.40 – 5.19 (m, 1H), 4.79 – 4.63 (m, 1H), 3.75 – 3.64 (m, 2H), 3.43 – 3.34 (m, 1H), 3.14 – 3.02 (m, 1H), 2.69 – 2.60 (m, 1H), 2.59 (s, 3H), 2.17 – 1.90 (m, 1H). Scheme 18. Synthesis of Example 18. 3,3,3-Trifluoro-N-[4-[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]oxy-1- naphthyl]propanamide;hydrochlorideScheme 18 Step 1. Synthesis of tert-butyl (3S,5S)-3-fluoro-5-[[4-[2-methyl-4-[[4-(3,3,3- trifluoropropanoylamino)-1-naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1- carboxylate

[0273] 3,3,3-Trifluoropropanoyl chloride (14 μL, 0.13 mmol) was added to an ice cooled stirred solution of tert-butyl (3S,5S)-3-[[4-[4-[(4-amino-1-naphthyl)oxy]-2-methyl-thiazol-5- yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate (Scheme 9 Step 3) (60 mg, 0.11 mmol) and N-ethyl-N-isopropyl-propan-2-amine (52 μL, 0.298 mmol) in DCM (anhydrous, 1.5 mL). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature over 1 h. The reaction was diluted with DCM (2 mL) and saturated aqueous sodium bicarbonate solution (1 mL). The organic layer was separated using a hydrophobic frit and concentrated in vacuo. The material was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) to afford the title compound as a solid. (58 mg, 0.0834 mmol, 77% yield). LC-MS (Method B): m / z (ESI+) = 661.5 [M+H]+, Rt = 3.90 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 10.08 (s, 1H), 8.30 (d, J = 5.2 Hz, 1H), 8.23 – 8.14 (m, 1H), 8.12 – 8.06 (m, 1H), 7.72 – 7.56 (m, 3H), 7.23 (d, J = 5.2 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 5.08 – 4.85 (m, 1H), 4.20 – 3.90 (m, 3H), 3.65 (q, J = 11.2 Hz, 2H), 3.24 – 3.10 (m, 1H), 3.01 – 2.85 (m, 1H), 2.56 (s, 3H), 2.30 – 2.15 (m, 1H), 2.00 – 1.77 (m, 1H), 1.41 (s, 9H).Scheme 18 Step 2. Synthesis of 3,3,3-trifluoro-N-[4-[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]oxy-1- naphthyl]propanamide;hydrochloride

[0274] 4 M Hydrogen chloride in 1,4-dioxane (90 μL, 0.360 mmol) was added to a solution of tert-butyl (3S,5S)-3-fluoro-5-[[4-[2-methyl-4-[[4-(3,3,3-trifluoropropanoylamino)-1- naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (58 mg, 0.09 mmol) in 1,4-dioxane (0.5 mL). Water (10 μL) was added and the reaction was stirred at room temperature for 4 h. 4 M Hydrogen chloride in 1,4-dioxane (90 μL, 0.360 mmol) was added and the reaction was stirred at room temperature for 6 h. The solvent was removed under a stream of nitrogen and the product was lyophilised overnight to afford the title compound as a solid. (29 mg, 0.0486 mmol, 55% yield). LC-MS (Method B): m / z (ESI+) = 561.3 [M+H]+, Rt = 2.15 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.90 – 9.85 (m, 1H), 9.44 – 8.95 (m, 1H), 8.36 (d, J = 5.4 Hz, 1H), 8.15 – 8.07 (m, 2H), 7.91 – 7.87 (m, 1H), 7.73 – 7.56 (m, 3H), 7.33 (d, J = 5.5 Hz, 1H), 7.22 – 7.15 (m, 1H), 5.34 – 5.08 (m, 1H), 4.55 – 4.30 (m, 1H), 3.73 (q, J = 11.2 Hz, 2H), 3.60 – 3.33 (m, 2H), 3.31 – 3.10 (m, 1H), 2.97 – 2.76 (m, 1H), 2.56 (s, 3H), 2.43 – 2.22 (m, 1H), 2.02 – 1.80 (m, 1H).

[0275] The compounds of the following tabulated Examples (Table 6) were prepared analogously to Scheme 18 Step 1 using tert-butyl (3S,5S)-3-[[4-[4-[(4-amino-1-naphthyl)oxy]-2- methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate (Scheme 9 step 3) and the appropriate commercially available acid chloride. The boc protecting group was removed using 4 M hydrogen chloride in 1,4-dioxane analogously to Scheme 18 Step 2. Table 6: Exemplary compounds of the disclosureScheme 19. Synthesis of Example 19. 3,3,3-Trifluoro-N-[3-methyl-4-[2-methyl-5-[2-[[(3S)-3- piperidyl]amino]pyrimidin-4-yl]thiazol-4-yl]oxy-1-naphthyl]propanamide;hydrochlorideScheme 19 Step 1. Synthesis of tert-butyl (3S)-3-[[4-(4-chloro-2-methyl-thiazol-5- yl)pyrimidin-2-yl]amino]piperidine-1-carboxylate

[0276] (E)-1-(4-Chloro-2-methyl-thiazol-5-yl)-3-(dimethylamino)prop-2-en-1-one (Scheme 9 Step 1) (80%, 6.9 g, 23.9 mmol), tert‐butyl (3S)‐3‐carbamimidamidopiperidine‐1‐carboxylate (Intermediate C) (70%, 12.6 g, 36.40 mmol) and tert‐butyl (3S)‐3‐carbamimidamidopiperidine‐1‐ carboxylate (Intermediate C) (75%, 1.0 g, 3.10 mmol) were suspended in ethanol (80 mL) and sparged with nitrogen for 5 min. Potassium carbonate (20 g, 144.71 mmol) was added and the reaction was stirred at 85 °C for 20 h. The reaction was filtered under vacuum, the collected solids were washed with methanol (approx. 200 mL), and the filtrate was concentrated in vacuo. The resulting material was dissolved in DCM (250 mL), and the organic layer was washed with water (2 x 200 mL), brine (200 mL), dried with sodium sulfate, and concentrated in vacuo. The product was purified by silica chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane) to afford the title compound as a powder. (8.0 g, 18.35 mmol, 77% yield). LC-MS (Method B): m / z (ESI+) = 410.2 [M(35Cl)+], 412.2 [M(37Cl)+], Rt = 3.95 min, UV purity = 100%. 1H NMR (400 MHz, DMSO, 353 K) δ 8.45 – 8.38 (m, 1H), 7.34 – 7.26 (m, 1H), 6.96 – 6.88 (m, 1H), 3.92 – 3.60 (m, 3H), 3.04 – 2.93 (m, 2H), 2.70 – 2.64 (m, 3H), 2.00 – 1.87 (m, 1H), 1.78 – 1.74 (m, 1H), 1.62 – 1.56 (m, 1H), 1.49 – 1.31 (m, 10H).Scheme 19 Step 2. Synthesis of tert-butyl (3S)-3-[[4-[4-[(4-amino-2-methyl-1-naphthyl)oxy]- 2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate

[0277] 4-Amino-2-methyl-naphthalen-1-ol (Intermediate B) (1.2 g, 6.93 mmol) and tert-butyl (3S)-3-[[4-(4-chloro-2-methyl-thiazol-5-yl)pyrimidin-2-yl]amino]piperidine-1-carboxylate (2.0 g, 4.59 mmol) were flushed with nitrogen for 2 min. NMP (anhydrous, 25 mL) was added and the reaction was stirred under a flow of nitrogen for 5 min. Cesium carbonate (7.5 g, 23.0 mmol) was added and the reaction was flushed with nitrogen for a further 1 min and then stirred at 130 °C for 4 h. The reaction mixture was cooled to room temperature and filtered through a pad of celite which was washed with ethyl acetate (approx. 400 mL). The organics were collected and washed with water (3 x 350 mL), brine (2 x 350 mL), dried over sodium sulfate and concentrated in vacuo. The combined aqueous layers were extracted with ethyl acetate (200 mL) and the organic layer was washed with water (2 x 200 mL), brine (2 x 200 mL), dried over sodium sulfate and concentrated in vacuo. The combined organic extracts were purified by silica chromatography (KP-NH column, eluting with a gradient of 0-100% ethyl acetate in heptane followed by 0-20% MeOH in ethyl acetate) followed by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)). The product containing fractions were treated with saturated aqueous sodium bicarbonate solution and the product was extracted with DCM (2 x 10 mL). The organic layer was passed through a hydrophobic frit and concentrated in vacuo to afford the title compound as a power. (300 mg, 0.466 mmol, 10% yield). LC-MS (Method B): m / z (ESI+) = 547.3 [M+H]+, Rt = 3.72 min, UV purity = 97%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 8.36 – 8.30 (m, 1H), 8.08 – 8.01 (m, 1H), 7.67 – 7.60 (m, 1H), 7.42 – 7.30 (m, 3H), 6.71 (d, J = 7.3 Hz, 1H), 6.60 (s, 1H), 5.40 (s, 2H), 3.92 – 3.76 (m, 2H), 3.69 – 3.61 (m, 1H), 3.07 – 2.94 (m, 2H), 2.42 (s, 3H), 2.17 (s, 3H), 2.01 – 1.93 (m, 1H), 1.81 – 1.72 (m, 1H), 1.66 – 1.55 (m, 1H), 1.51 – 1.40 (m, 1H), 1.38 (s, 9H). Scheme 19 Step 3. Synthesis of tert-butyl (3S)-3-[[4-[2-methyl-4-[[2-methyl-4-(3,3,3- trifluoropropanoylamino)-1-naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1- carboxylate

