MENIN-MLL Interaction Inhibitors

Abstract

The present disclosure is directed to inhibitors of Formula (0), or a stereoisomer thereof, or pharmaceutically acceptable salt thereof, of the interaction of menin with MLL and MLL fusion proteins, pharmaceutical compositions containing the same, and their use in the treatment of cancer and other diseases mediated by the menin-MLL interaction.

Description

[0001] INHIBITORS OF THE MENIN-MLL INTERACTION CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit on U.S. Provisional Application No.63 / 188,704, filed May 14, 2021, which is incorporated by reference herein in its entirety. BACKGROUND The mixed-lineage leukemia (MLL) protein is a histone methyltransferase that is mutated in clinically and biologically distinctive subsets of acute leukemia. Rearranged mixed lineage leukemia (MLL-r) involves recurrent translocations of the 11q23 chromosome locus which lead to an aggressive form of acute leukemia with limited therapeutic options. These translocations target the MLL gene creating an oncogenic fusion protein comprising the amino-terminus of MLL fused in frame with more than 60 different fusion protein partners. Menin, a ubiquitously expressed, nuclear protein encoded by the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene, has a high affinity binding interaction with MLL fusion proteins and is an essential co-factor of oncogenic MLL-r fusion proteins. Disruption of this interaction leads to selective growth inhibition and apoptosis of MLL-r leukemia cells both in vitro and in vivo. The menin-MLL complex plays a role in castration-resistant / advanced prostate cancer, and a menin-MLL inhibitor has been shown to reduce tumor growth in vivo. Additionally, a menin- MLL inhibitor has been shown to enhance human ȕ cell proliferation, supporting a role for inhibitors of the menin-MLL interaction in the treatment of diabetes. The interaction between menin and MLL or MLL fusion proteins is an attractive target for therapeutic intervention, and there is a need for novel agents that inhibit the menin-MLL interaction for the treatment of various diseases and conditions, including leukemia, other cancers and diabetes. Additionally, hERG potassium channels are essential for normal electrical activity in the heart. Inherited mutations in the hERG gene cause long QT syndrome, a disorder that predisposes individuals to life-threatening arrhythmias. Arrhythmia can also be induced by a blockage of hERG channels by a surprisingly diverse group of drugs. This side effect is a common reason for drug failure in preclinical safety trials and compounds displaying low off-target hERG binding are of paramount importance in drug design with significant clinical need. Therefore, in drug development it is extremely important to determine the potential of a candidate compound to block hERG channels, but this property is not easily determined from the structure of the compound and closely related compounds may have vastly different potential to block hERG channels. Therefore, there is an urgent need to develop efficacious compounds that cause minimum blockage of hERG channels. SUMMARY In one aspect, the present disclosure is directed to a compound of Formula 0, Formula (0), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein W, X, Y, R1, R2, R3, R4, and R5 are defined herein. In some aspects, the present application relates to a pharmaceutical composition comprising a compound of the application, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. In some aspects, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the application, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. In some aspects, the present application relates to a pharmaceutical composition comprising a compound of the application, and a pharmaceutically acceptable carrier. In some aspects, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the application, and a pharmaceutically acceptable carrier. The present disclosure further provides a method of inhibiting the interaction between menin and MLL comprising contacting the menin and MLL with a compound of Formulae I, Ia, II, IIa, III, or IIIa, or a stereoisomer, or pharmaceutically acceptable salt thereof. The present disclosure further provides a method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formulae 0, 0a, I, Ia, II, IIa, III, or IIIa, or a stereoisomer, or a pharmaceutically acceptable salt thereof. The present disclosure further provides a method of inhibiting the interaction between menin and MLL comprising contacting the menin and MLL with a compound of Formulae 0, 0a, I, Ia, II, IIa, III, or IIIa. The present disclosure further provides a method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formulae 0, 0a, I, Ia, II, IIa, III, or IIIa. The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, illustrative methods and materials are now described. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. The references cited herein are not admitted to be prior art to the application. DETAILED DESCRIPTION In one aspect, the present disclosure is directed to a compound of Formula 0,

[0002] a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein W is N or CH; X is C=O, S(=O)(=NR5), or S(=O)2;Y is NH, O, or a bond; R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C12cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R1 and R2 optionally form a 3- to 12-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more C1-C6alkyl, halo, OH, CN, or C1-C6alkoxy; R3is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C12cycloalkyl, NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, C6-C10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or aryl; R4is H, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, or N(RN)2; each RNis independently H, C1-C6alkyl, or C1-C6haloalkyl; and each R5 is independently H, C1-C6 alkyl, or C1-C6 haloalkyl. Formula (0a), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein W is N or CH; X is C=O, S(=O)(=NR5), or S(=O)2;Y is NH, O, or a bond; R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C12cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R1 and R2 optionally form a 3- to 12-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more C1-C6alkyl, halo, OH, CN, or C1-C6alkoxy; R3is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C12cycloalkyl, NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, C6-C10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or aryl; R4 is H, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or N(RN)2; each RNis independently H, C1-C6alkyl, or C1-C6haloalkyl; and each R5is independently H, C1-C6alkyl, or C1-C6haloalkyl. I h di l i di d d f F l I Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is C=O, S(=O)(=NR5), or S(=O)2;Y is NH, O, or a bond; R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C12cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R1 and R2 optionally form a 3- to 12-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more C1-C6alkyl, halo, OH, CN, or C1-C6alkoxy; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, C6-C10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or aryl; R4 is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; each RNis independently H, C1-C6alkyl, or C1-C6haloalkyl; and each R5 is independently H, C1-C6 alkyl, or C1-C6 haloalkyl. In one aspect, the present disclosure is directed to a compound of Formula Ia, Formula (Ia), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is C=O, S(=O)(=NR5), or S(=O)2; Y is NH, O, or a bond; R1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C12cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy; R1and R2optionally form a 3- to 12-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more C1-C6 alkyl, halo, OH, CN, or C1-C6 alkoxy; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, NH2, NH-C1-C6alkyl, N-(C1-C6alkyl)2, C6-C10aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6 alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C1-C6alkoxy, or aryl; R4is H, halo, C1-C6alkyl, or C1-C6haloalkyl; each RN is independently H, C1-C6 alkyl, or C1-C6 haloalkyl; and each R5 is independently H, C1-C6 alkyl, or C1-C6 haloalkyl. In one aspect, the present disclosure is directed to a compound of Formula II, Formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C12cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R1 and R2 optionally form a 3- to 12-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more C1-C6alkyl, halo, OH, CN, or C1-C6alkoxy; R3is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C12cycloalkyl, NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, C6-C10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or aryl; and each RN is independently H, C1-C6 alkyl, or C1-C6 haloalkyl; and In one aspect, the present disclosure is directed to a compound of Formula IIa, Formula (IIa), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C12cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy; R1 and R2 optionally form a 3- to 12-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more C1-C6 alkyl, halo, OH, CN, or C1-C6 alkoxy; R3is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C12cycloalkyl, NH2, NH-C1-C6alkyl, N-(C1-C6alkyl)2, C6-C10aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C1-C6alkoxy, or aryl; and each RN is independently H, C1-C6 alkyl, or C1-C6 haloalkyl; and In one aspect, the present disclosure is directed to a compound of Formula III, Formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C12cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R1 and R2 optionally form a 3- to 12-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more C1-C6 alkyl, halo, OH, CN, or C1-C6 alkoxy; R6is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C12cycloalkyl, C6- C10aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C1- C6alkoxy, or aryl; and each RN is independently H, C1-C6 alkyl, or C1-C6 haloalkyl; and In one aspect, the present disclosure is directed to a compound of Formula IIIa, Formula (IIIa), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C12cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy; R1 and R2 optionally form a 3- to 12-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more C1-C6alkyl, halo, OH, CN, or C1-C6alkoxy; R6 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6- C10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, N(RN)2, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C1- C6 alkoxy, or aryl; and each RNis independently H, C1-C6alkyl, or C1-C6haloalkyl; and Embodiments For any of Formulae 0, 0a, I, Ia, II, IIa, III, or IIIa where applicable, the following embodiments are considered both alone and in conjunction with another where a stable compound is formed. In some embodiments, X is C=O, S(=O)(=NR5), or S(=O)2. In some embodiments, X is C=O. In some embodiments, X is S(=O)(=NR5). In some embodiments, X is S(=NR5)2. In some embodiments, when X is each R5 is independently selected and can be the same or different. In some embodiments, X is S(=O)2. In some embodiments, X is C=O, or S(=O)2. In some embodiments, X is C=O, S(=O)(=NR5), or S(=O)2. In some embodiments, X is S(=O)(=NR5), or S(=O)2. In some embodiments, Y is NH. In some embodiments, Y is O. In some embodiments, Y is a bond. In some embodiments, Y is absent. In some embodiments, Y being a bond or absent means that R3is directly connected to X. In some embodiments, Y being a bond or absent means that R6 is directly connected to X. In some embodiments, R1 is C1-C6 alkyl. In some embodiments, R1 is C1-C5 alkyl. In some embodiments, R1 is C1-C4 alkyl. In some embodiments, R1 is C1-C3 alkyl. In some embodiments, R1is C1-C2alkyl. In some embodiments, R1is methyl. In some embodiments, R1is ethyl. In some embodiments, R1is propyl. In some embodiments, R1is isopropyl. In some embodiments, R1 is butyl. In some embodiments, R1 is tert-butyl. In some embodiments, R1is methyl substituted with cyclopropane. In some embodiments, R1is methyl substituted with cyclobutene. In some embodiments, R1is methyl substituted with methoxy. In some embodiments, R1 is ethyl substituted with methoxy. In some embodiments, R1 is methyl, substituted with one or more halo. In some embodiments, R1 is methyl substituted with 1 halo, with 2 halo, or with 3 halo. In some embodiments, R1is ethyl, substituted with one or more halo. In some embodiments, R1 is ethyl substituted with 1 halo, with 2 halo, or with 3 halo. In some embodiments, R1 is -CH2-CHF2. In some embodiments, R1is ethyl, substituted with 2 halo atoms. In some embodiments, R1is ethyl, substituted with 3 halo atoms. In some embodiments, R1is ethyl substituted by 1 fluorine atoms. In some embodiments, R1 is ethyl substituted by 2 fluorine atoms. In some embodiments, R1is ethyl substituted by 3 fluorine atoms. In some embodiments, R1is -CH2-CF3. In some embodiments, R1is -CF2-CF3. In some embodiments, R1is difluoroethyl. In some embodiments, R1 is cyclopropyl. In some embodiments, R1 is cyclobutyl. In some embodiments, R1is oxetanyl. In some embodiments, R1is 2-oxetanyl. In some embodiments, R1is 3-oxetanyl. In some embodiments, R1 is C2-C6 alkyl, wherein alkyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. In some embodiments, R1is C3-C6alkyl, wherein alkyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. In some embodiments, R1 is C1-C5 alkyl, wherein alkyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy. In some embodiments, R1is C2-C5alkyl, wherein alkyl is optionally substituted by one or more halo OH OBn oxo CN C C alkyl C C haloalkyl C C cycloalkyl or C C alkoxy In some embodiments, R1 