[0278] 3,3,3-Trifluoropropanoyl chloride (7 μL, 0.06 mmol) was added to an ice cooled stirred solution of tert-butyl (3S)-3-[[4-[4-[(4-amino-2-methyl-1-naphthyl)oxy]-2-methyl-thiazol-5- yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (35 mg, 0.05 mmol) and N-ethyl-N-isopropyl- propan-2-amine (27 μL, 0.155 mmol) in DCM (anhydrous, 0.5 mL). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature over 3 h. The reaction was diluted withDCM (2 mL) and saturated aqueous sodium bicarbonate solution (1 mL). The organic layer was separated using a hydrophobic frit and concentrated in vacuo. The material was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) to afford the title compound as a powder. (26 mg, 0.04 mmol, 73% yield). LC-MS (Method B): m / z (ESI+) = 657.5 [M+H]+, Rt = 4.08 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 10.08 (s, 1H), 8.37 – 8.32 (m, 1H), 8.07 – 8.02 (m, 1H), 7.85 – 7.80 (m, 1H), 7.62 – 7.49 (m, 3H), 7.40 (d, J = 5.2 Hz, 1H), 6.77 (d, J = 7.3 Hz, 1H), 3.92 – 3.77 (m, 2H), 3.71 – 3.60 (m, 3H), 3.06 – 3.04 (m, 2H), 2.43 (s, 3H), 2.28 (s, 3H), 2.01 – 1.93 (m, 1H), 1.81 – 1.73 (m, 1H), 1.65 – 1.56 (m, 1H), 1.50 – 1.41 (m, 1H), 1.38 (s, 9H). Scheme 19 Step 4. Synthesis of 3,3,3-trifluoro-N-[3-methyl-4-[2-methyl-5-[2-[[(3S)-3- piperidyl]amino]pyrimidin-4-yl]thiazol-4-yl]oxy-1-naphthyl]propanamide;hydrochloride

[0279] 4 M Hydrogen chloride in 1,4-dioxane (50 μL, 0.2 mmol) was added to a solution of tert-butyl (3S)-3-[[4-[2-methyl-4-[[2-methyl-4-(3,3,3-trifluoropropanoylamino)-1- naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (26 mg, 0.0392 mmol) in 1,4-dioxane (0.5 mL) and the reaction was stirred at room temperature for 1 h. The reaction was retreated with 4 M Hydrogen chloride in 1,4-dioxane (50 μL, 0.2 mmol) and stirred at room temperature for 2.5 h. The solvent was removed under a stream of nitrogen and the product was lyophilised overnight to afford the title compound as a powder. (22.4 mg, 0.037 mmol, 95% yield). LC-MS (Method B): m / z (ESI+) = 557.3 [M+H]+, Rt = 2.19 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.16 – 8.88 (m, 2H), 8.41 (d, J = 5.6 Hz, 1H), 8.09 – 8.05 (m, 1H), 8.02 – 7.68 (m, 2H), 7.62 – 7.50 (m, 4H), 4.22 – 4.14 (m, 1H), 3.79 – 3.63 (m, 3H), 3.42 – 3.34 (m, 1H), 3.22 – 3.15 (m, 1H), 2.92 – 2.84 (m, 1H), 2.46 (s, 3H), 2.28 (s, 3H), 2.04 – 1.97 (m, 1H), 1.96 – 1.88 (m, 1H), 1.80 – 1.70 (m, 1H), 1.68 – 1.58 (m, 1H).Scheme 20. Synthesis of Example 20.2,2,2-Trifluoro-N-[2-fluoro-3-methyl-4-[2-methyl-5-[2- [[(3S)-3-piperidyl]amino]pyrimidin-4-yl]thiazol-4-yl]oxy-1- naphthyl]ethanesulfonamide;hydrochlorideScheme 20 Step 1. Synthesis of tert-butyl (3S)-3-[[4-[4-[(4-amino-3-fluoro-2-methyl-1- naphthyl)oxy]-2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate

[0280] A solution of tert-butyl (3S)-3-[[4-[4-[(4-amino-2-methyl-1-naphthyl)oxy]-2-methyl- thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (Scheme 19 Step 2) (85%, 145 mg, 0.225 mmol) in THF (anhydrous, 1.5 mL) was stirred in an ice bath and sparged with nitrogen for 5 min. A solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (72 mg, 0.228 mmol) in THF (anhydrous, 1.5 mL) was added slowly dropwise over 15 min. The reaction was stirred in the ice bath and allowed to equilibrate to room temperature over 6 h. The reaction was treated with saturated aqueous sodium thiosulphate solution (5 mL) and extracted with ethyl acetate (2 x 5 mL). The combined organics were washed with saturated aqueous sodium bicarbonate solution (10 mL), brine (10 mL), dried using sodium sulfate, filtered, and concentrated in vacuo. The product was purified by low pH reverse phase chromatography (eluting with a gradient of 10- 100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)). Product containing fractions were combined and the organics were removed in vacuo. The resulting aqueous emulsion was treated with saturated aqueous sodium bicarbonate solution and extracted with DCM (2 x 5 mL). The organic layer was passed through a hydrophobic frit and concentrated in vacuo to afford the title compound as a powder. (40 mg, 0.067 mmol, 30% yield). LC-MS (Method B): m / z (ESI+) = 565.4 [M+H]+, Rt = 4.22 min, UV purity = 98%.1H (400 MHz, DMSO-d6, 353 K) δ 8.35 (d, J = 5.2 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.45 – 7.33 (m, 3H), 6.75 (d, J = 7.1 Hz, 1H), 5.32 (s, 2H), 3.91 – 3.75 (m, 2H), 3.69 – 3.61 (m, 1H), 3.01 – 2.93 (m, 2H), 2.42 (s, 3H), 2.22 – 2.16 (m, 3H), 2.01 – 1.92 (m, 1H), 1.81 – 1.73 (m, 1H), 1.66 – 1.55 (m, 1H), 1.50 – 1.41 (m, 1H), 1.38 (s, 9H). Scheme 20 Step 2. Synthesis of tert-butyl (3S)-3-[[4-[4-[[3-fluoro-2-methyl-4-(2,2,2- trifluoroethylsulfonylamino)-1-naphthyl]oxy]-2-methyl-thiazol-5-yl]pyrimidin-2- yl]amino]piperidine-1-carboxylate