is C3-C5 alkyl, wherein alkyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. In some embodiments, R1is C1-C4alkyl, wherein alkyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. In some embodiments, R1 is C2-C4 alkyl, wherein alkyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy. In some embodiments, R1is C3-C4alkyl, wherein alkyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. In some embodiments, R1is C1alkyl, wherein alkyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy. In some embodiments, R1 is C2 alkyl, wherein alkyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. In some embodiments, R1is C3alkyl, wherein alkyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. In some embodiments, R1 is C3-C6 cycloalkyl, wherein cycloalkyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy. In some embodiments, R1is C3-cycloalkyl, wherein cycloalkyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. In some embodiments, R1is C4-cycloalkyl, wherein cycloalkyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. In some embodiments, R1is C5-cycloalkyl, wherein cycloalkyl is optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. In some embodiments, R1is 4-, 5- or 6-membered heterocyclyl with 1 or 2 heteroatoms each selected from N or O, wherein the heterocyclyl optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. In some embodiments, R1is 4- or 5-membered heterocyclyl with 1 or 2 heteroatoms each selected from N or O, wherein the heterocyclyl optionally substituted by one or more halo, OH, OBn oxo CN C C alkyl C C haloalkyl C C cycloalkyl or C C alkoxy In some embodiments, R1 is 5- or 6-membered heterocyclyl with 1 or 2 heteroatoms each selected from N or O, wherein the heterocyclyl optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy. In some embodiments, R1 is 4-membered heterocyclyl with 1 or 2 heteroatoms each selected from N or O, wherein the heterocyclyl optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy. In some embodiments, R1is 5-membered heterocyclyl with 1 or 2 heteroatoms each selected from N or O, wherein the heterocyclyl optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or C1-C6alkoxy. In some embodiments, R1is 6-membered heterocyclyl with 1 or 2 heteroatoms each selected from N or O, wherein the heterocyclyl optionally substituted by one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. In some embodiments, R1is C1-C6alkyl or C3-C6cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by one or more halo, OH, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. In some embodiments, R1 is C1-C6 alkyl or 4-, 5- or 6-membered heterocyclyl with 1 or 2 heteroatoms each selected from N or O, wherein the alkyl or heterocyclyl is optionally substituted by one or more halo, OH, oxo, CN, C1-C6alkyl, C1-C6haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy. In some embodiments, R1is C3-C6cycloalkyl or 4-, 5- or 6-membered heterocyclyl with 1 or 2 heteroatoms each selected from N or O, optionally substituted by one or more halo, C1-C6alkoxy or CN. In some embodiments, R1is C2-C6alkenyl. In some embodiments, R1is C2-C6alkynyl. In some embodiments, R1is C1-C6alkoxy. In some embodiments, R1is C1-C6alkoxy substituted with one, with two, or with three halo. In some embodiments, R1 is C3-C12 cycloalkyl. In some embodiments, R1 is C3-C6 cycloalkyl. In some embodiments, R1 is C3-C5 cycloalkyl. In some embodiments, R1is C3-C4cycloalkyl. In some embodiments, R1 is C3-C12 cycloalkyl substituted with one, with two or with three halo. In some embodiments, R1 is C3-C6 cycloalkyl substituted with one, with two or with three halo. In some embodiments, R1is C3-C5cycloalkyl substituted with one, with two or with three halo. In some embodiments, R1is C3-C4cycloalkyl substituted with one, with two or with three halo In some embodiments R is C C cycloalkyl substituted with C C haloalkyl In some embodiments, R1 is C3-C4 cycloalkyl substituted with C1-C6 haloalkyl. In some embodiments, R1 is cyclopropyl substituted with C1-C6 haloalkyl. In some embodiments, R1 is cyclobutyl substituted with C1-C6haloalkyl. In some embodiments, R1is cyclobutyl substituted with CHF2. In some embodiments, R1 is cis-cyclobutyl substituted with CHF2. In some embodiments, R1 is trans- cyclobutyl substituted with CHF2. In some embodiments, R1 is cyclobutyl substituted with CF3. In some embodiments, R1is cis-cyclobutyl substituted with CF3. In some embodiments, R1is trans- cyclobutyl substituted with CF3. In some embodiments, R1is cyclobutyl substituted with halo. In some embodiments, R1 is cis-cyclobutyl substituted with halo. In some embodiments, R1 is trans- cyclobutyl substituted with halo. In some embodiments, R1is cyclobutyl substituted with fluorine. In some embodiments, R1is cis-cyclobutyl substituted with fluorine. In some embodiments, R1is trans-cyclobutyl substituted with fluorine. In some embodiments, R1 is trans-cyclobutyl substituted with OH. In some embodiments, R1 is cyclobutyl substituted with OH. In some embodiments, R1is cis-cyclobutyl substituted with OH. In some embodiments, R1is trans- cyclobutyl substituted with 3-OH. In some embodiments, R1 is cyclobutyl substituted with 3-OH. In some embodiments, R1 is cis-cyclobutyl substituted with 3-OH. In some embodiments, R1is oxabicyclo[3.1.0]hexan-6-yl. In some embodiments, R1is 2-oxaspiro[3.3]heptan-6-yl. In some embodiments, R1 is oxabicyclo[2.2.1]heptan-2-yl. In some embodiments, R1is oxetanyl. In some embodiments, R1is tetrahydro-2H-pyran-4-yl. In some embodiments, R1 is 3-hydroxycyclobutyl. In some embodiments, R1is 3,3-difluorocyclobutyl. In some embodiments, R1is (E1)-2-hydroxycyclobutyl. In some embodiments, R1 is (E2)-2-hydroxycyclobutyl. In some embodiments, R1 is (1R,2S)-2-hydroxycyclobutyl. In some embodiments, R1is (1r,3r)-3-hydroxycyclobutyl. In some embodiments, R1 is (3R,5R)-3,5-dimethylmorpholinyl. In some embodiments, R1 is (R)-tetrahydrofuran-3-yl. In some embodiments, R1is (S)-tetrahydrofuran-3-yl. In some embodiments, R1is cyanomethyl. In some embodiments R is 2 cyanoethyl In some embodiments, R1 is (1r,3r)-3-fluorocyclobutyl. In some embodiments, R1 is (1s,3s)-3-fluorocyclobutyl. In some embodiments, R1is (1r,3r)-3-(difluoromethyl)cyclobutyl. In some embodiments, R1 is (1s,3s)-3-(difluoromethyl)cyclobutyl. In some embodiments, R1 is C6-C10 aryl. In some embodiments, R1 is C6 aryl. In some embodiments, R1is C6-C10aryl substituted with one, with two or with three halo. In some embodiments, R1is C6aryl substituted with one, with two or with three halo. In some embodiments, R1 is 5- to 10-membered heteroaryl. In some embodiments, R1 is 5- to 7-membered heteroaryl. In some embodiments, R1is 5- to 6-membered heteroaryl. In some embodiments, R1is 5-membered heteroaryl with 2 heteroatoms selected from N, O, and S. In some embodiments, R1is 6-membered heteroaryl with 2 heteroatoms selected from N, O, and S. In some embodiments, R1 is 5-membered heteroaryl with 2 nitrogen heteroatoms. In some embodiments, R1 is 6- membered heteroaryl with 2 nitrogen heteroatoms. In some embodiments, R1is 5-membered heteroaryl with 1 heteroatom selected from N, O, and S. In some embodiments, R1 is 6-membered heteroaryl with 1 heteroatom selected from N, O, and S. In some embodiments, R1 is 3- to 10- membered heterocyclyl. In some embodiments, R1is 3- to 9-membered heterocyclyl. In some embodiments, R1is 3- to 8-membered heterocyclyl. In some embodiments, R1 is 3- to 7-membered heterocyclyl. In some embodiments, R1is 3- to 6-membered heterocyclyl. In some embodiments, R1is 3- to 5- membered heterocyclyl. In some embodiments, R1is 3-membered heterocyclyl. In some embodiments, R1 is 4-membered heterocyclyl. In some embodiments, R1 is 3-membered heterocyclyl, optionally substituted with one, with two or with three halo. In some embodiments, R1is 4-membered heterocyclyl, optionally substituted with one, with two or with three halo. In some embodiments, R1 is 5-membered heterocyclyl, optionally substituted with one, with two or with three halo. In some embodiments, R1 is 6-membered heterocyclyl, optionally substituted with one, with two or with three halo. In some embodiments, R1is 3-membered heterocyclyl, substituted with one, with two or with three halo. In some embodiments, R1 is 4-membered heterocyclyl, substituted with one, with two or with three halo. In some embodiments, R1 is 5- membered heterocyclyl, substituted with one, with two or with three halo. In some embodiments, R1is 6-membered heterocyclyl, substituted with one, with two or with three halo. In some embodiments, R1 is oxetanyl. In some embodiments, R1 is 2-oxetanyl. In some embodiments, R1 is 3-oxetanyl. In some embodiments, R1 is oxetanyl, optionally substituted with haloalkyl. In some embodiments, R1is oxetanyl, optionally substituted with -CHF2. In some embodiments, R1 is oxetanyl, optionally substituted with -CF3. In some embodiments, R1 is 2- oxetanyl, optionally substituted with haloalkyl. In some embodiments, R1 is 2-oxetanyl, optionally substituted with -CHF2. In some embodiments, R1is 2-oxetanyl, optionally substituted with -CF3.In some embodiments, R1is 3-oxetanyl, optionally substituted with haloalkyl. In some embodiments, R1 is 3-oxetanyl, optionally substituted with -CHF2. In some embodiments, R1 is 3- oxetanyl, optionally substituted with -CF3. In some embodiments, R1is tetrahydrofuranyl. In some embodiments, R1is 2-tetrahydrofuranyl. In some embodiments, R1is 3- tetrahydrofuranyl. In some embodiments, R1 is tetrahydrofuranyl, optionally substituted with haloalkyl. In some embodiments, R1 is tetrahydrofuranyl, optionally substituted with -CHF2. In some embodiments, R1is tetrahydrofuranyl, optionally substituted with -CF3. In some embodiments, R1is 2- tetrahydrofuranyl, optionally substituted with haloalkyl. In some embodiments, R1 is 2- tetrahydrofuranyl, optionally substituted with -CHF2. In some embodiments, R1 is 2- tetrahydrofuranyl, optionally substituted with -CF3. In some embodiments, R1is 3- tetrahydrofuranyl, optionally substituted with haloalkyl. In some embodiments, R1is 3- tetrahydrofuranyl, optionally substituted with -CHF2. In some embodiments, R1 is 3- tetrahydrofuranyl, optionally substituted with -CF3. In some embodiments, R1is a 7-10 membered spirocyclic heterocycyl. In some embodiments, R1is a 7 membered spirocyclic heterocycyl. In some embodiments, R1 is a 7 membered bicyclic heterocycyl. In some embodiments, R1 is a 2- oxaspiro[3.3]heptanyl. In some embodiments, R1and R2form a 4-, 5- or 6- membered heterocyclyl with 1 or 2 heteroatoms each selected from N, O, or S, wherein the heterocyclyl is optionally substituted by one or more alkyl groups. In some embodiments, R1 and R2 form a 5-membered heterocyclyl with 1 or 2 heteroatoms each selected from N, O, or S, wherein the heterocyclyl is optionally substituted by one or more alkyl groups. In some embodiments, R1 and R2 form a 5-membered heterocyclyl with 1 heteroatom selected from N, O, or S, wherein the heterocyclyl is optionally substituted by one or more alkyl groups. In some embodiments, R1and R2form a 5-membered heterocyclyl with 2 heteroatoms each selected from N, O, or S, wherein the heterocyclyl is optionally substituted by one or more alkyl groups In some embodiments R and R form a 6 membered heterocyclyl with 1 or 2 heteroatoms each selected from N, O, or S, wherein the heterocyclyl is optionally substituted by one or more alkyl groups. In some embodiments, R1 and R2form a 6-membered heterocyclyl with 1 heteroatom selected from N, O, or S, wherein the heterocyclyl is optionally substituted by one or more alkyl groups. In some embodiments, R1 and R2 form a 6-membered heterocyclyl with 2 heteroatoms each selected from N or O, wherein the heterocyclyl is optionally substituted by one or more alkyl groups. In some embodiments, R1and R2form a 4-, 5- or 6- membered heterocyclyl with 1 or 2 heteroatoms each selected from N or O, wherein the heterocyclyl is substituted by two alkyl groups. In some embodiments, R1 and R2 form a 5-membered heterocyclyl with 1 or 2 heteroatoms each selected from N or O, wherein the heterocyclyl is substituted by two alkyl groups. In some embodiments, R1and R2form a 5- membered heterocyclyl with 1 heteroatom selected from N or O, wherein the heterocyclyl is substituted by two alkyl groups. In some embodiments, R1 and R2 form a 5-membered heterocyclyl with 2 heteroatoms each selected from N or O, wherein the heterocyclyl is substituted by two alkyl groups. In some embodiments, R1 and R2 form a 6-membered heterocyclyl with 1 or 2 heteroatoms each selected from N or O, wherein the heterocyclyl is substituted by two alkyl groups. In some embodiments, R1and R2form a 6-membered heterocyclyl with 1 heteroatom selected from N or O, wherein the heterocyclyl is substituted by two alkyl groups. In some embodiments, R1 and R2 form a 6-membered heterocyclyl with 2 heteroatoms each selected from N or O, wherein the heterocyclyl is substituted by two alkyl groups. In some embodiments, R3is C1-C6alkyl, C3-C6cycloalkyl, NH-C1-C6alkyl, N-(C1-C6alkyl)2, phenyl, 3-6 membered heterocyclyl with 1 or 2 heteroatoms each selected from N, O, or S, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted by C1-C6alkyl, or C1-C6alkoxy. In some embodiments, R3is C1-C6alkyl, wherein alkyl is optionally substituted by C3-C6cycloalkyl or C1-C6 alkoxy. In some embodiments, R3 is C1-C6 alkyl, wherein alkyl is optionally substituted by C3-C6 cycloalkyl. In some embodiments, R3 is C1-alkyl, wherein alkyl is optionally substituted by C3-cycloalkyl. In some embodiments, R3is C2-alkyl, wherein alkyl is optionally substituted by