[0281] A solution of tert-butyl (3S)-3-[[4-[4-[(4-amino-3-fluoro-2-methyl-1-naphthyl)oxy]-2- methyl-thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (94%, 50 mg, 0.0832 mmol) in pyridine (anhydrous, 0.5 mL) was stirred in an ice bath for the addition of 2,2,2- trifluoroethanesulfonyl chloride (12 μL, 0.11 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature for 2.5 h. The reaction mixture was cooled in an ice bath for the addition of 2,2,2-trifluoroethanesulfonyl chloride (12 μL, 0.109 mmol). The reaction mixture was stirred in the ice bath and allowed to equilibrate to room temperature for 18 h. The solvent was removed using a stream of nitrogen and the resulting residue was re-dissolved in pyridine (anhydrous, 0.5 mL) and stirred in an ice bath for the addition of 2,2,2- trifluoroethanesulfonyl chloride (12 μL, 0.109 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature for 2.5 h. The solvent was removed using a stream of nitrogen and the residue was dissolved in ethyl acetate (2 mL). The organic layer was washed with water (1 mL), saturated aqueous sodium bicarbonate solution (1 mL), brine (2 mL), dried using sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) to afford the title compound as a powder. (42 mg, 0.059 mmol, 71% yield). LC-MS (Method B): m / z (ESI+) = 711.6 [M+H]+, Rt = 4.33 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 10.32 – 9.94 (m, 1H), 8.38 – 8.31 (m, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.39 – 7.30 (m, 1H), 6.81 (d, J = 7.3 Hz, 1H), 4.51 (q, J = 9.7 Hz, 2H), 3.92 – 3.77 (m, 2H), 3.69 – 3.61 (m, 1H), 3.02 – 2.92 (m, 2H), 2.46 – 2.42 (m, 3H), 2.26 (s, 3H), 2.02 – 1.93 (m, 1H), 1.81 – 1.73 (m, 1H), 1.67 – 1.57 (m, 1H), 1.50 – 1.33 (m, 10H).Scheme 20 Step 3. Synthesis of 2,2,2-trifluoro-N-[2-fluoro-3-methyl-4-[2-methyl-5-[2-[[(3S)- 3-piperidyl]amino]pyrimidin-4-yl]thiazol-4-yl]oxy-1- naphthyl]ethanesulfonamide;hydrochloride

[0282] 4 M Hydrogen chloride in 1,4-dioxane (80 μL, 0.320 mmol) was added to a solution of tert-butyl (3S)-3-[[4-[4-[[3-fluoro-2-methyl-4-(2,2,2-trifluoroethylsulfonylamino)-1- naphthyl]oxy]-2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (40 mg, 0.0563 mmol) in 1,4-dioxane (0.4 mL) and the reaction was stirred at room temperature for 3 h. The reaction was retreated with 4 M hydrogen chloride in 1,4-dioxane (80 μL, 0.320 mmol) and the reaction was stirred at room temperature for 4.5 h. The solvent was removed under a stream of nitrogen and the product was lyophilised overnight to afford the title compound as a powder. (35 mg, 0.054 mmol, 96% yield). LC-MS (Method B): m / z (ESI+) = 611.4 [M+H]+, Rt = 2.36 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.08 – 8.92 (m, 2H), 8.41 (d, J = 5.4 Hz, 1H), 8.21 – 8.18 (m, 1H), 7.81 – 7.52 (m, 4H), 7.45 (d, J = 5.5 Hz, 1H), 4.62 (q, J = 9.7 Hz, 2H), 4.21 – 4.13 (m, 1H), 3.41 – 3.34 (m, 1H), 3.22 – 3.14 (m, 1H), 2.93 – 2.81 (m, 2H), 2.47 (s, 3H), 2.26 – 2.23 (m, 3H), 2.04 – 1.87 (m, 2H), 1.79 – 1.57 (m, 2H).

[0283] The compounds of the following tabulated Examples (Table 7) were prepared analogously to Scheme 20 Step 2 using tert-butyl (3S)-3-[[4-[4-[(4-amino-3-fluoro-2-methyl-1- naphthyl)oxy]-2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate and the appropriate commercially available sulfonyl chloride. The boc protecting group was removed using 4 M hydrogen chloride in 1,4-dioxane analogously to Scheme 20 Step 3. Table 7: Exemplary compounds of the disclosureScheme 21. Synthesis of Example 21.3,3,3-Trifluoro-N-[2-fluoro-3-methyl-4-[2-methyl-5-[2- [[(3S)-3-piperidyl]amino]pyrimidin-4-yl]thiazol-4-yl]oxy-1- naphthyl]propanamide;hydrochlorideScheme 21 Step 1. Synthesis of tert-butyl (3S)-3-[[4-[4-[[3-fluoro-2-methyl-4-(3,3,3- trifluoropropanoylamino)-1-naphthyl]oxy]-2-methyl-thiazol-5-yl]pyrimidin-2- yl]amino]piperidine-1-carboxylate

[0284] A solution of tert-butyl (3S)-3-[[4-[4-[(4-amino-3-fluoro-2-methyl-1-naphthyl)oxy]-2- methyl-thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (Scheme 20 Step 1) (40 mg, 0.06 mmol) in DCM (anhydrous, 0.5 mL) was stirred in an ice bath for the sequential addition of N-ethyl-N-isopropyl-propan-2-amine (35 μL, 0.200 mmol) and 3,3,3-trifluoropropanoyl chloride (8 μL, 0.07 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature over 1 h. The reaction mixture was retreated with 3,3,3-trifluoropropanoyl chloride (3 μL, 0.027 mmol) and stirred at room temperature overnight. The reaction was diluted with DCM (2 mL) and saturated aqueous sodium bicarbonate solution (2 mL). The organic layer was separated using a hydrophobic frit and concentrated in vacuo. The product was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) to afford the title compound as a powder. (26 mg, 0.039 mmol, 60% yield). LC-MS (Method F): m / z (ESI+) = 675.3 [M+H]+, Rt = 4.15 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.38 (d, J = 5.2 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.84 – 7.78 (m, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.41 – 7.35 (m, 1H), 7.28 – 7.12 (m, 1H), 3.80 – 3.66 (m, 4H), 3.45 – 3.37 (m, 2H), 3.29 – 3.24 (m, 1H), 2.45 (s, 3H), 2.23 (s, 3H), 1.99 – 1.90 (m, 1H), 1.85 – 1.72 (m, 1H), 1.68 – 1.51 (m, 1H), 1.46 – 1.25 (m, 10H). Scheme 21 Step 2. Synthesis of 3,3,3-trifluoro-N-[2-fluoro-3-methyl-4-[2-methyl-5-[2-[[(3S)- 3-piperidyl]amino]pyrimidin-4-yl]thiazol-4-yl]oxy-1-naphthyl]propanamide;hydrochloride

[0285] 4 M Hydrogen chloride in 1,4-dioxane (45 μL, 0.180 mmol) was added to a solution of tert-butyl (3S)-3-[[4-[4-[[3-fluoro-2-methyl-4-(3,3,3-trifluoropropanoylamino)-1- naphthyl]oxy]-2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (22 mg, 0.0326 mmol) in 1,4-dioxane (0.4 mL). The reaction was stirred at room temperature for 16 h. The solvent was removed under a stream of nitrogen and the product was lyophilised overnight to afford the title compound as a powder. (17.8 mg, 0.028 mmol, 87% yield). LC-MS (Method B): m / z (ESI+) = 575.4 [M+H]+, Rt = 2.19 min, UV purity = 99%. 1H (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.92 – 8.81 (m, 2H), 8.42 (d, J = 5.4 Hz, 1H), 7.99 – 7.95 (m, 1H), 7.83 – 7.79 (m, 1H), 7.67 – 7.44 (m, 4H), 4.21 – 4.10 (m, 1H), 3.73 (q, J = 11.2 Hz,2H), 3.52 – 3.47 (m, 1H), 3.24 – 3.16 (m, 1H), 2.93 – 2.82 (m, 2H), 2.48 (s, 3H), 2.25 – 2.23 (m, 3H), 2.04 – 1.88 (m, 2H), 1.79 – 1.57 (m, 2H). Scheme 22. Synthesis of Example 22.2,2,2-Trifluoro-N-[3-methyl-4-[2-methyl-5-[2-[[(3R)-3- piperidyl]amino]pyrimidin-4-yl]thiazol-4-yl]oxy-1- naphthyl]ethanesulfonamide;hydrochlorideIntermediate F. Synthesis of tert-butyl (3R)-3-guanidinopiperidine-1- carboxylate;hydrochloride