C3-cycloalkyl. In some embodiments, R3 is C3-alkyl, wherein alkyl is optionally substituted by C3-cycloalkyl. In some embodiments, R3 is C4-alkyl, wherein alkyl is optionally substituted by C3-cycloalkyl. In some embodiments, R3is C5-alkyl, wherein alkyl is optionally substituted by C3-cycloalkyl. In some embodiments, R3is C6-alkyl, wherein alkyl is optionally substituted by C cycloalkyl In some embodiments R is C C alkyl wherein alkyl is optionally substituted by C3-cycloalkyl. In some embodiments, R3 is C1-C3 alkyl, wherein alkyl is optionally substituted by C3-cycloalkyl. In some embodiments, R3 is C1-C4 alkyl, wherein alkyl is optionally substituted by C3-cycloalkyl. In some embodiments, R3is C1-C5alkyl, wherein alkyl is optionally substituted by C3-cycloalkyl. In some embodiments, R3 is C1-C6 alkyl, wherein alkyl is optionally substituted by C3-cycloalkyl. In some embodiments, R3 is C1-C6 alkyl, wherein alkyl is optionally substituted by C1-alkoxy. In some embodiments, R3is C1-C6alkyl, wherein alkyl is optionally substituted by C1-C6alkoxy. In some embodiments, R3is C1-C6alkyl, wherein alkyl is optionally substituted by C1-C6 alkoxy. In some embodiments, R3 is C3-C6 cycloalkyl, wherein cycloalkyl is optionally substituted by C3-C6cycloalkyl or C1-C6alkoxy. In some embodiments, R3is C3-C6- heterocyclyl with 1 or 2 heteroatoms each selected from N or O, wherein the heterocyclyl is optionally substituted by C3-C6 cycloalkyl or C1-C6 alkoxy. In some embodiments, R1 and R2 together form a morpholino ring, optionally substituted with one or more C1-C6 alkyl. In some embodiments, R1and R2together form a 3,5-dimethylmorpholino ring. In some embodiments, R1is ethyl, optionally substituted by one or more halo or C1-C6 alkoxy, and R2 is iso-propyl, optionally substituted by one or more halo or C1-C6 alkoxy. In some embodiments, R1is isopropyl, optionally substituted by one or more halo or C1- C6alkoxy, and R2is isopropyl, optionally substituted by one or more halo or C1-C6alkoxy. In some embodiments, R1 is tetrahydrofuranyl and R2 is isopropyl. In some embodiments, R1 is tetrahydrofuranyl and R2is ethyl. In some embodiments, R1is cyclopropyl and R2is isopropyl. In some embodiments, R1is cyclopropyl and R2is ethyl. In some embodiments, R1and R2together form a methylmorpholino ring. In some embodiments, R1 and R2 together form a (3R,5R)-3,5- dimethylmorpholine ring. In some embodiments, R1and R2together form a (3S,5R)-3,5- dimethylmorpholine ring. In some embodiments, R1and R2together form a (3R,5S)-3,5- dimethylmorpholine ring. In some embodiments, R1 and R2 together form a (3S,5S)-3,5- dimethylmorpholine ring. In some embodiments, R2is methyl. In some embodiments, R2is ethyl. In some embodiments, R2 is propyl. In some embodiments, R2 is isopropyl. In some embodiments, R2 is butyl. In some embodiments, R2 is tert-butyl. In some embodiments, R2 is methyl substituted with cyclopropane. In some embodiments, R2is methyl substituted with cyclobutene. In some embodiments, R2is CH2-O-OH3. In some embodiments, R2is ethyl substituted with methoxy. In some embodiments R is ethyl substituted with one or more halo In some embodiments R is ethyl substituted with 1 halo, with 2 halo, or with 3 halo. In some embodiments, R2 is -CH2-CHF2. In some embodiments, R2 is ethyl, substituted with 2 halo. In some embodiments, R2 is ethyl, substituted with 3 halo. In some embodiments, R2is ethyl substituted by 1 fluorine. In some embodiments, R2 is ethyl substituted by 2 fluorine. In some embodiments, R2 is ethyl substituted by 3 fluorine. In some embodiments, R2 is -CH2-CF3. In some embodiments, R2 is propyl, substituted with 2 halo. In some embodiments, R2is propyl, substituted with 3 halo. In some embodiments, R2is propyl substituted by 1 fluorine. In some embodiments, R2is propyl substituted by 2 fluorine. In some embodiments, R2 is propyl substituted by 3 fluorine. In some embodiments, R2is isopropyl, substituted with 2 halo. In some embodiments, R2is isopropyl, substituted with 3 halo. In some embodiments, R2is isopropyl substituted by 1 fluorine. In some embodiments, R2 is isopropyl substituted by 2 fluorine. In some embodiments, R2 is isopropyl substituted by 3 fluorine. In some embodiments, R2 is cyclopropyl. In some embodiments, R2 is cyclobutyl. In some embodiments, R2is oxetanyl. In some embodiments, R2is 2-oxetanyl or 3- oxetanyl. In some embodiments, R2 is tetrahydrofunanyl. In some embodiments, R1 and R2 are the same. In some embodiments, R1 and R2 are different. In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3 is propyl. In some embodiments, R3 is isopropyl. In some embodiments, R3 is butyl. In some embodiments, R3is tert-butyl. In some embodiments, R3is methyl substituted with cyclopropane. In some embodiments, R3is methyl substituted with cyclobutene. In some embodiments, R3 is CH2-O-OH3. In some embodiments, R3 is ethyl substituted with methoxy. In some embodiments, R3is ethyl, substituted with one or more halo. In some embodiments, R3is ethyl substituted with 1 halo, with 2 halo, or with 3 halo. In some embodiments, R3is -CH2-CHF2. In some embodiments, R3 is ethyl, substituted with 2 halo. In some embodiments, R3 is ethyl, substituted with 3 halo. In some embodiments, R3 is ethyl substituted by 1 fluorine. In some embodiments, R3is ethyl substituted by 2 fluorine. In some embodiments, R3is ethyl substituted by 3 fluorine. In some embodiments, R3 is -CH2-CF3. In some embodiments, R3 is cyclopropyl. In some embodiments, R3 is dialkyl amino. In some embodiments, R3 is dimethylamino. In some embodiments, R3is a NH-C1-C6alkyl. In some embodiments, R3is a NH-C1-C3alkyl. In some embodiments, R3is a NH-C1-C2alkyl. In some embodiments, R3is a NH-methyl. In some embodiments R is a NH ethyl In some embodiments R is a NH propyl In some embodiments R3 is a NH-i-propyl. In some embodiments, R3 is a NH-butyl. In some embodiments, R3 is a NH- i-butyl. In some embodiments, R3 is a NH-sec-butyl. In some embodiments, R3 is a NH-t-butyl. In some embodiments, R3is a 4-membered heterocyclyl. In some embodiments, R3is a 4- membered N-heterocycle. In some embodiments, R3 is an azetane. In some embodiments, R3 is a N-azetane. In some embodiments, R3 is a 5-membered heterocyclyl, optionally substituted with C1-C6alkyl. In some embodiments, R3is a 6-membered heterocyclyl, optionally substituted with C1-C6alkyl. In some embodiments, R3is a morpholinyl. In some embodiments, R3is an N- morpholinyl. In some embodiments, R3 is a 2-oxaspiro[3.3]heptanyl. In some embodiments, R3is a 5-membered heteroaryl, optionally substituted with C1-C6alkyl. In some embodiments, R3is a 6-membered heteroaryl, optionally substituted with C1-C6alkyl. In some embodiments, R3 is a 5-membered heterocycle, optionally substituted with methyl. In some embodiments, R3 is a 6-membered heterocycle, optionally substituted with methyl. In some embodiments, R3is a 5-membered heteroaryl, optionally substituted with methyl. In some embodiments, R3 is a 6-membered heteroaryl, optionally substituted with methyl. In some embodiments, R3 is a diazolyl, optionally substituted with C1-C6 alkyl. In some embodiments, R3 is a pyrazolyl ring, optionally substituted with C1-C6alkyl. In some embodiments, R3is a diazolyl, optionally substituted with one or more methyl. In some embodiments, R3is a diazolyl, optionally substituted with one or more C1-C6 alkyl. In some embodiments, R3 is a diazolyl, optionally substituted with a methyl and an ethyl. In some embodiments, R3is a diazolyl, optionally substituted with a heterocyclic N-C1-C6alkyl. In some embodiments, R3is a diazolyl, optionally substituted with a heterocyclic N-C1-C2 alkyl. In some embodiments, R3is 5- to 10-membered heteroaryl. In some embodiments, R3is 5- to 7-membered heteroaryl. In some embodiments, R3is 5- to 6-membered heteroaryl. In some embodiments, R3 is 5-membered heteroaryl with 2 heteroatoms selected from N, O, and S. In some embodiments, R3 is 6-membered heteroaryl with 2 heteroatoms selected from N, O, and S. In some embodiments, R3is 5-membered heteroaryl with 2 nitrogen heteroatoms. In some embodiments, R3 is 6-membered heteroaryl with 2 nitrogen heteroatoms. In some embodiments, R3 is 5-membered heteroaryl with 1 heteroatom selected from N, O, and S. In some embodiments, R3is 6-membered heteroaryl with 1 heteroatom selected from N, O, and S. In some embodiments, R3is 3- to 10-membered heterocyclyl. In some embodiments, R3 is a diazoyl ring, optionally substituted with methyl. In some embodiments, R3 is a pyrazolyl ring, optionally substituted with methyl. In some embodiments, R3 is a diazoyl ring, substituted with -CHF2. In some embodiments, R3is a pyrazolyl ring, substituted with -CHF2. In some embodiments, R3 is a pyrazolyl ring, substituted with N-methyl. In some embodiments, R3 is a diazoyl ring, substituted with N-methyl. In some embodiments, R3 is a pyrazolyl ring, substituted with N-CHF2. In some embodiments, R3is a diazoyl ring, substituted with N-CHF2. In some embodiments, R3is a 1-methyl-1H-pyrazolyl. In some embodiments, R3is a 1-methyl-1H-pyrazolyl, connected at the 3-position. In some embodiments, R3 is a 1-methyl- 1H-pyrazolyl, connected at the 4 position. In some embodiments, R3is a 1-methyl-1H-pyrazolyl connected at the 5-position. In some embodiments, R3is an oxa-6-azaspiro[3.3]heptane. In some embodiments, R3 is an azaspiro[3.3]heptane. In some embodiments, R3 is an azaspiro[3.3]heptane with an oxygen heteroatom in the ring. In some embodiments, R3is cyclobutyl. In some embodiments, R3is oxetanyl. In some embodiments, R3 is 2-oxetanyl or 3-oxetanyl. In some embodiments, R3 is tetrahydrofunanyl. In some embodiments, R3 is aryl, wherein the aryl is optionally substituted. In some embodiments, R3is phenyl. In some embodiments, R3is pyrazolyl. In some embodiments, R3 is 1-methyl-1H-pyrazolyl. In some embodiments, R3is thiazolyl. In some embodiments, R3is 2-methylthiazolyl. In some embodiments, R3 is morpholinyl. In some embodiments, R3is tetrahydro-2H-pyranyl. In some embodiments, R3is azetidinyl. In some embodiments, R3 is 3,3-difluoroazetidiyl. In some embodiments, R3 is oxazolyl. In some embodiments, R3is 2-methyloxazolyl. In some embodiments, R3 is 3-methyloxazolyl. In some embodiments, R3 is 4-methyloxazolyl. In some embodiments, R3is 1-methyl-6-oxo-1,6-dihydropyridinyl. In some embodiments, R3is 4-methyl-6-oxo-1,6-dihydropyridinyl. In some embodiments R is 5 chloro 1 methyl 1H pyrazolyl In some embodiments, R3 is 1-cyclopropyl-1H-pyrazolyl. In some embodiments, R3 is 1-(difluoromethyl)-1H-pyrazolyl. In some embodiments, R3is N-isopropyl-N-methyl. In some embodiments, R3 is 1,5-dimethyl-1H-pyrazolyl. In some embodiments, R3 is 1-ethyl-1H-pyrazolyl. In some embodiments, R3is tetrahydro-2H-pyran-3-yl. In some embodiments, R3is (R)-2-methylpyrrolidinyl. In some embodiments, R3 is (S)-2-methoxypyrrolidinyl. In some embodiments, R3is (R)-2-methoxypyrrolidinyl. In some embodiments, R3is (S)-2-methylpyrrolidinyl. In some embodiments, R3 is (R)-3-methylpyrrolidinyl. In some embodiments, R3 is (S)-3-methylpyrrolidinyl. In some embodiments, R3is (R)-3-methoxypyrrolidinyl. In some embodiments, R3 is (S)-3-methoxypyrrolidinyl. In some embodiments, R3 is (R)-2-(methoxymethyl)pyrrolidinyl. In some embodiments, R3is (S)-2-(methoxymethyl)pyrrolidinyl. In some embodiments, R3is N-(3-hydroxypropyl)-N-methyl. In some embodiments, R3 is 2-methyl-6-oxo-1,6-dihydropyridinyl. In some embodiments, R3is 5-methyl-6-oxo-1,6-dihydropyridinyl. In some embodiments, R3is 2,7-diazaspiro[3.5]nonan-2-yl. In some embodiments, R3 is 2-oxa-6-azaspiro[3.3]heptanyl. In some embodiments, R3is 6-oxa-2-azaspiro[3.4]octanyl. In some embodiments, R3is hexahydro-1H-furo[3,4-c]pyrrolyl. In some embodiments, R3 is 3-(benzyloxy)azetidinyl. In some embodiments, R3 is 3-hydroxyazetidinyl. In some embodiments, R3is N-(2-hydroxyethyl)-N-methyl. In some embodiments, R3 is 4-fluoro-1-methyl-1H-pyrazolyl. In some embodiments, R3 is a diazoyl ring, optionally substituted with cyclopropyl. In some embodiments, R3is a pyrazolyl ring, optionally substituted with cyclopropyl. In some embodiments, R3is a thiazolyl. In some embodiments, R3is a thiazolyl optionally substituted In some embodiments R is a thiazolyl optionally substituted with a methyl group In some embodiments, R3 is a thiazolyl optionally substituted with a 2-methyl group. In some embodiments, R3 is a phenyl. In some embodiments, R3 is tolyl. In some embodiments, R3 is ortho- tolyl. In some embodiments, R3is meta-tolyl. In some embodiments, R3is para-tolyl. In some embodiments, R3 is a phenyl optionally substituted by a methyl. In some embodiments, R3 is a phenyl optionally substituted by a halo. In some embodiments, R3 is a phenyl optionally substituted by a chloro. In some embodiments, R3is a phenyl optionally substituted by a 2-chloro. In some embodiments, R3is a phenyl optionally substituted by a 3-chloro. In some embodiments, R3is a phenyl optionally substituted by a 4-chloro. In some embodiments, R3 is a pyridyl. In some embodiments, R3is an ortho-pyridyl. In some embodiments, R3is a meta-pyridyl. In some embodiments, R3is a para-pyridyl. In some embodiments, R3is an anisolyl In some embodiments, R3 is an ortho-anisolyl. In some embodiments, R3 is a meta-anisolyl. In some embodiments, R3 is a para-anisolyl. In some embodiments, R3is -CDH-CD3. In some embodiments, R3is -CD2-CHD2. In some embodiments, R3 is -CH2-CD3. In some embodiments, R3 is -CD2-CH3. In some embodiments, R3 is -CD2-CD3. In some embodiments, R3 is -CD2-CD3. In some embodiments, R4is H, halo, or C1-C6alkyl. In some embodiments, R4is H. In some embodiments, R4is