[0286] N-ethyl-N-isopropyl-propan-2-amine (2.8 mL, 16.03 mmol) was added to a solution of tert-butyl (3R)-3-aminopiperidine-1-carboxylate (2.00 g, 9.99 mmol) and 1H-pyrazole-1- carboximidamide hydrochloride (1:1) (1.7 g, 11.6 mmol) in DMF (anhydrous, 10 mL), and the reaction was stirred at 80 °C for 24 h. The reaction was cooled to room temperature, diethyl ether (100 mL) was added, and the reaction was stirred for 16 h at room temperature. The reaction was concentrated in vacuo and the resulting oil was triturated with a mixture of acetonitrile:diethyl ether (1:9, 20 mL), sonicated for 2 min and the solvent was decanted. This procedure was repeated twice, and then repeated five times with TBME (20 mL). The resulting residue was dissolved in DCM (10 mL) and concentrated in vacuo. This was repeated five times to afford the title compound as a solid. (1.7 g, 4.878 mmol, 49% yield). LC-MS (Method B): m / z (ESI+) = 243.2 [M+H]+, Rt = 1.29 min, ELS purity = 100%. 1H NMR (400 MHz, CDCl3) δ 8.13 – 8.07 (m, 1H), 7.75 – 7.70 (m, 1H), 7.17 – 7.13 (m, 2H), 4.16 – 4.11 (m, 1H), 3.92 – 3.84 (m, 1H), 3.70 – 3.51 (m, 2H), 3.13 – 3.06 (m, 1H), 2.75 – 2.70 (m, 1H), 2.40 – 2.35 (m, 1H), 2.12 – 2.04 (m, 1H), 1.79 – 1.71 (m, 1H), 1.40 (s, 9H).Scheme 22 Step 1. Synthesis of tert-butyl (3R)-3-[[4-(4-chloro-2-methyl-thiazol-5- yl)pyrimidin-2-yl]amino]piperidine-1-carboxylate

[0287] (E)-1-(4-Chloro-2-methyl-thiazol-5-yl)-3-(dimethylamino)prop-2-en-1-one (Scheme 9 Step 1) (650 mg, 2.25 mmol) and tert-butyl (3R)-3-guanidinopiperidine-1- carboxylate;hydrochloride (Intermediate F) (940 mg, 3.38 mmol) were suspended in ethanol (8 mL) and sparged with nitrogen for 5 min. Potassium carbonate (1.88 g, 13.6 mmol) was added and the reaction was stirred at 85 °C overnight. The reaction was cooled to room temperature, filtered under vacuum, and the solids washed with MeOH (approx.200 mL). The filtrate was concentrated in vacuo and the residue was dissolved in DCM (50 mL), washed with water (2 x 50 mL), brine (50 mL), dried with magnesium sulfate, filtered, and concentrated in vacuo. The material was purified by silica chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane). The resulting oil was triturated with heptane and the collected solids were dried under vacuum at 40oC to afford the title compound as a solid. (740 mg, 1.769 mmol, 79% yield). LC-MS (Method A): m / z (ESI+) = 410.1 [M(35Cl)+], 412.1 [M(37Cl)+], Rt = 0.98 min, UV purity = 98%. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 5.2 Hz, 1H), 7.42 – 7.26 (m, 2H), 4.10 – 3.46 (m, 3H), 3.26 – 2.77 (m, 2H), 2.67 (s, 3H), 1.98 – 1.84 (m, 1H), 1.83 – 1.66 (m, 1H), 1.68 – 1.47 (m, 2H), 1.43 – 1.19 (m, 9H). Scheme 22 Step 2. Synthesis of tert-butyl (3R)-3-[[4-[4-[(4-amino-2-methyl-1-naphthyl)oxy]- 2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate

[0288] 4-Amino-2-methyl-naphthalen-1-ol (Intermediate B) (0.47 g, 2.73 mmol) and tert- butyl (3R)-3-[[4-(4-chloro-2-methyl-thiazol-5-yl)pyrimidin-2-yl]amino]piperidine-1-carboxylate (0.74 g, 1.81 mmol) were dissolved in NMP (anhydrous, 6 mL) and sparged with nitrogen for 5 min before the addition of cesium carbonate (2.95 g, 9.06 mmol). The reaction was sparged with nitrogen for 5 min and then stirred at 130 °C for 4 h. The reaction was stood overnight at room temperature and then filtered through celite which was washed with ethyl acetate (300 mL). The organics were diluted with water (100 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 100 mL), the combined organic layers were washed with water (100 mL), brine (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by silica chromatography (KP-NH column, eluting with a gradient of 0-100% ethyl acetate in heptane) followed by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)). Productcontaining fractions were combined and concentrated in vacuo to remove the MeCN. The remaining aqueous was treated with saturated aqueous sodium bicarbonate solution. DCM (20 mL) was added and the layers were separated. The aqueous was extracted with DCM (2 x 10 mL), the combined organic layers were passed through a hydrophobic frit and concentrated in vacuo to afford the title compound as a solid. (77 mg, 0.141 mmol, 8% yield). LC-MS (Method A): m / z (ESI+) = 547.5 [M+H]+, Rt = 1.06 min, UV purity = 100%. 1H NMR (500 MHz, DMSO-d6) δ 8.35 (d, J = 5.2 Hz, 1H), 8.10 – 8.04 (m, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.40 – 7.31 (m, 3H), 7.23 – 7.05 (m, 1H), 6.56 (s, 1H), 5.67 (s, 2H), 4.21 – 3.46 (m, 4H), 3.16 – 2.88 (m, 1H), 2.42 (s, 3H), 2.15 (s, 3H), 2.00 – 1.87 (m, 1H), 1.86 – 1.70 (m, 1H), 1.68 – 1.49 (m, 1H), 1.44 – 1.24 (m, 10H). Scheme 22 Step 3. Synthesis of tert-butyl (3R)-3-[[4-[2-methyl-4-[[2-methyl-4-(2,2,2- trifluoroethylsulfonylamino)-1-naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine- 1-carboxylate

[0289] A stirring solution of tert-butyl (3R)-3-[[4-[4-[(4-amino-2-methyl-1-naphthyl)oxy]-2- methyl-thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (64 mg, 0.12 mmol) in pyridine (anhydrous, 0.3 mL) was stirred in an ice bath for the addition of 2,2,2- trifluoroethanesulfonyl chloride (16 μL, 0.14 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature for 2 h. The reaction was concentrated under a stream of nitrogen and the resulting residue was dissolved in DCM (2 mL) and diluted with water (2 mL). The layers were separated, and the aqueous layer was extracted with DCM (3 x 2 mL). The combined organic layers were passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) and the product containing fractions were concentrated to remove the MeCN. The aqueous was treated with saturated aqueous sodium bicarbonate solution and the product was extracted using DCM (3 x 2 mL). The combined organic layers were passed through a hydrophobic frit and concentrated in vacuo to afford the title compound as a solid. (54 mg, 0.078 mmol, 67% yield). LC-MS (Method A): m / z (ESI+) = 693.6 [M+H]+, Rt = 1.13 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.37 (d, J = 5.2 Hz, 1H), 8.22 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.65 – 7.49 (m, 3H), 7.45 – 7.30 (m, 1H), 7.28 – 7.10 (m, 1H), 4.70 – 4.56 (m, 2H), 3.82 – 3.52 (m, 5H), 2.44 (s, 3H), 2.29 (s, 3H), 2.01 – 1.88 (m, 1H), 1.87 – 1.71 (m, 1H), 1.68 – 1.52 (m, 1H), 1.43 – 1.25 (m, 10H).Scheme 22 Step 4. Synthesis of 2,2,2-trifluoro-N-[3-methyl-4-[2-methyl-5-[2-[[(3R)-3- piperidyl]amino]pyrimidin-4-yl]thiazol-4-yl]oxy-1- naphthyl]ethanesulfonamide;hydrochloride

[0290] 4 M Hydrogen chloride in 1,4-dioxane (108 μL, 0.43 mmol) was added to a solution of tert-butyl (3R)-3-[[4-[2-methyl-4-[[2-methyl-4-(2,2,2-trifluoroethylsulfonylamino)-1- naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (54 mg, 0.0779 mmol) in 1,4-dioxane (0.8 mL) and water (10 μL). The reaction was stirred at room temperature for 4 h. The reaction was retreated with 4 M hydrogen chloride in 1,4-dioxane (108 μL, 0.43 mmol) and stirred at room temperature for 3 h. The reaction was concentrated in vacuo, the product was lyophilised overnight and then dried under vacuum at 40oC for 1 h to afford the title compound as a solid. (47 mg, 0.075 mmol, 96% yield). LC-MS (Method B): m / z (ESI+) = 593.4 [M+H]+, Rt = 2.28 min, UV purity = 100%. 1H NMR (500 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.10 – 8.84 (m, 2H), 8.41 (d, J = 5.5 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.82 – 7.77 (m, 1H), 7.74 – 7.39 (m, 5H), 4.67 (q, J = 9.8 Hz, 2H), 4.23 – 4.11 (m, 1H), 3.41 – 3.33 (m, 1H), 3.24 – 3.13 (m, 1H), 2.98 – 2.76 (m, 2H), 2.46 (s, 3H), 2.30 (s, 3H), 2.05 – 1.87 (m, 2H), 1.80 – 1.56 (m, 2H). Scheme 23. Synthesis of Example 23. 2,2,2-Trifluoro-N-[4-[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]oxy-3-methyl-1- naphthyl]ethanesulfonamide;hydrochlorideScheme 23 Step 1. Synthesis of tert-butyl (3S,5S)-3-[[4-[4-[(4-amino-2-methyl-1- naphthyl)oxy]-2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1- carboxylate

[0291] 4-Amino-2-methyl-naphthalen-1-ol (Intermediate B) (1.65 g, 9.53 mmol) and tert- butyl (3S,5S)-3-[[4-(4-chloro-2-methyl-thiazol-5-yl)pyrimidin-2-yl]amino]-5-fluoro-piperidine- 1-carboxylate (Scheme 9 Step 2) (3.00 g, 6.31 mmol) were flushed with nitrogen for 2 min. NMP (anhydrous, 25 mL) was added and the reaction was stirred under a flow of nitrogen for 5 min. Cesium carbonate (8.25 g, 25.3 mmol) was added and the reaction was stirred under a flow of nitrogen for 1 min before stirring at 140 °C for 4 h. The reaction was cooled to room temperature and filtered through a pad of celite which was washed with ethyl acetate (approx. 400 mL). The organic layer was washed with water (350 mL) and the layers were separated. The organic layer was washed with water (2 x 350 mL), brine (2 x 350 mL) and dried over sodium sulfate. The aqueous layer was extracted with ethyl acetate (200 mL) which was then washed with water (2 x 200 mL), brine (2 x 200 mL) and dried over sodium sulfate. The two organic fractions were then combined and concentrated in vacuo. The product was purified by silica chromatography (KP-NH column, eluting with a gradient of 0-100% ethyl acetate in heptane followed by 0-20% MeOH in ethyl acetate) followed by low pH reverse phase chromatography (eluting in a gradient of 10- 100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)). Product containing fractions were combined and concentrated in vacuo to remove the MeCN. The aqueous suspension was treated with saturated aqueous sodium bicarbonate solution, extracted with DCM (2 x 10 mL), passed through a hydrophobic frit, and concentrated in vacuo to afford the title compound as a powder. (400 mg, 0.687 mmol, 11% yield). LC-MS (Method B): m / z (ESI+) = 565.5 [M+H]+, Rt = 3.57 min, UV purity = 97%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 8.34 (d, J = 5.3 Hz, 1H), 8.07 – 8.01 (m, 1H), 7.65 – 7.60 (m, 1H), 7.43 – 7.31 (m, 3H), 6.94 – 6.88 (m, 1H), 6.60 (s, 1H), 5.40 (s, 2H), 5.06 – 4.87 (m, 1H), 4.19 – 3.91 (m, 3H), 3.23 – 3.10 (m, 2H), 2.41 (d, J = 2.4 Hz, 3H), 2.28 – 2.13 (m, 4H), 1.96 – 1.79 (m, 1H), 1.40 (s, 9H). Scheme 23 Step 2. Synthesis of tert-butyl (3S,5S)-3-fluoro-5-[[4-[2-methyl-4-[[2-methyl-4- (2,2,2-trifluoroethylsulfonylamino)-1-naphthyl]oxy]thiazol-5-yl]pyrimidin-2- yl]amino]piperidine-1-carboxylate

[0292] A solution of tert-butyl (3S,5S)-3-[[4-[4-[(4-amino-2-methyl-1-naphthyl)oxy]-2- methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate (28 mg, 0.0476mmol) in pyridine (anhydrous, 0.2 mL) was stirred in an ice bath for the addition of 2,2,2- trifluoroethanesulfonyl chloride (7 μL, 0.06 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature over 2 h. The reaction was concentrated under a stream of nitrogen and the resulting residue was dissolved in ethyl acetate (2 mL). The organic layer was washed with water (1 mL), saturated aqueous sodium bicarbonate solution (1 mL), brine (2 mL), dried using sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) to afford the title compound as a powder. (18.4 mg, 0.025 mmol, 53% yield). LC-MS (Method B): m / z (ESI+) = 711.5 [M+H]+, Rt = 4.05 min, UV purity = 97%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 10.16 (s, 1H), 8.36 (d, J = 5.2 Hz, 1H), 8.25 – 8.21 (m, 1H), 7.84 – 7.81 (m, 1H), 7.61 – 7.51 (m, 3H), 7.40 (d, J = 5.2 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 5.07 – 4.89 (m, 1H), 4.53 (q, J = 9.7 Hz, 2H), 4.18 – 3.93 (m, 3H), 3.24 – 3.11 (m, 2H), 2.44 (s, 3H), 2.32 – 2.18 (m, 4H), 1.98 – 1.79 (m, 1H), 1.40 – 1.35 (m, 9H). Scheme 23 Step 3. Synthesis of 2,2,2-trifluoro-N-[4-[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]oxy-3-methyl-1- naphthyl]ethanesulfonamide;hydrochloride

[0293] 4 M Hydrogen chloride in 1,4-dioxane (35 μL, 0.140 mmol) was added to a solution of tert-butyl (3S,5S)-3-fluoro-5-[[4-[2-methyl-4-[[2-methyl-4-(2,2,2- trifluoroethylsulfonylamino)-1-naphthyl]oxy]thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1- carboxylate (97%, 18 mg, 0.0246 mmol) in 1,4-dioxane (0.2 mL) and the reaction was stirred at room temperature for 16 h. The reaction was retreated with 4 M hydrogen chloride in 1,4-dioxane (35 μL, 0.140 mmol) and stirred at room temperature for 2 h. The solvent was removed using a stream of nitrogen and the product was lyophilised overnight to afford the title compound as a powder. (14.2 mg, 0.021 mmol, 85% yield). LC-MS (Method B): m / z (ESI+) = 611.4 [M+H]+, Rt = 2.29 min, UV purity = 100%. 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.68 – 8.99 (m, 2H), 8.41 (d, J = 5.4 Hz, 1H), 8.24 – 8.18 (m, 1H), 7.82 – 7.75 (m, 1H), 7.72 – 7.44 (m, 5H), 5.31 – 5.16 (m, 1H), 4.71 – 4.47 (m, 3H), 3.54 – 3.37 (m, 2H), 3.33 – 3.12 (m, 1H), 2.92 – 2.79 (m, 1H), 2.45 (s, 3H), 2.38 – 2.26 (m, 4H), 2.02 – 1.80 (m, 1H).Scheme 24. Synthesis of Example 24. 2,2,2-Trifluoro-N-[2-fluoro-4-[5-[2-[[(3S,5S)-5-fluoro- 3-piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]oxy-3-methyl-1- naphthyl]ethanesulfonamide;hydrochlorideScheme 24 Step 1. Synthesis of tert-butyl (3S,5S)-3-[[4-[4-[(4-amino-3-fluoro-2-methyl-1- naphthyl)oxy]-2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1- carboxylate

[0294] A solution of tert-butyl (3S,5S)-3-[[4-[4-[(4-amino-2-methyl-1-naphthyl)oxy]-2- methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate (95%, 180 mg, 0.303 mmol) in THF (anhydrous 1.5 mL) was stirred in an ice bath and sparged with nitrogen for 1 min. A solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (100 mg, 0.317 mmol) in THF (anhydrous, 1.5 mL) was added slowly dropwise over 30 min and the reaction was stirred in the ice bath for 2 h before being allowed to equilibrate to room temperature over 1 h. The reaction mixture was treated with saturated aqueous sodium thiosulphate solution (3 mL) and extracted with ethyl acetate (2 x 5 mL). The combined organics were washed with saturated aqueous sodium bicarbonate solution (1 x 10 mL), brine (1 x 10 mL), filtered, and concentrated in vacuo. The resulting product was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)). Product containing fractions were combined and concentrated in vacuo to remove the MeCN. The resulting aqueous emulsion was treated with saturated aqueous sodium bicarbonate solution and extracted with DCM (2 x 5 mL). The organic layer was passed through a hydrophobic frit and concentrated in vacuo to afford the title compound as a powder. (52 mg, 0.088 mmol, 29% yield). LC-MS (Method B): m / z (ESI+) = 583.5 [M+H]+, Rt = 4.04 min, UV purity = 99%.1H NMR (400 MHz, DMSO-d6, 353 K) δ 8.36 (d, J = 5.2 Hz, 1H), 8.20 – 8.13 (m, 1H), 7.70 – 7.63 (m, 1H), 7.46 – 7.33 (m, 3H), 6.95 (d, J = 7.6 Hz, 1H), 5.32 (s, 2H), 5.05 – 4.89 (m, 1H), 4.19 – 3.92 (m, 3H), 3.24 – 3.10 (m, 1H), 2.96 – 2.91 (m, 1H), 2.42 (s, 3H), 2.28 – 2.17 (m, 4H), 1.99 – 1.79 (m, 1H), 1.40 (s, 9H). Scheme 24 Step 2. Synthesis of tert-butyl (3S,5S)-3-fluoro-5-[[4-[4-[[3-fluoro-2-methyl-4- (2,2,2-trifluoroethylsulfonylamino)-1-naphthyl]oxy]-2-methyl-thiazol-5-yl]pyrimidin-2- yl]amino]piperidine-1-carboxylate