halo. In some embodiments, R4is fluorine. In some embodiments, R4is CH3. In some embodiments, R4 is ethyl. In some embodiments, R4 is propyl. In some embodiments, R5is H or C1-C6alkyl. In some embodiments, R5is H. In some embodiments, R5is CH3. In some embodiments, R5is ethyl. In some embodiments, R5is propyl. In some embodiments, X is absent. In some embodiments, Y is absent. In some embodiments, X and Y are both absent. In some embodiments, X and Y are both absent and R3 is H. In some embodiments, R1 is C1-C6 alkyl and R2 is C1-C6 alkyl, wherein the alkyl is optionally substituted with 1, 2 or 3 halogens. In some embodiments, R1 is methyl, ethyl, or propyl, and R2 is methyl, ethyl, or propyl, wherein the methyl, ethyl, or propyl is optionally substituted with 1, 2 or 3 halogens. In some embodiments, R1is C1-3alkyl, and R2is C1-3alkyl, wherein the alkyl is optionally substituted with 2 or 3 fluorine. In some embodiments R is C alkyl and R is ethyl optionally substituted 2 or 3 fluorine In some embodiments, R1 is isopropyl, and R2 is ethyl optionally substituted with 2 or 3 fluorine. In some embodiments, R1is isopropyl, and R2is ethyl substituted with 2 or 3 fluorine. In some embodiments, R1 is isopropyl, and R2 is ethyl substituted with 2 fluorine. In some embodiments, R1 is isopropyl, and R2 is ethyl substituted with 3 fluorine. In some embodiments, R1is C1-C6alkyl, or C3-C12cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1-C6haloalkyl, or C1-C6alkoxy; R2 ethyl, propyl, or isopropyl; R1 and R2 optionally form 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two C1-C6alkyl, or halo; R3is H, C1-C6alkyl, 5- to 6- membered heteroaryl, 3- to 6-membered heterocyclyl, wherein the alkyl, heteroaryl or heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, C1-C6 alkyl, R4 is H; and each R5 is H. In some embodiments, R1is C1-C6alkyl, or C3-C12cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1-C6 haloalkyl, or C1-C6 alkoxy; R2 is ethyl, propyl, or isopropyl; R1 and R2 optionally form 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two C1-C6alkyl, or halo; R3is C1-C6alkyl, 5-membered heteroaryl, 5-membered heterocyclyl, wherein the alkyl, heteroaryl or heterocyclyl is optionally substituted with one or more halo, or C1-C6 alkyl, R4 is H; and each R5 is H. In some embodiments, R1is C1-C6alkyl, or C3-C12cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1-C6haloalkyl, or C1-C6alkoxy; R2 is ethyl, propyl, or isopropyl; R1 and R2 optionally form 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two C1-C6alkyl, or halo; R3is C1-C6alkyl, 5-membered heteroaryl, wherein the alkyl, heteroaryl is optionally substituted with one or more halo, or C1-C6alkyl, R4 is H; and each R5 is H. In some embodiments, R1 is C1-C6 alkyl, or C3-C12 cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1-C6haloalkyl, or C1-C6alkoxy; R2 is ethyl, propyl, or isopropyl; R1 and R2 optionally form 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two methyl groups, or halo; R3 is C1-C6 alkyl, 5- membered heteroaryl, 5-membered heterocyclyl, wherein the alkyl, heteroaryl or heterocyclyl is optionally substituted with one or more halo, or C1-C6alkyl, R4is H; and each R5is H. In some embodiments, R1 is C1-C4 alkyl, or C3-C4 cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1-C6 haloalkyl, or C1-C6 alkoxy; R2is ethyl, propyl, or isopropyl; R1and R2optionally form 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two methyl groups, or halo; R3 is C1-C6 alkyl, 5- membered heteroaryl, 5-membered heterocyclyl, wherein the alkyl, heteroaryl or heterocyclyl is optionally substituted with one or more halo, or C1-C6alkyl, R4is H; and each R5is H. In some embodiments, Y is NH, or a bond; R1is C1-C6alkyl, or C3-C12cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1-C6 haloalkyl, or C1- C6alkoxy; R2ethyl, propyl, or isopropyl; R1and R2optionally form 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two C1-C6alkyl, or halo; R3is H, C1-C6alkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, wherein the alkyl, heteroaryl or heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, C1-C6 alkyl, R4 is H; and each R5is H. In some embodiments, Y is NH; R1 is C1-C6 alkyl, or C3-C12 cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1-C6 haloalkyl, or C1-C6 alkoxy; R2is ethyl, propyl, or isopropyl; R1and R2optionally form 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two C1-C6alkyl, or halo; R3is C1-C6alkyl, 5-membered heteroaryl, 5-membered heterocyclyl, wherein the alkyl, heteroaryl or heterocyclyl is optionally substituted with one or more halo, or C1-C6alkyl, R4is H; and each R5is H. In some embodiments, Y is NH; R1is C1-C6alkyl, or C3-C12cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1-C6 haloalkyl, or C1-C6 alkoxy; R2is ethyl, propyl, or isopropyl; R1and R2optionally form 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two C1-C6alkyl, or halo; R3is C1-C6alkyl, 5-membered heteroaryl, wherein the alkyl, heteroaryl is optionally substituted with one or more halo, or C1-C6 alkyl, R4 is H; and each R5 is H. In some embodiments, Y is NH; R1is C1-C6alkyl, or C3-C12cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1-C6 haloalkyl, or C1-C6 alkoxy; R2 is ethyl, propyl, or isopropyl; R1 and R2 optionally form 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two methyl groups, or halo; R3is C1-C6alkyl, 5- membered heteroaryl, 5-membered heterocyclyl, wherein the alkyl, heteroaryl or heterocyclyl is optionally substituted with one or more halo or C C alkyl R is H; and each R is H In some embodiments, Y is NH; R1 is C1-C4 alkyl, or C3-C4 cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1-C6 haloalkyl, or C1-C6 alkoxy; R2is ethyl, propyl, or isopropyl; R1and R2optionally form 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two methyl groups, or halo; R3 is C1-C6 alkyl, 5- membered heteroaryl, 5-membered heterocyclyl, wherein the alkyl, heteroaryl or heterocyclyl is optionally substituted with one or more halo, or C1-C6alkyl, R4is H; and each R5is H In some embodiments, X is C=O, or S(=O)2;Y is NH, or a bond; R1is C1-C6alkyl, or C3- C12 cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1-C6haloalkyl, or C1-C6alkoxy; R2ethyl, propyl, or isopropyl; R1and R2optionally form 6- membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two C1-C6alkyl, or halo; R3 is H, C1-C6 alkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, wherein the alkyl, heteroaryl or heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, C1-C6alkyl, R4is H; and each R5is H. In some embodiments, X is S(=O)2; Y is NH; R1 is C1-C6 alkyl, or C3-C12 cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1-C6 haloalkyl, or C1-C6alkoxy; R2is ethyl, propyl, or isopropyl; R1and R2optionally form 6- membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two C1-C6alkyl, or halo; R3 is C1-C6 alkyl, 5-membered heteroaryl, 5-membered heterocyclyl, wherein the alkyl, heteroaryl or heterocyclyl is optionally substituted with one or more halo, or C1-C6alkyl, R4is H; and each R5is H. In some embodiments, X is S(=O)2; Y is NH; R1 is C1-C6 alkyl, or C3-C12 cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1-C6haloalkyl, or C1-C6alkoxy; R2is ethyl, propyl, or isopropyl; R1and R2optionally form 6- membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two C1-C6 alkyl, or halo; R3 is C1-C6 alkyl, 5-membered heteroaryl, wherein the alkyl, heteroaryl is optionally substituted with one or more halo, or C1-C6alkyl, R4is H; and each R5is H. In some embodiments, X is S(=O)2; Y is NH; R1 is C1-C6 alkyl, or C3-C12 cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1-C6 haloalkyl, or C1-C6alkoxy; R2is ethyl, propyl, or isopropyl; R1and R2optionally form 6- membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two methyl groups, or halo; R is C C alkyl 5 membered heteroaryl 5 membered heterocyclyl wherein the alkyl heteroaryl or heterocyclyl is optionally substituted with one or more halo, or C1-C6 alkyl, R4 is H; and each R5 is H. In some embodiments, X is S(=O)2;Y is NH; R1is C1-C4alkyl, or C3-C4cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1-C6 haloalkyl, or C1-C6 alkoxy; R2 is ethyl, propyl, or isopropyl; R1 and R2 optionally form 6- membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two methyl groups, or halo; R3is C1-C6alkyl, 5-membered heteroaryl, 5-membered heterocyclyl, wherein the alkyl, heteroaryl or heterocyclyl is optionally substituted with one or more halo, or C1-C6 alkyl, R4 is H; and each R5is H. In some embodiments, W is CH; X is C=O, or S(=O)2;Y is NH, or a bond; R1is C1-C6alkyl, or C3-C12 cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1-C6 haloalkyl, or C1-C6 alkoxy; R2 ethyl, propyl, or isopropyl; R1 and R2 optionally form 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two C1-C6 alkyl, or halo; R3 is H, C1-C6 alkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, wherein the alkyl, heteroaryl or heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, C1-C6alkyl, R4is H; and each R5is H. In some embodiments, W is CH; X is S(=O)2;Y is NH; R1is C1-C6alkyl, or C3-C12cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1- C6haloalkyl, or C1-C6alkoxy; R2is ethyl, propyl, or isopropyl; R1and R2optionally form 6- membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two C1-C6alkyl, or halo; R3 is C1-C6 alkyl, 5-membered heteroaryl, 5-membered heterocyclyl, wherein the alkyl, heteroaryl or heterocyclyl is optionally substituted with one or more halo, or C1-C6alkyl, R4is H; and each R5is H. In some embodiments, W is CH; X is S(=O)2; Y is NH; R1 is C1-C6 alkyl, or C3-C12 cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1- C6haloalkyl, or C1-C6alkoxy; R2is ethyl, propyl, or isopropyl; R1and R2optionally form 6- membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two C1-C6 alkyl, or halo; R3 is C1-C6 alkyl, 5-membered heteroaryl, wherein the alkyl, heteroaryl is optionally substituted with one or more halo, or C1-C6alkyl, R4is H; and each R5is H. In some embodiments, W is CH; X is S(=O)2;Y is NH; R1is C1-C6alkyl, or C3-C12cycloalkyl; wherein the alkyl or cycloalkyl is optionally substituted by one or more halo OH C C6 haloalkyl, or C1-C6 alkoxy; R2 is ethyl, propyl, or isopropyl; R1 and R2 optionally form 6- membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two methyl groups, or halo; R3is C1-C6alkyl, 5-membered heteroaryl, 5-membered heterocyclyl, wherein the alkyl, heteroaryl or heterocyclyl is optionally substituted with one or more halo, or C1-C6 alkyl, R4 is H; and each R5 is H. In some embodiments, W is CH; X is S(=O)2;Y is NH; R1is C1-C4alkyl, or C3-C4cycloalkyl; wherein the alkyl, or cycloalkyl, is optionally substituted by one or more halo, OH, C1- C6 haloalkyl, or C1-C6 alkoxy; R2 is ethyl, propyl, or isopropyl; R1 and R2 optionally form 6- membered heterocyclyl, wherein the heterocyclyl is optionally substituted with two methyl groups, or halo; R3is C1-C6alkyl, 5-membered heteroaryl, 5-membered heterocyclyl, wherein the alkyl, heteroaryl or heterocyclyl is optionally substituted with one or more halo, or C1-C6 alkyl, R4 is H; and each R5 is H. In some embodiments, the compound of the present disclosure is of Formula III or IIIa, wherein R1 is C1-C6 alkyl, wherein the alkyl is optionally substituted with one halo, with two halo, or with three halo; R2 is isopropyl; R6 is C1-C3 alkyl, optionally substituted with one or more deuterium, or a C5-C6heteroaryl, optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluorine. In some embodiments, each RN is independently H or C1-C6 alkyl. In some embodiments, each RNis independently H or C1-C6alkyl. In some embodiments, each RNis independently H or C1-C3alkyl. In some embodiments, each RN is independently H or C1-C2 alkyl. In some embodiments, each RNis independently H or C1alkyl. In some embodiments, each RNis independently H or C2alkyl. In some embodiments, each RN is independently H or C3 alkyl. In some embodiments, each RN is H. In some embodiments, each RNis C1-C6alkyl. In some embodiments, each RN is C1-C3 alkyl. In some embodiments, each RN is C1-C2 alkyl. In some embodiments, each RNis C1alkyl. In some embodiments, each RNis C2alkyl. In some embodiments each R is C alkyl In some embodiments, R1 is C1-C6 alkyl, substituted with one halo, with two halo, or with three halo; R2 is isopropyl; R6 is CD2-CD3. In some embodiments, R1is C1-C3alkyl, substituted with one halo, with two halo, or with three halo; R2 is isopropyl; R6 is CD2-CD3. In some embodiments, R1 is C1-C2 alkyl, substituted with one halo, with two halo, or with three halo; R2is isopropyl; R6is CD2-CD3. In some embodiments, R1is C1alkyl, substituted with one halo, with two halo, or with three halo; R2 is isopropyl; R6 is CD2-CD3. In some embodiments, R1is C2alkyl, substituted with one halo, with two halo, or with three halo; R2is isopropyl; R6is CD2-CD3. In some embodiments, R1 is C1-C6 alkyl, substituted with two halo, or with three halo; R2 is isopropyl; R6 is CD2-CD3. In some embodiments, R1is C1-C3alkyl, substituted with two halo, or with three halo; R2is isopropyl; R6 is CD2-CD3. In some embodiments, R1 is C1-C2 alkyl, substituted with two halo, or with three halo; R2 is isopropyl; R6is CD2-CD3. In some embodiments, R1is C1alkyl, substituted with two halo, or with three halo; R2is isopropyl; R6 is CD2-CD3. In some embodiments, R1is C2alkyl, substituted with two halo, or with three halo; R2is isopropyl; R6is CD2-CD3. In some embodiments, R1 is C1-C6 alkyl, substituted with three halo; R2 is isopropyl; R6 is CD2-CD3. In some embodiments, R1is C1-C3alkyl, substituted with three halo; R2is