[0295] A solution of tert-butyl (3S,5S)-3-[[4-[4-[(4-amino-3-fluoro-2-methyl-1- naphthyl)oxy]-2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate (30 mg, 0.0510 mmol) in pyridine (anhydrous, 0.3 mL) was stirred in an ice bath for the addition of 2,2,2-trifluoroethanesulfonyl chloride (8 μL, 0.07 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature over 1 h and then stirred at room temperature for 1 h. The solvent was removed using a stream of nitrogen and the residue was dissolved in ethyl acetate (2 mL). The organic solution was washed with water (1 mL), saturated aqueous sodium bicarbonate solution (1 mL), brine (2 mL), dried using sodium sulfate, filtered, and concentrated in vacuo. The product was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid) to afford the title compound as a powder. (15 mg, 0.018 mmol, 36% yield). LC-MS (Method F): m / z (ESI+) = 729.4 [M+H]+, Rt = 2.28 min, UV purity = 89%. 1H NMR (400 MHz, DMSO-d6, 353 K) δ 10.13 (br. s, 1H), 8.38 (d, J = 5.2 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.70 – 7.62 (m, 1H), 7.57 – 7.49 (m, 1H), 7.39 (d, J = 5.2 Hz, 1H), 7.04 – 6.98 (m, 1H), 5.06 – 4.90 (m, 1H), 4.52 (q, J = 9.7 Hz, 2H), 4.19 – 3.93 (m, 3H), 3.25 – 3.17 (m, 2H), 2.45 (s, 3H), 2.29 – 2.20 (m, 4H), 1.99 – 1.79 (m, 1H), 1.40 (s, 9H). Scheme 24 Step 3. Synthesis of 2,2,2-trifluoro-N-[2-fluoro-4-[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]oxy-3-methyl-1- naphthyl]ethanesulfonamide;hydrochloride

[0296] 4 M Hydrogen chloride in 1,4-dioxane (40 uL, 0.160 mmol) was added to a solution of tert-butyl (3S,5S)-3-fluoro-5-[[4-[4-[[3-fluoro-2-methyl-4-(2,2,2-trifluoroethylsulfonylamino)-1- naphthyl]oxy]-2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (19 mg, 0.0261 mmol) in 1,4-dioxane (0.4 mL) and the reaction was stirred at room temperature for 17 h. The solvent was removed under a stream of nitrogen and the product was purified by low pH preparative HPLC (Preparative Method B). The product fractions were combined and concentratedin vacuo. The resulting residue was treated with 4 M hydrogen chloride in 1,4-dioxane (0.2 mL) and stirred at room temperature for 30 minutes. The solvent was removed using a stream of nitrogen and the product was lyophilised overnight to afford the title compound as a powder. (7.6 mg, 0.0114 mmol, 44% yield). LC-MS (Method B): m / z (ESI+) = 629.4 [M+H]+, Rt = 2.37 min, UV purity = 100%. 1H NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.54 – 9.03 (m, 2H), 8.42 (d, J = 5.3 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.70 – 7.66 (m, 1H), 7.61 – 7.42 (m, 3H), 5.30 – 5.17 (m, 1H), 4.62 (q, J = 9.7 Hz, 2H), 4.49 – 4.35 (m, 1H), 3.53 – 3.37 (m, 2H), 3.32 – 3.14 (m, 1H), 2.91 – 2.79 (m, 1H), 2.46 (s, 3H), 2.40 – 2.29 (m, 1H), 2.26 – 2.23 (m, 3H), 1.98 – 1.82 (m, 1H).

[0297] The compounds of the following tabulated Examples (Table 8) were prepared analogously to Scheme 24 Step 2 using tert-butyl (3S,5S)-3-[[4-[4-[(4-amino-3-fluoro-2-methyl- 1-naphthyl)oxy]-2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate and the appropriate commercially available sulfonyl chloride. The boc protecting group was removed using 4 M hydrogen chloride in 1,4-dioxane analogously to Scheme 24 Step 3.

[0298] The Step 3 boc deprotection of Examples 24.4 and 24.5, was carried out using TFA / DCM at 0 °C followed by an aqueous work up to afford the free base.

[0299] Table 8: Exemplary compounds of the disclosure24.3Scheme 25. Synthesis of Example 25. 3,3,3-Trifluoro-N-[2-fluoro-4-[5-[2-[[(3S,5S)-5-fluoro- 3-piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]oxy-3-methyl-1- naphthyl]propanamide;hydrochlorideScheme 25 Step 1. Synthesis of tert-butyl (3S,5S)-3-fluoro-5-[[4-[4-[[3-fluoro-2-methyl-4- (3,3,3-trifluoropropanoylamino)-1-naphthyl]oxy]-2-methyl-thiazol-5-yl]pyrimidin-2- yl]amino]piperidine-1-carboxylate

[0300] A solution of tert-butyl (3S,5S)-3-[[4-[4-[(4-amino-3-fluoro-2-methyl-1- naphthyl)oxy]-2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]-5-fluoro-piperidine-1-carboxylate (Scheme 24 Step 1) (22 mg, 0.04 mmol) in DCM (anhydrous, 0.3 mL) was stirred in an ice bath for the sequential addition of N-ethyl-N-isopropyl-propan-2-amine (20 μL, 0.115 mmol) and 3,3,3-trifluoropropanoyl chloride (5 μL, 0.05 mmol). The reaction was stirred in the ice bath and allowed to equilibrate to room temperature overnight. The reaction was diluted with DCM (2 mL) and saturated aqueous sodium bicarbonate solution (2 mL). The organic layer was passed through a hydrophobic frit and concentrated in vacuo. The material was purified by low pH reverse phase chromatography (eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid)) to afford the title compound as a powder. (7.5 mg, 0.011 mmol, 29% yield). LC-MS (Method F): m / z (ESI+) = 693.5 [M+H]+, Rt = 3.98 min, UV purity 99%.Scheme 25 Step 2. Synthesis of 3,3,3-trifluoro-N-[2-fluoro-4-[5-[2-[[(3S,5S)-5-fluoro-3- piperidyl]amino]pyrimidin-4-yl]-2-methyl-thiazol-4-yl]oxy-3-methyl-1- naphthyl]propanamide;hydrochloride

[0301] 4 M Hydrogen chloride in 1,4-dioxane (16 μL, 0.0643 mmol) was added to a solution of tert-butyl (3S,5S)-3-fluoro-5-[[4-[4-[[3-fluoro-2-methyl-4-(3,3,3-trifluoropropanoylamino)-1- naphthyl]oxy]-2-methyl-thiazol-5-yl]pyrimidin-2-yl]amino]piperidine-1-carboxylate (7.5 mg, 0.0107 mmol) in 1,4-dioxane (0.2 mL) and the reaction was stirred at room temperature for 2.5 h. The solvent was removed using a stream of nitrogen and the product was lyophilised overnight to afford the title compound as a powder. (6.5 mg, 0.01 mmol, 95% yield). LC-MS (Method B): m / z (ESI+) = 593.3 [M+H]+, Rt = 2.25 min. UV purity = 98%. 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.60 – 9.48 (m, 1H), 9.26 – 9.01 (m, 1H), 8.46 – 8.40 (m, 1H), 8.00 – 7.89 (m, 1H), 7.84 – 7.76 (m, 1H), 7.69 – 7.42 (m, 4H), 5.33 – 5.14 (m, 1H), 4.50 – 4.31 (m, 1H), 3.79 – 3.67 (m, 2H), 3.54 – 3.36 (m, 2H), 3.32 – 3.13 (...