isopropyl; R6is CD2-CD3. In some embodiments, R1 is C1-C2 alkyl, substituted with three halo; R2 is isopropyl; R6 is CD2-CD3. In some embodiments, R1 is C1 alkyl, substituted with three halo; R2 is isopropyl; R6 is CD2-CD3. In some embodiments, R1is C2alkyl, substituted three halo; R2is isopropyl; R6is CD2- CD3. In some embodiments, R1 is C1-C6 alkyl, substituted with two halo; R2 is isopropyl; R6 is CD2-CD3. In some embodiments, R1is C1-C3alkyl, substituted with two halo; R2is isopropyl; R6is CD2-CD3. In some embodiments, R1 is C1-C2 alkyl, substituted with two halo; R2 is isopropyl; R6 is CD2-CD3. In some embodiments, R1is C1alkyl, substituted with two halo; R2is isopropyl; R6is CD2-CD3. In some embodiments, R1is C2alkyl, substituted with two halo; R2is isopropyl; R6is CD2-CD3. In some embodiments, R1 is C1-C6 alkyl, substituted with one halo, with two halo, or with three halo; R2 is isopropyl; R6 is ethyl. In some embodiments, R1is C1-C3alkyl, substituted with one halo, with two halo, or with three halo; R2 is isopropyl; R6 is ethyl. In some embodiments, R1 is C1-C2 alkyl, substituted with one halo, with two halo, or with three halo; R2is isopropyl; R6is ethyl. In some embodiments, R1is C1alkyl, substituted with one halo, with two halo, or with three halo; R2 is isopropyl; R6 is ethyl. In some embodiments, R1is C2alkyl, substituted with one halo, with two halo, or with three halo; R2is isopropyl; R6is ethyl. In some embodiments, R1 is C1-C6 alkyl, substituted with two halo, or with three halo; R2 is isopropyl; R6is ethyl. In some embodiments, R1is C1-C3alkyl, substituted with two halo, or with three halo; R2is isopropyl; R6 is ethyl. In some embodiments, R1 is C1-C2 alkyl, substituted with two halo, or with three halo; R2 is isopropyl; R6is ethyl. In some embodiments, R1 is C1 alkyl, substituted with two halo, or with three halo; R2 is isopropyl; R6 is ethyl. In some embodiments, R1is C2alkyl, substituted with two halo, or with three halo; R2is isopropyl; R6is ethyl. In some embodiments, R1 is C1-C6 alkyl, substituted with three halo; R2 is isopropyl; R6 is ethyl. In some embodiments, R1is C1-C3alkyl, substituted with three halo; R2is isopropyl; R6is ethyl. In some embodiments, R1 is C1-C2 alkyl, substituted with three halo; R2 is isopropyl; R6 is ethyl. In some embodiments, R1is C1alkyl, substituted with three halo; R2is isopropyl; R6is ethyl. In some embodiments, R1is C2alkyl, substituted three halo; R2is isopropyl; R6is ethyl. In some embodiments, R1is C1-C6alkyl, substituted with two halo; R2is isopropyl; R6is ethyl. In some embodiments, R1 is C1-C3 alkyl, substituted with two halo; R2 is isopropyl; R6 is ethyl. In some embodiments, R1 is C1-C2 alkyl, substituted with two halo; R2 is isopropyl; R6 is ethyl. In some embodiments, R1is C1alkyl, substituted with two halo; R2is isopropyl; R6is ethyl. In some embodiments, R1 is C2 alkyl, substituted with two halo; R2 is isopropyl; R6 is ethyl. In some embodiments, R1is C1-C6alkyl, substituted with N(RN)2. In some embodiments, R1 is C1-C3 alkyl, N(RN)2. In some embodiments, R1is C1-C2alkyl, N(RN)2. In some embodiments, R1is C1alkyl, N(RN)2. In some embodiments, R1 is C2 alkyl, N(RN)2. In some embodiments, R1 is C1-C6 alkyl, N(RN)2; R2 is isopropyl. In some embodiments, R1is C1-C3alkyl, N(RN)2; R2is isopropyl. In some embodiments, R1 is C1-C2 alkyl, N(RN)2; R2 is isopropyl. In some embodiments, R1 is C1 alkyl, N(RN)2; R2 is isopropyl. In some embodiments, R1is C2alkyl, N(RN)2; R2is isopropyl. In some embodiments, R1is C1-C6alkyl, N(RN)2; R6is ethyl. In some embodiments R is C C alkyl N(R ) ; R is ethyl In some embodiments, R1 is C1-C2 alkyl, substituted N(RN)2; R6 is ethyl. In some embodiments, R1 is C1 alkyl, substituted N(RN)2; R6 is ethyl. In some embodiments, R1is C2alkyl, substituted N(RN)2; R6is ethyl. In some embodiments, R1 is C1-C6 alkyl, N(RN)2; R2 is CD2-CD3. In some embodiments, R1 is C1-C3 alkyl, N(RN)2; R2 is CD2-CD3. In some embodiments, R1is C1-C2alkyl, N(RN)2; R2is CD2-CD3. In some embodiments, R1is C1alkyl, N(RN)2; R2is CD2-CD3. In some embodiments, R1 is C2 alkyl, N(RN)2; R2 is CD2-CD3. In some embodiments, R3is C1-C6alkyl, substituted with N(RN)2. In some embodiments, R3is C1-C3alkyl, N(RN)2. In some embodiments, R3 is C1-C2 alkyl, N(RN)2. In some embodiments, R3 is C1 alkyl, N(RN)2. In some embodiments, R3is C2alkyl, N(RN)2. In some embodiments, R3 is C1-C6 alkyl, N(RN)2; R2 is isopropyl. In some embodiments, R3 is C1-C3 alkyl, N(RN)2; R2 is isopropyl. In some embodiments, R3is C1-C2alkyl, N(RN)2; R2is isopropyl. In some embodiments, R3is C1alkyl, N(RN)2; R2is isopropyl. In some embodiments, R3 is C2 alkyl, N(RN)2; R2 is isopropyl. In some embodiments, R3is C1-C6alkyl, N(RN)2; R6is ethyl. In some embodiments, R3is C1-C3alkyl, N(RN)2; R6is ethyl. In some embodiments, R3 is C1-C2 alkyl, substituted N(RN)2; R6 is ethyl. In some embodiments, R3is C1alkyl, substituted N(RN)2; R6is ethyl. In some embodiments, R3is C2alkyl, substituted N(RN)2; R6is ethyl. In some embodiments, R3 is C1-C6 alkyl, N(RN)2; R2 is CD2-CD3. In some embodiments, R3 is C1-C3 alkyl, N(RN)2; R2 is CD2-CD3. In some embodiments, R3is C1-C2alkyl, N(RN)2; R2is CD2-CD3. In some embodiments, R3 is C1 alkyl, N(RN)2; R2 is CD2-CD3. In some embodiments, R3 is C2 alkyl, N(RN)2; R2 is CD2-CD3. In some embodiments, R1is C1-C6alkyl, substituted with N(RN)2; R2is isopropyl; R6is In some embodiments R is C C alkyl N(R ) ; R is isopropyl; R is CD CD In some embodiments, R1 is C1-C2 alkyl, N(RN)2; R2 is isopropyl; R6 is CD2-CD3. In some embodiments, R1 is C1 alkyl, N(RN)2; R2 is isopropyl; R6 is CD2-CD3. In some embodiments, R1is C2alkyl, N(RN)2; R2is isopropyl; R6is CD2-CD3. In some embodiments, R1 is C1-C6 alkyl, N(RN)2; R2 is isopropyl; R6 is ethyl. In some embodiments, R1 is C1-C3 alkyl, N(RN)2; R2 is isopropyl; R6 is ethyl. In some embodiments, R1is C1-C2alkyl, N(RN)2; R2is isopropyl; R6is ethyl. In some embodiments, R1is C1alkyl, N(RN)2; R2is isopropyl; R6is ethyl. In some embodiments, R1 is C2 alkyl, N(RN)2; R2 is isopropyl; R6 is ethyl. In some embodiments, R1is C1-C6alkyl, N(RN)2; R2is isopropyl; R6is ethyl. In some embodiments, R1is C1-C3alkyl, N(RN)2; R2is isopropyl; R6is ethyl. In some embodiments, R1 is C1-C2 alkyl, substituted N(RN)2; R2 is isopropyl; R6 is ethyl. In some embodiments, R1 is C1 alkyl, substituted N(RN)2; R2 is isopropyl; R6 is ethyl. In some embodiments, R1is C2alkyl, substituted N(RN)2; R2is isopropyl; R6is ethyl. In some embodiments, the compound of Formulae 0, 0a, I, Ia, II, IIa, III, or IIIa is not 5- fluoro-N,N-diisopropyl-2-((4-(7-(((2R,5S)-5-(methylsulfonamido)tetrahydro-2H-pyran-2- yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide. In some embodiments, the compound is of Formulae 0, 0a, I, Ia, II, IIa, III, or IIIa combined with any of the embodiments described herein. Any of the groups described above for any variable can be combined with any of the other groups described above, where applicable, for any of the Formulae described herein. Representative compounds of the present disclosure are shown in the table below. Table 1. Representative Compounds of the Present Disclosure

[0003] In some embodiments, a compound according to any embodiments herein (e.g., Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) exhibits an inhibition activity against the binding of menin and MLL. In some embodiments, a compound according to any embodiments herein (e.g., Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) exhibits an inhibition activity against the binding of menin and MLL. In some embodiments, a compound according to any embodiments herein e.g., Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) exhibits an inhibition activity against the binding of menin and MLL which is useful in the treatment and / or prevention of one or more diseases in hi h i d MLL l l I b di d di embodiments herein (e.g., Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) exhibits low hERG binding. In some embodiments, a compound according to any embodiments herein (e.g., Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) is useful for the treatment of one or more diseases in which menin and MLL play a role and minimizes hERG binding. Without being bound to any theory, one of the primary causes of QT prolongation is thought to be blockage of the hERG potassium channel in cardiac myocytes. In some embodiments, the compounds of the present disclosure (e.g., Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) do not significantly block the hERG potassium channel. In some embodiments, the compounds of the present disclosure (e.g., Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) do not significantly block the hERG potassium channel (e.g., an IC50greater than 1 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 35 μM, 40 μM, or 50 μM) as measured by a standard patch clamp hERG assay. In some embodiments, the compounds of the present disclosure (e.g., Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) do not significantly block the hERG potassium channel (e.g., an IC50 greater than 1 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 35 μM, 40 μM, or 50 μM). In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin-MLL interaction comprising a pyran substitution (e.g., Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) where the pyran substitution has been found to reduce hERG inhibition. In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin-MLL interaction (e.g., Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) which are resistant to metabolism. In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin- MLL interaction (e.g., Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) which are resistant to metabolism, where the metabolites are inhibitors of the hERG potassium channel. In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin-MLL interaction (e.g., Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) which are resistant to metabolism, where the metabolism decreases the bioavailability of the inhibitor. In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin-MLL interaction (e.g., Formulae 0, 0a, I, Ia, II, IIa, III IIIa and Table 1) which are resistant to metabolism where the metabolism decreases the bioavailability of the inhibitor and the corresponding metabolites are more effective (e.g., by IC50, etc.) at binding the hERG potassium channel. Another aspect is an isotopically labeled compound of any of the formulae delineated herein. Such compounds have one or more isotope atoms which may or may not be radioactive (e.g.,3H,2H,14C,1 introduced into the compound. Such compounds are useful for drug metabolism studies and diagnostics, as well as therapeutic applications. In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table I, or a pharmaceutically acceptable salt thereof. It is understood that the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%. In some embodiments, the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium. It is understood that the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a deuterium labeled reagent for a non-deuterium labeled reagent. A compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the disclosure. Further, substitution with 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. For the avoidance of doubt, it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group. Potency can also be determined by IC value A compound with a lower IC value as determined under substantially similar conditions, is more potent relative to a compound with a higher IC50 value. The compounds of the application are defined herein by their chemical structures and / or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity. In another aspect, the application provides a method of synthesizing a compound disclosed herein. The synthesis of the compounds of the application can be found herein and in the Examples below. Other embodiments are a method of making a compound of any of the formulae herein using any one, or combination of, reactions delineated herein. The method can include the use of one or more intermediates or chemical reagents delineated herein. It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. At various places in the present specification, substituents of compounds of the disclosure are disclosed in groups or in ranges. It is specifically intended that the disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6alkyl” is specifically intended to individually disclose methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl. At various places in the present specification various cycloalkyl, and heterocyclyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “a pyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring. For compounds of the disclosure in which a variable appears more than once, each variable can be a different moiety independently selected from the group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound, the two R groups can represent different moieties independently selected from the group defined for R. As used herein, “alkyl”, “C1, C2, C3, C4, C5or C6alkyl” or “C1-C6alkyl” is intended to include C C C C C or C straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6alkyl is intends to include C1, C2, C3, C4, C5and C6alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms. As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy. As used herein, the term "amino," employed alone or in combination with other terms, refers to a group of formula –NH2. In some embodiments, an amine can be substituted by one or more groups, e.g., -N-(C1-C6 alkyl)2. In some embodiments, when two groups are attached to an amine they can be the same or different. Each group is selected independently of each other and can be each independently optionally substituted. As used herein, "Ci-j haloalkoxy," employed alone or in combination with other terms, refers to a group of formula –O-haloalkyl having i to j carbon atoms. An example haloalkoxy group is OCF3. An additional example haloalkoxy group is OCHF2. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments, the haloalkoxy group is C1-4 haloalkoxy. As used herein, the term “halogen” or "halo," employed alone or in combination with other terms, refers to a halogen atom selected from F, Cl, I or Br. In some embodiments, "halo" refers to a halogen atom selected from F, Cl, or Br. In some embodiments, the halo substituent is F. The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms. In some embodiments, the haloalkyl group is fluorinated. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the haloalkyl group is fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, the haloalkyl group is trifluoromethyl. In some embodiments, the haloalkyl group is 2,2,2-trifluoroethyl. In some embodiments, the haloalkyl group is 2,2-difluoroethyl. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms. As used herein the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6for straight chain, C3-C6for branched chain). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “C3-C6” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6alkenylene linker” or “C2-C6alkynylene linker” is intended to include C2, C3, C4, C5or C6chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2-C6alkenylene linker is intended to include C2, C3, C4, C5and C6alkenylene linker groups. As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato,s lf l lf id it t ifl th l id h t l l lk l l aromatic or heteroaromatic moiety. Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and c As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non-aromatic. In some embodiments, cycloalkyl may optionally contain one or more alkenylene groups as part of the ring structure. Cycloalkyl groups can include mono- or polycyclic ring systems. Polycyclic ring systems can include fused ring systems and spirocycles. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or pyrido derivatives of cyclopentane, cyclopentene, cyclohexane, and the like. A heterocyclyl group that includes a fused aromatic (e.g., aryl or heteroaryl) moiety can be attached to the molecule through an atom from either the aromatic or non-aromatic portion. One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized to form carbonyl linkages. In some embodiments, cycloalkyl is C3-10 cycloalkyl, C3-7 cycloalkyl, or C5-6cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and the like. Further exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Additional example cycloalkyl groups, where the cycloalkyl group has a fused aryl or heteroaryl moiety, include tetrahydronaphthalen-2-yl, 2,3-dihydro-1H-inden-2-yl; 2,3,4,9-tetrahydro-1H-carbazol-7-yl; 2,6,7,8-tetrahydrobenzo[cd]indazol-4-yl; and 5,6,7,8,9,10-hexahydrocyclohepta[b]indol-3-yl. As used herein, the term “aryl,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon, such as, but not limited to phenyl 1 naphthyl 2 naphthyl anthracenyl phenanthrenyl and the like In some embodiments, aryl is C6-10 aryl. In some embodiments, aryl is C6-14 aryl. In some embodiments, the aryl group is a naphthalene ring or phenyl ring. In some embodiments, the aryl group is phenyl. As used herein, the term “heteroaryl,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic heterocylic moiety, having one or more heteroatom ring members selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group has 1, 2, 3, or 4 heteroatom ring members. In some embodiments, the heteroaryl group has 1, 2, or 3 heteroatom ring members. In some embodiments, the heteroaryl group has 1 or 2 heteroatom ring members. In some embodiments, the heteroaryl group has 1 heteroatom ring member. In some embodiments, the heteroaryl group is 5- to 10- membered or 5- to 6-membered. In some embodiments, the heteroaryl group is 5-membered. In some embodiments, the heteroaryl group is 6-membered. In some embodiments, the heteroaryl group is 9- or 10-membered bicyclic. In some embodiments, the heteroaryl is 9-member bicyclic. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides. Example heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, furanyl, thiophenyl, triazolyl, tetrazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiopheneyl, benzofuranyl, benzisoxazolyl, benzoimidazolyl, imidazo[1, 2-b]thiazolyl, purinyl, triazinyl, and the like. In some embodiments, the heteroaryl group is 9H-carbazol-2-yl; 1H-benzo[d]imidazol-6-yl; 1H-indol-6-yl; 1H-indazol-6-yl; 2H- indazol-4-yl; 1H-benzo[d][1,2,3]triazol-6-yl; benzo[d]oxazol-2-yl; quinolin-6-yl; or benzo[d]thiazol-2-yl. Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, deazapurine, indolizine. The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy arylcarbonyloxy alkoxycarbonyloxy aryloxycarbonyloxy carboxylate alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxole-5-yl). As used herein, the phrase "optionally substituted" means unsubstituted or substituted. As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. 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 in 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 formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds. When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R Also combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds. As used herein, the term "heterocyclyl," employed alone or in combination with other terms, refers to a non-aromatic heterocyclic ring system, which may optionally contain one or more unsaturations as part of the ring structure, and which has at least one heteroatom ring member independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heterocyclyl group has 1, 2, 3, or 4 heteroatom ring members. In some embodiments, the heterocyclyl group has 1, 2, or 3 heteroatom ring members. In some embodiments, the heterocyclyl group has 1 or 2 heteroatom ring members. In some embodiments, the heterocyclyl group has 1 heteroatom ring member. When the heterocyclyl group contains more than one heteroatom in the ring, the heteroatoms may be the same or different. Example ring-forming members include CH, CH2, C(O), N, NH, O, S, S(O), and S(=O)2. Heterocyclyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems. Polycyclic rings can include both fused systems and spirocycles. Also included in the definition of heterocyclyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non-aromatic ring, for example, 1, 2, 3, 4-tetrahydro-quinoline, dihydrobenzofuran and the like. A heterocyclyl group that includes a fused aromatic moiety can be attached to the molecule through an atom from either the aromatic or non-aromatic portion. The carbon atoms or heteroatoms in the ring(s) of the heterocyclyl group can be oxidized to form a carbonyl, sulfinyl, or sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized. In some embodiments, heterocyclyl is 5- to 10-membered, 4- to 10-membered, 4- to 7-membered, 5-membered, or 6-membered. Examples of heterocyclyl groups include 1, 2, 3, 4-tetrahydro-quinolinyl, dihydrobenzofuranyl, azetidinyl, azepanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and pyranyl. Examples of heterocyclyl groups that include one or more fused aromatic groups (e.g., aryl or heteroaryl) include N-(2'- oxospiro[cyclohexane-1,3'-indolin]-6'-yl; 1,2,3,4-tetrahydroisoquinolin-6-yl; 2,3-dihydro-1H- benzo[d]imidazol-5-yl; 1,3-dihydrospiro[indene-2,3'-indolin]-6'-yl; 2,3-dihydrobenzo[d]oxazol- 5-yl; 1,2-dihydroquinolin-7-yl; indolin-6-yl; spiro[cyclopentane-1,3'-indolin]-6'-yl; spiro[cyclohexane-1,3'-indolin]-6'-yl; chroman-6-yl; 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl; and benzo[d][1,3]dioxol-5-yl. As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.” As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents. As used herein, the term “chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.1966, 5, 385; errata 511; Cahn et al., Angew. Chem.1966, 78, 413; Cahn and Ingold, J. Chem. Soc.1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ.1964, 41, 116). As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules. It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity. It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity. As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases. As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose. It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others. Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R and S sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture” The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereoisomers, are intended unless otherwise indicated. Where a compound name or structure is silent with respect to the stereochemistry of a stereocenter, all possible configurations at the stereocenter are intended. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. When the compounds of the disclosure contain a chiral center, the compounds can be any of the possible stereoisomers. In compounds with a single chiral center, the stereochemistry of the chiral center can be (R) or (S). In compounds with two chiral centers, the stereochemistry of the chiral centers can each be independently (R) or (S) so the configuration of the chiral centers can be (R) and (R), (R) and (S); (S) and (R), or (S) and (S). In compounds with three chiral centers, the stereochemistry each of the three chiral centers can each be independently (R) or (S) so the configuration of the chiral centers can be (R), (R) and (R); (R), (R) and (S); (R), (S) and (R); (R), (S) and (S); (S), (R) and (R); (S), (R) and (S); (S), (S) and (R); or (S), (S) and (S). Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as E-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of D-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms), 2- phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1, 2- diaminocyclohexane, and the like. Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art. When a disclosed compound is named or depicted without indicating the stereochemistry of one or more stereocenters, each of the stereoisomers resulting from the possible stereochemistries at the undefined stereocenter(s) are intended to be encompassed. For example, if a stereocenter is not designated as R or S, then either or both are intended. Compounds of the disclosure also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone – enol pairs, amide - imidic acid pairs, lactam – lactim pairs, amide - imidic acid pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1, 2, 4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. Compounds of the disclosure can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. Isotopes of constituent atoms of the compounds of the disclosure can be present in natural or non-natural abundance. Examples of isotopes of hydrogen include deuterium and tritium. In some embodiments, the compounds of the disclosure are deuterated, meaning at least one deuterium atom is present in the place of a hydrogen atom. In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogens in a compound of the disclosure are replaced by deuterium. Methods for replacing hydrogen with deuterium in a molecule are known in the art. The term "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified (e.g., in the case of purine rings, unless otherwise indicated, when the compound name or structure has the 9H tautomer, it is understood that the 7H tautomer is also encompassed). All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated. It will be understood that the compounds of the present disclosure and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds. In some embodiments, the compounds of the disclosure, or salts thereof, or crystalline forms of any of the aforementioned, are purified or substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in a compound of the disclosure. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the disclosure, or salt thereof. In some embodiments, the compounds of the disclosure, or salts thereof, or crystalline forms of any of the aforementioned, can be prepared with a purity of about 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 ºC to about 30 ºC. The present disclosure also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (MeCN) are preferred. The compounds disclosed herein include the compounds themselves, as well as their salts, their solvates, and their prodrugs, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., protonated amino) on a compound of this disclosure. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluroacetate). The term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a compound of this disclosure. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. The compounds of this disclosure also include those salts containing quaternary nitrogen atoms. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing active compounds of this disclosure. Additionally, physiologically acceptable, i.e., pharmaceutically compatible, salts can be salts of the compounds disclosed herein with inorganic or organic acids. Preference is given to salts with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or to salts with organic carboxylic or sulphonic acids, such as, for example, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid. Other pharmaceutically compatible salts which may be mentioned are salts with customary bases such as for example alkali metal salts (for example sodium or potassium salts) alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts, derived from ammonia or organic amines, such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine or methylpiperidine. As used herein, “pharmaceutically acceptable salts” can refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc. Other examples of pharmaceutically acceptable salts can include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, or an alkaline earth metal ion, e.g., an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, diethylamine, diethylaminoethanol, ethylenediamine, imidazole, lysine, arginine, morpholine, 2-hydroxyethylmorpholine, dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine, tetramethylammonium hydroxide and the like. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt. It is to be understood that, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to provide such treatment or prevention as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to prepare a medicament to treat or prevent such condition. The treatment or prevention includes treatment or prevention of human or non-human animals including rodents and other disease models. It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment includes use of the compounds to prepare a medicament to treat such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models. As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the subject is a human. As used herein, the term “subject in need thereof” refers to a subject having a disease or having an increased risk of developing the disease. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy. As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model. It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes. As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder. It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18thedition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure. It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier. The compounds of the present disclosure may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the sulfonylurea group in a compound of the any one of the Formulae disclosed herein. Accordingly, the present disclosure includes those compounds of the present disclosure as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of the present disclosure that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the present disclosure may be a synthetically-produced compound or a metabolically-produced compound. A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p.113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor) “Bioreversible Carriers in Drug Design” Pergamon Press 1987 A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the present disclosure containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1- ylmethyl and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include D-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups. A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-C4alkylamine such as methylamine, a (C1- C4 alkyl)2amine such as dimethylamine, N-ethyl N-methylamine or diethylamine, a C1-C4 alkoxy C2-C4 alkylamine such as 2 methoxyethylamine, a phenyl C1-C4alkylamine such as benzylamine and amino acids such as glycine or an ester thereof. A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. The in vivo effects of a compound of the present disclosure may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a d f th t di l A t t d h i b f th i i ff t f d f the present disclosure may also be exerted by way of metabolism of a precursor compound (a prodrug). All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure. In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer. All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow. As use herein, the phrase “compound of the disclosure” refers to those compounds which are disclosed herein, both generically and specifically. Synthesis In some aspects, the present disclosure provides a method of preparing a compound disclosed herein. In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps as described herein. In some aspects, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound described herein. In some aspects, the present disclosure provides an intermediate being suitable for use in a method for preparing a compound described herein. The compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples. In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilized. It will be appreciated that during the synthesis of the compounds of the disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl (Bn) The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group such as a tert butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon. A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon. Once a compound of the present disclosure has been synthesized by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound of the present disclosure into another compound of the present disclosure; (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof. The resultant compounds of the present disclosure can be isolated and purified using techniques well known in the art Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert- butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methylisobutylketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the said solvents or mixtures with water. The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used. Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours. Moreover, by utilizing the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. As will be understood by the person skilled in the art of organic synthesis, compounds of the present disclosure are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples. The skilled person will easily recognize which kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance – wherever necessary or useful – in order to obtain the compounds of the present disclosure. Furthermore, some of the compounds of the present disclosure can readily be synthesized by reacting other compounds of the present disclosure under suitable conditions for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilled person will apply – whenever necessary or useful – synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well-known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons).The compounds of the disclosure can be synthesized by the methods described in Schemes 1-8 below. The synthesis of various hydroxyl-substituted heterocycles is well documented in the literature and can be synthesized by known literature methods. The depicted intermediates may also be available as commercial reagents from numerous vendors. The compounds of the present disclosure can be prepared according to the general methods illustrated in the following Schemes. General Scheme 1 Scheme 1 illustrates the general methods for the preparation of key intermediates like compound 1-K. A suitably substituted 2-halophenol, for instance 4-fluoro-2-bromophenol (1-A), is reacted with a 5-halopyrimidine (1-B), for example 5-bromopyrimidine or 5-iodopyrimidine, to afford the corresponding diaryl ether (1-C). This reaction is typically conducted in the presence (diispropylethylamine, also known as Huning’s base), in a suitable, neutral solvent, such as DMA (dimethyl acetamide) or NMP (N-methylpyrrolidinone). In some instances, this transformation can be facilitated by addition of an appropriate catalyst, typically Cu2O or CuI, in the presence of a suitable ligand, for example rel-(1R,2R)-N1,N2-bis(2-pyridinylmethylene)-1,2- cyclohexanediamine or 3,4,7,8-tetramethyl-1,10-phenanthroline. Conversion of compound 1-C to compound 1-D can be readily achieved by carbonylation under Pd catalysis, in the presence of an acid scavenger and suitable alcohol (typically used as the solvent in the reaction). Oftentimes, Pd(dppf)Cl2 (dppf = 1,1-bis(diphenylphosphino)ferrocene) is used as the palladium catalyst, but other catalyst systems, such as Pd(Ph3P)2Cl2(Ph3P = triphenylphosphine) or Pd(OAc)2with Ph3P, can also be used. Commonly, Et3N or (i-Pr)2NEt are used as the acid scavengers, and methanol is used as the solvent. These reactions are most typically run under an atmosphere of CO, but other CO sources, for example oxalic acid, can be used in some instances. The ester group of compound 1-D is subsequently saponified to the corresponding carboxylic acid 1-E. Typically, this transformation is accomplished using LiOH, NaOH or KOH, in an aqueous solvent system, such as methanol / water or THF / water. The carboxylic acid is then converted to an amide (1-F). Many different conditions have been developed to achieve this type of transformation, and will be generally familiar to those of skill in the art. For instance, the carboxylic acid can be reacted with thionyl chloride or oxalyl chloride, which forms the corresponding acid chloride. This reaction can be conducted in a suitable, neutral solvent like CH2Cl2, or if thionyl chloride is used, can be run with thionyl chloride as the reactant and solvent. The acid chloride is subsequently reacted with a suitable amine, R1R2NH, in the presence of an appropriate acid scavenger, for example Et3N, (i-Pr)2NEt, or pyridine, in a neutral solvent like CH2Cl2or THF. In some instances, pyridine can be used as the acid scavenger and the solvent for the reaction. Alternatively, the carboxylic acid and amine R1R2NH can be combined together and coupled using a reagent such as DCC (dicyclohexyl carbodiimide), EDC (1-ethyl-3-(4-dimethylaminopropyl)carbodiimide), or HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), in a neutral solvent, oftentimes DMF, CH2Cl2 or THF. In some instances, when DCC or EDC is used as the coupling reagent, HOBt (hydroxybenzotriazole) might be added to the reaction to facilitate the desired coupling reaction. Reaction of 1-F with a suitable oxidizing agent, such as urea hydroperoxide in the presence of trifluoroacetic anhydride, or meta- chloroperoxybenzoic acid (mCPBA) in a suitable solvent typically CH Cl or THF affords the pyrimidine N-oxide 1-G. This then can be chlorinated to afford compound 1-H using an appropriate chlorinating agent, typically POCl3 or oxalyl chloride, in the presence of an acid scavenger, usually Et3N, (i-Pr)2NEt, in a neutral solvent like CH2Cl2or isopropyl acetate. The chloride of compound 1-H can be readily displaced with an amine, or a suitably protected diamine, for instance tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (1-I), to afford compounds like 1- J. This reaction is conducted in the presence of an acid scavenger, usually Et3N or (i-Pr)2NEt, in a neutral solvent like CH2Cl2, THF, DMF, or isopropyl acetate. When a protected diamine is used, the protecting group can be removed subsequently according to the nature of the protecting group. The use of protecting groups in organic synthesis is well-known to those of skill in the art, and conditions for adding and removing protecting groups are described in established reference volumes, for instance Greene's Protective Groups in Organic Synthesis, 4thEdition (ISBN:9780470053485). For example, the Boc (tert-butyloxycarbonyl) protecting group in compound 1-J can be removed under acidic conditions, using acids like HCl, TFA (trifluoracetic acid), or p-TsOH (para-toluenesulfonic acid), in a suitable solvent, oftentimes CH2Cl2 or THF. The Boc group can also be removed using TMSCl in 2,2,2-trifluoroethanol. The desired, deprotected amine can be isolated as the salt, for instance the salt 1-K, wherein HX denotes the salt form, or as the free base, following work-up under standard basic conditions. After removal of the protecting group, the amine can be alkylated with a wide range of alkylating agents, as illustrated in Scheme 3. General Scheme 2 Scheme 2 illustrates an alternative method to prepare the key intermediate 1-K. The benzoic acid derivative 2-A is converted to the corresponding amide 2-B, according to the general diti f i id f b li id d ib d i S h 1 ( 1 E t 1 F) The methyl ether protecting group in 2-B can then be removed in a variety of ways as described in Greene's Protective Groups in Organic Synthesis, 4thEdition (ISBN:9780470053485). For example, reaction of 2-B with boron tribromide (BBr3), in a neutral solvent, typically CH2Cl2, provides phenol 2-C. This phenol can be reacted with a 5-halopyrimidine (1-B), as described in Scheme 1 (see 1-A to 1-C), to afford the diaryl ether 1-F. This compound can then be transformed into the key intermediate 1-K as described in Scheme 1. General Scheme 3 Scheme 3 illustrates methods for preparing selected, pyran-based alkylating agents, that can be used to alkylate key intermediates like 1-K. Commercially available 1,5-anhydro-2,3,4- trideoxy-2-[[(1,1-dimethylethoxy)carbonyl]amino]-D-erythro-hexitol (3-A) is reacted with a suitable sulfonyl chloride, preferably p-toluenesulfonyl chloride (TsCl) or methanesulfonyl chloride (MsCl), to afford the sulfonate derivative 3-B (R3= p-MePh or Me) Alternatively, 3-A might be converted to the corresponding bromide or iodide under standard conditions know to those of skill in the art. For example, reaction of 3-A with CBr4 in the presence of PPh3, in a neutral solvent, typically CH2Cl2, can provide the halide 3-C (X = Br). Compound 2-C (X = Br or I) might also be obtained by reaction of 3-B with a source of anionic halide, like LiBr or LiI, in a neutral solvent like THF or diethyl ether. Compounds 3-B and 3-C can be used to alkylate key intermediates like 1-K as illustrated in Scheme 4.