Claims

CLAIMS 1. A compound of Formula (I’):or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, wherein X1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl; Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl; L1is selected from the group consisting of -NRB-S(=O)2-, -S(=O)2-NRB-, -NRB-, - NRBC(=O)-, -C(=O)NRB-, -NRBC(=O)NRB-, -O-, and bond; R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl; R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, C1-C6haloalkoxy, C3-C4cycloalkyl, and oxo, wherein the C1-C6alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl;R5is selected from the group consisting of C1-C6alkyl, C2-C4alkenyl, C2-C4alkynyl, C1- C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, phenyl, 4-12 membered monocyclic or bicyclic heterocyclyl, and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the C1-C6alkyl is optionally substituted with cyano or a C3-C8cycloalkyl further optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine, wherein the phenyl or 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; or R4and R5together with the atoms to which R4and R5are attached to and contiguous atoms, form a 5-6 membered heterocyclyl optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6haloalkyl, and oxo; n is integer 0-2; m is integer 0-4; and p is integer 0-4; provided that i) when L1is -NH-S(=O)2-, -NH-C(=O)-, or -C(=O)-NH-, X1is N, X2is -O-, and ring A is N-containing 6-7 membered heterocyclyl optionally comprising an additional ring O atom, then R5is not phenyl substituted with -Cl; and ii) when L1is -NH- S(=O)2-, X1is N, X2is -O-, ring A is N-containing 6-membered heterocyclyl, m is 0 or 1, R3is F, ring B is naphthyl, p is 1 or 2, and each R4is methyl or F, then R5is not C1-C4alkyl or C2-C4haloalkyl.

2. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein X1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl; Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl; L1is selected from the group consisting of -NRB-S(=O)2-, -S(=O)2-NRB-, -NRB-, - NRBC(=O)-, -C(=O)NRB-, and bond; R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1- C6haloalkyl; R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, and C1-C6haloalkoxy, wherein the C1-C6alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl; R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, phenyl, 4-12 membered monocyclic or bicyclic heterocyclyl, and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy,wherein the phenyl or 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; n is integer 0-2; m is integer 0-4; and p is integer 0-4; provided that when L1is -NH-S(=O)2- or -NH-C(=O)-, X1is N, X2is -O-, A is N-containing 6-membered heterocyclyl, and m is 0, then R5is not phenyl substituted with -Cl.

3. A compound of Formula (II’):or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, wherein X1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl; Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl; L1is selected from the group consisting of -NRB-S(=O)2-, -S(=O)2-NRB-, -NRB-, - NRBC(=O)-, -C(=O)NRB-, -NRBC(=O)NRB-, -O-, and bond; R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl;R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, C1-C6haloalkoxy, C3-C4cycloalkyl, and oxo, wherein the C1-C6alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl; when L1is selected from the group consisting of -S(=O)2-NRB-, -NRB-, -NRBC(=O)-, - C(=O)NRB-, -NRBC(=O)NRB-, and -O-, R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, and 4-12 membered monocyclic or bicyclic heterocyclyl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl further optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine; when L1is -NRB-S(=O)2-, R5is selected from the group consisting of C1-C6heteroalkyl, C3-C8cycloalkyl, 4-12 membered monocyclic or bicyclic heterocyclyl, and C1- C6alkyl substituted with C3-C8cycloalkyl further optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine; and when L1is bond, R5is 4-12 membered monocyclic or bicyclic heterocyclyl optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine; or R4and R5together with the atoms to which R4and R5are attached to and contiguous atoms, form a 5-6 membered heterocyclyl optionally substituted with 1-4 substituents eachindependently selected from the group consisting of halo, C1-C6alkyl, C1-C6haloalkyl, and oxo; n is integer 0-2; m is integer 0-4; and p is integer 0-4.

4. A compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein X1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl; Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl; L1is selected from the group consisting of -NRB-S(=O)2-, -S(=O)2-NRB-, -NRB-, - NRBC(=O)-, -C(=O)NRB-, and bond; R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1- C6haloalkyl; R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy;R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, and C1-C6haloalkoxy, wherein the C1-C6alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl; R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, and 4-12 membered monocyclic or bicyclic heterocyclyl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; n is integer 0-2; m is integer 0-4; and p is integer 0-4.

5. A compound of Formula (III):or a pharmaceutically acceptable salt thereof, wherein X1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl; Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl;R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl; R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, and C1-C6haloalkoxy, wherein the C1- C6alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl; R5is C3-C8cycloalkyl optionally substituted with 1-4 substituents selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; n is integer 0-2; m is integer 0-4; and p is integer 0-4.

6. A compound of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein X1is selected from the group consisting of N, CH, and CF; X2is selected from the group consisting of -O-, -C(RA)2-, and -NRB-; RAis each independently selected from the group consisting of H, halo, C1-C4alkyl, and C1-C4haloalkyl; RBis each independently selected from the group consisting of H, C1-C4alkyl, and C1-C4haloalkyl; Ring A is selected from the group consisting of 4-12 membered monocyclic or bicyclic carbocyclyl, and 4-12 membered monocyclic or bicyclic heterocyclyl;Ring B is selected from the group consisting of phenyl, naphthyl, 5-12 membered monocyclic or bicyclic heteroaryl, partially unsaturated 4-12 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 4-12 membered monocyclic or bicyclic heterocyclyl; R1is each independently selected from the group consisting of halo, cyano, hydroxy, nitro, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; R2is selected from the group consisting of H, halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl; R3is each independently selected from the group consisting of halo, C1-C6alkyl, amine, C1-C6alkylamine, di-(C1-C6alkyl)amine, hydroxy, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R4is each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, hydroxy, C1-C6alkoxy, and C1-C6haloalkoxy, wherein the C1- C6 alkyl, C1-C6heteroalkyl, or C1-C6haloalkyl is optionally substituted with 4-12 membered monocyclic or bicyclic heterocyclyl; R5is C1-C4alkyl-C3-C6cycloalkyl or C1-C4haloalkyl; n is integer 0-2; m is integer 0-4; and p is integer 0-4, provided that when X1is N, X2is -O-, ring A is N-containing 6-membered heterocyclyl, m is 0 or 1, R3is F, ring B is naphthyl, p is 1 or 2, and each R4is methyl or F, then R5is not C2-C4haloalkyl.

7. The compound of claim 1, wherein L1is selected from the group consisting of -NRB- S(=O)2-, -S(=O)2-NRB-, -NRB-, -NRBC(=O)-, -C(=O)NRB-, -NRBC(=O)NRB-, and -O-, and R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, phenyl, 4-12 membered monocyclic or bicyclic heterocyclyl, and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl further optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine,wherein the phenyl or 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; or L1is bond, and R5is selected from the group consisting of 4-12 membered monocyclic or bicyclic heterocyclyl and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine, wherein the 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy.

8. The compound of claim 2, wherein L1is selected from the group consisting of -NRB- S(=O)2-, -S(=O)2-NRB-, -NRB-, -NRBC(=O)-, and -C(=O)NRB-, and R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, H, phenyl, 4-12 membered monocyclic or bicyclic heterocyclyl, and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy, wherein the phenyl or 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; or L1is bond, and R5is selected from the group consisting of 4-12 membered monocyclic or bicyclic heterocyclyl and 5-12 membered monocyclic or bicyclic heteroaryl, wherein the 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy,wherein the 5-12 membered monocyclic or bicyclic heteroaryl is optionally substituted with 1-4 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy.

9. The compound of claim 3, wherein L1is selected from the group consisting of -NRB-, - NRBC(=O)-, -C(=O)NRB-, -NRBC(=O)NRB-, and -O-, and R5is selected from the group consisting of C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, and 4-12 membered monocyclic or bicyclic heterocyclyl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl further optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine; or L1is -NRB-S(=O)2-, and R5is selected from the group consisting of C1-C6heteroalkyl, C3-C8cycloalkyl, 4-12 membered monocyclic or bicyclic heterocyclyl, and C1-C6alkyl substituted with C3-C8cycloalkyl further optionally substituted with 1-2 substituents each independently selected from the group consisting of halo, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine; or L1is bond, and R5is 4-12 membered monocyclic or bicyclic heterocyclyl optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, hydroxy, and amine.

10. The compound of claim 4, wherein L1is selected from the group consisting of -NRB-, - NRBC(=O)-, and -C(=O)NRB-, and R5is selected from the group consisting of C1-C6alkyl, C1- C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, and 4-12 membered monocyclic or bicyclic heterocyclyl, wherein the C1-C6alkyl is optionally substituted with C3-C8cycloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the groupconsisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; or L1is -NRB-S(=O)2-, and R5is selected from the group consisting of C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, and 4-12 membered monocyclic or bicyclic heterocyclyl, and C1-C6alkyl substituted with C3-C8cycloalkyl, wherein the C3-C8cycloalkyl or 4-12 membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy; or L1is bond, and R5is 4-12 membered monocyclic or bicyclic heterocyclyl optionally substituted with 1-4 substituents each independently selected from the group consisting of oxo, halo, C1-C6alkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, cyano, and hydroxy.

11. The compound of any one of claims 1-10, wherein X1is N.

12. The compound of any one of claims 1-11, wherein X2is -O-.

13. The compound of any one of claims 1-11, wherein X2is -NH-.

14. The compound of any one of claims 1-11, wherein X2is -CH2-.

15. The compound of any one of claims 1-10, wherein the compound is a compound of Formula I-A:or a pharmaceutically acceptable salt thereof.

16. The compound of any one of claims 1-4 and 7-10, wherein the compound is a compound of Formula I-B:or a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 1-4 and 7-10, wherein the compound is a compound of Formula I-C:or a pharmaceutically acceptable salt thereof.

18. The compound of any one of claims 1-4 and 7-10, wherein the compound is a compound of Formula I-D:or a pharmaceutically acceptable salt thereof.

19. The compound of any one of claims 1-18, wherein ring A is 5-8 membered monocyclic carbocyclyl or 5-8 membered monocyclic heterocyclyl.

20. The compound of any one of claims 1-19, wherein ring A is selected from the group consisting of cyclohexyl, piperidyl, azetidinyl, and tetrahydropyranyl.

21. The compound of any one of claims 1-20, wherein ring A is cyclohexyl.

22. The compound of any one of claims 1-20, wherein ring A is piperidyl.

23. The compound of any one of claims 1-22, wherein ring B is selected from the group consisting of phenyl, naphthyl, 5-10 membered monocyclic or bicyclic heteroaryl, partiallyunsaturated 5-10 membered monocyclic or bicyclic carbocyclyl, and partially unsaturated 5-10 membered monocyclic or bicyclic heterocyclyl.

24. The compound of any one of claims 1-23, wherein ring B is selected from the group consisting of naphthyl, phenyl, pyridyl, indolyl, quinolinyl, indanyl, benzofuranyl, tetralinyl, indazolyl, benzothiophenyl, and indenyl.

25. The compound of any one of claims 1-24, wherein ring B is naphthyl.

26. The compound of any one of claims 1-24, wherein ring B is phenyl.

27. The compound of any one of claims 1-26, wherein R1is halo or C1-C2alkyl.

28. The compound of any one of claims 1-27, wherein R2is H or C1-C6alkyl.

29. The compound of any one of claims 1-28, wherein R2is H.

30. The compound of any one of claims 1-28, wherein R2is methyl.

31. The compound of any one of claims 1-30, wherein R3is each independently selected from the group consisting of halo, C1-C6alkyl, and amine.

32. The compound of any one of claims 1-31, wherein R3is each independently selected from the group consisting of fluoro, methyl, and amine.

33. The compound of any one of claims 1-32, wherein R3is fluoro.

34. The compound of any one of claims 1-32, wherein R3is amine.

35. The compound of any one of claims 1-34, wherein R4is each independently selected from the group consisting of halo, C1-C6alkyl, and C1-C6alkoxy.

36. The compound of any one of claims 1-35, wherein R4is each independently selected from the group consisting of fluoro, chloro, methyl, and methoxy.

37. The compound of any one of claims 1-36, wherein R5is selected from the group consisting of C1-C6alkyl optionally substituted with C3-C4cycloalkyl, C1-C4alkyl-C3-C4cycloalkyl optionally substituted with C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, H, and phenyl, wherein the C3-C6cycloalkyl or phenyl is each optionally substituted with 1-2 halo, amine, or methyl or wherein the 4-6 membered heterocyclyl is optionally substituted with 1-2 oxo, 1-2 halo, or methyl.

38. The compound of any one of claims 1-36, wherein R5is selected from the group consisting of C1-C6alkyl optionally substituted with C3-C6cycloalkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 5-6 membered N-bound heterocyclyl, H, and phenyl, wherein the C3-C6cycloalkyl or phenyl is each optionally substituted with 1-2 halo or methyl or wherein the 5-6 membered N- bound heterocyclyl is optionally substituted with oxo and 1-2 halo or methyl.

39. The compound of any one of claims 1-36, wherein R5is selected from the group consisting of C3-C6alkyl, C1-C2alkyl substituted with C3-C4cycloalkyl, C2-C4haloalkyl, C3-C4cycloalkyl, 5-6 membered N-bound heterocyclyl, and phenyl, wherein the C3-C4cycloalkyl or phenyl is each optionally substituted with 1-2 halo or methyl or wherein the 5-6 membered N- bound heterocyclyl is optionally substituted with oxo and 1-2 halo or methyl.

40. The compound of any one of claims 1-36, wherein R5is selected from the group consisting of C1-C2alkyl substituted with C3-C4cycloalkyl, C2-C4haloalkyl, C3-C4cycloalkyl, pyrrolidinone, and phenyl, wherein the C3-C4cycloalkyl or phenyl is each optionally substituted with 1-2 halo or methyl or wherein the pyrrolidinone is optionally substituted with 1-2 halo or methyl.

41. The compound of any one of claims 1-36, wherein R5is selected from the group consisting of C1-C2alkyl substituted with C3-C4cycloalkyl, C2-C4haloalkyl, and C3-C4cycloalkyl, wherein the C3-C4cycloalkyl is each optionally substituted with methyl.

42. The compound of any one of claims 1-36, wherein R5is C3-C6cycloalkyl optionally substituted with methyl.

43. The compound of any one of claims 1-36, wherein R5is C3-C4cycloalkyl substituted with methyl.

44. The compound of any one of claims 1-36, wherein R5is C1-C2alkyl substituted with C3- C4cycloalkyl.

45. The compound of any one of claims 1, 11-14, and 19-36, wherein L1-R5is selected from the group consisting of:.

46. The compound of any one of claims 1, 11-14, and 19-36, wherein L1-R5is selected from the group consisting of:.

47. The compound of any one of claims 1-46, wherein n is 0.

48. The compound of any one of claims 1-46, wherein n is 1.

49. The compound of any one of claims 1-48, wherein m is integer 0-2.

50. The compound of any one of claims 1-49, wherein m is 1 or 2.

51. The compound of any one of claims 1-49, wherein m is 0.

52. The compound of any one of claims 1-49, wherein m is 1.

53. The compound of any one of claims 1-49, wherein m is 2.

54. The compound of any one of claims 1-53, wherein p is integer 0-2.

55. The compound of any one of claims 1-54, wherein p is 1 or 2.

56. The compound of any one of claims 1-54, wherein p is 0.

57. The compound of any one of claims 1-54, wherein p is 1.

58. The compound of any one of claims 1-54, wherein p is 2.

59. A compound selected from the group consisting of: ,,,,,,,,,,, , ,,,,and pharmaceutically acceptable salts, enantiomers, and stereoisomers thereof.

60. A pharmaceutical composition comprising a compound of any one of claims 1-59, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, and at least one pharmaceutically acceptable carrier or diluent.

61. A method of treating an IRE1α mediated disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-59, or a pharmaceutically acceptable salt, enantiomer, orstereoisomer thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 60.

62. A method of treating an IRE1β mediated disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-59, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 60.

63. A method of treating an IRE1α and IRE1β mediated disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-59, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 60.

64. A method of treating diabetes mellitus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-57, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 60.

65. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-59, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 60.

66. The method of claim 65, wherein the cancer is selected from the group consisting of kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophagus cancer, liver cancer, lymphoma, and multiple myeloma.

67. A method of treating a neurodegenerative disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-59, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 60.

68. A method of treating fibrosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-59, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 60.

69. A method of treating a dermatologic disease and disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-59, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 60.

70. A method of treating an autoimmune disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-59, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 60.

71. A method of treating an inflammatory disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-59, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 60.

72. A method of treating a hepatic disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-59, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 60.

73. A method of treating an ophthalmologic disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-59, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 60.

74. A method of treating a renal disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-59, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 60.

75. A method of treating a posterior eye indication in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-59, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 60.

76. A method of treating peripheral neuropathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-59, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 60.

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