[0004] General Scheme 4 Scheme 4 illustrates methods for converting the key intermediate 1-K into the compounds of the present disclosure (4-D). Reaction of 1-K , which can be prepared according to the general procedures described in Schemes 1 and 2, with an appropriate alkylating agent, for instance compounds 3-B or 3-C, in the presence of an acid scavenger like Et3N, or (iPr)2NEt, in a neutral solvent like CH2Cl2, THF, DMF or NMP, affords compound 4-A. Sometimes, KI or tetrabutylammonium iodide (TBAI) can be added to facilitate the reaction. The Boc protecting group in 4-A can be removed according to the general methods for removing Boc groups described in Scheme 1 (see 1-J to 1-K), to afford 4-B, which can be prepared as the free base or a suitable salt, as described in Scheme 1. Reaction of 4-B with a suitable acylating or sulfonylating agent, in the presence of an acid scavenger like Et3N, or (iPr)2NEt, in a neutral solvent like CH2Cl2, THF, DMF or NMP, affords the compounds of the present disclosure (4-D). For illustrative purposes, reaction of 4-B with an alkylsulfonyl chloride (4-C, R3 = an alkyl group) affords the sulfonyl derivative 4-D. Other compounds of the present disclosure can be formed similarly, via reaction with appropriate acylating agents like acid chlorides (to afford amides), alkyl chloroformates (to afford carbamates), or alkyl carbamoyl chlorides or alkyl isocyanates (to afford ureas). General Scheme 5 Scheme 5 illustrates the general methods for preparing the key intermediate 5-C. Compound 1-D, which can be prepared according to the general procedures described in Scheme 1, can be oxidized to the pyrimidine-N-oxide 5-A, according to the general methods described in Scheme 1 (see 1-F to 1-G). The N-oxide 5-A can then be chlorinated to the 4-chloropyrimidine derivative 5-B, according to the general methods described in Scheme 1 (see 1-G to 1-H). Subsequently, the chloro group of 5-B can be displaced by a suitable amine, for instance tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (1-I), to afford compound 5-C, according to the general methods described in Scheme 1 (see 1-H to 1-J). It will be appreciated by those of skill in the art that compound 5-C is a flexible intermediate that can be converted into the compounds of the present disclosure (4-D) in a variety of ways. Several of these ways are described below (see Schemes 6-8). General Scheme 6 Scheme 6 illustrates one general method for converting compound 5-C into the compounds of the present disclosure. The ester of compound 5-C (prepared according to the general procedures described in Scheme 5) can be saponified according to the general procedures described in Scheme 1 (see 1-D to 1-E). The resulting carboxylic acid 6-A can be converted to the corresponding amide 1-J according to the general methods for preparing amides from carboxylic acids described in Scheme 1 (see 1-E to 1-F). Compound 1-J can then be converted to the compounds of the present disclosure (4-D) as described above (see Schemes 1 and 4). General Scheme 7 Scheme 7 illustrates another general method for converting compound 5-C into the compounds of the present disclosure. Removal of the Boc group of 5-C can be accomplished using the general procedures for removing Boc groups described in Scheme 1 (see 1-J to 1-K). The resulting amine 7-A can be isolated as the free base or a suitable salt form, as is discussed in Scheme 1. The amine of compound 7-A can be alkylated as described in Scheme 4 (see 1-K to 4- A), to afford compound 7-B. Saponification of the ester of 7-B, as described in Scheme 1 (see 1- D to 1-E), provides the carboxylic acid derivative 7-C. This can be converted to the corresponding amide 4-A according to the general methods for amide formation described in Scheme 1 (see 1-E to 1-F). Compound 4-A can then be converted to the compounds of the present disclosure (4-D) as described in Scheme 4. General Scheme 8 Scheme 8 illustrates another general method for converting compound 7-B into the compounds of the present disclosure. The Boc group in compound 7-B (prepared according to the general procedures described in Scheme 7) can be removed using the general procedures for removing Boc groups described in Scheme 1 (see 1-J to 1-K). The resulting amine 8-A can be isolated as the free base or a suitable salt form, as is discussed in Scheme 1. The amine of compound 8-A can be acylated according to the general methods discussed in Scheme 4 (see 4-B to 4-D), to afford compound 8-B. Saponification of the ester of compound 8-B can be achieved via the general procedures for ester saponification described in Scheme 1 (see 1-D to 1-E). The resulting carboxylic acid 8-C can then the converted to the corresponding amide using the general methods for amide formation described in Scheme 1 (see 1-E to 1-F), to afford the compounds of the present disclosure (4-D). General Biological Methods Homogeneous Time-Resolved Fluorescence (HTRF) HTRF, is a premier TR-FRET (Time-Resolved Fluorescence Resonance Energy Transfer) technology on the market. TR-FRET technologies such as HTRF bring together the sensitivity of fluorescence with the homogeneous nature of FRET (Fluorescence Resonance Energy Transfer) and the low background of time resolution. HTRF uses two fluorophores, a donor and an acceptor dye, that transfer energy when in close proximity to each other. This creates a homogeneous assay format in which bound and unbound partners do not need to be separated as fluorescence emission from the acceptor is generated only upon binding. HTRF can be used in competitive and non- competitive formats and performed as cellular or biochemical assays in 96-, 384- and 1536-well plate formats. It has been applied to a variety of applications including GPCRs, kinases, epigenetics, biotherapeutics and quantification of a range of biomarkers and can be used according to the knowledge of a person of ordinary skill in the art to assess the compounds of the present disclosure. hERG Patch Clamp Assay The hERG inhibition assay uses a high throughput single cell planar patch clamp approach. Chinese hamster ovary cells transfected with the hERG gene (CHO-hERG) are dispensed into the PatchPlate. Amphotericin is used as a perforating agent to gain electrical access to the cells. The hERG tail current is measured prior to the addition of the test compound by perforated patch clamping. Following addition of the test compound at a defined concentration or range of concentrations a second recording of the hERG current is performed. The degree of inhibition (%) is obtained by measuring the tail current amplitude, which is induced by a one second test pulse to - 40 mV after a two second pulse to + 20 mV, before and after drug incubation (the difference current is normalized to control and multiplied by 100 to obtain the percent of inhibition). The patch clamp assay can be used according to the knowledge of a person of ordinary skill in the art to accordingly assess the compounds of the present disclosure. In any one of the embodiments described herein, the compound has an IC50of more than 10, 15, 20, 25, or 30 μM in a standard human ether-a-go-go related gene (hERG) patch clamp assay. A number of drugs have been withdrawn from late-stage clinical trials due to cardiotoxic effects, therefore it is important to identify and avoid compounds with potential for cardiotoxic effects early in drug discovery. The cardiovascular toxicity of a compound can be measured using a standard human ether-a-go-go related gene (hERG) assay. The human ether-a-go-go related gene (hERG) encodes the inward rectifying voltage gated potassium channel in the heart (IKr), which is involved in cardiac repolarization. Inhibition of the hERG current causes QT interval prolongation resulting in potentially fatal ventricular tachyarrhythmia called Torsade de Pointes. A compound having an IC50 of more than about 10 μM or more than about 15 μM, in the hERG assay may be considered as free from any cardiovascular toxicity. In some embodiments, the compounds of Formulae 0 0a I Ia II IIa III IIIa and / or Table 1 have reduced hERG binding compared to structural analogs. In some embodiments, the compounds of Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and / or Table 1 IC50 of more than 10 μM, 15 μM, 20 μM, 25 μM, or 30 μM in the standard patch clamp hERG assay. In some embodiments, the compounds of the present disclosure (e.g., Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) do not significantly block the hERG potassium channel (e.g., an IC50 greater than 1 μM, μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 35 μM, 40 μM, or 50 μM) in the standard patch clamp hERG assay. Methods of Use The compounds of the invention are inhibitors of the interaction of menin with MLL and MLL fusion proteins. In some embodiments, the present disclosure is directed to a method of inhibiting the interaction between menin and MLL or an MLL fusion protein by contacting menin and MLL or the MLL fusion protein with a compound of the disclosure. The contacting can be carried out in vitro or in vivo. In some embodiments, the compounds of the disclosure can bind to menin, thereby interfering with the binding of MLL to menin. In some embodiments, the present disclosure provides a method of inhibiting the activity of menin by contacting menin with a compound of the disclosure in the presence of MLL or an MLL fusion protein. In further embodiments, the present disclosure provides a method of inhibiting the binding of MLL or an MLL fusion protein to menin, comprising contacting menin with a compound of the disclosure in the presence of the MLL or MLL fusion protein. In some embodiments, compounds of the present disclosure minimize hERG interactions. In some embodiments, the present disclosure is directed to a method of inhibiting the interaction between menin and MLL or an MLL fusion protein by contacting menin and MLL or the MLL fusion protein with a compound of the disclosure while the compounds of the disclosure minimize hERG activity. In some embodiments, the present disclosure is directed to a method of inhibiting the interaction between menin and MLL or an MLL fusion protein by contacting menin and MLL or the MLL fusion protein with a compound of the disclosure while the compound of the disclosure avoids drug-induced blockade of hERG. Evaluating the hERG activity can be accomplished by many methods known in the art. Including, such methods for the assessment of hERG liability is the patch-clamp electrophysiological assay on hERG transfected cells. Various other strategies including radiolabeled binding assays, functional assays, and rubidium efflux assays also quantify hERG potency. The compounds of the disclosure are also useful in treating diseases associated with the menin-MLL interaction or menin-MLL fusion protein interaction. For example, diseases and conditions treatable according to the methods of the disclosure include cancer, such as leukemia, and other diseases or disorders mediated by the menin-MLL interaction or menin-MLL fusion protein interaction such as diabetes. Accordingly, the compounds of the disclosure are believed to be effective against a broad range of cancers, including, but not limited to, hematological cancer (e.g., leukemia and lymphoma), bladder cancer, brain cancer (e.g., glioma, diffuse intrinsic pontine glioma (DIPG)), breast cancer (e.g., triple-negative breast cancer, estrogen-receptor-positive breast cancer (i.e., ER+ breast cancer)), colorectal cancer, cervical cancer, gastrointestinal cancer (e.g., colorectal carcinoma, gastric cancer), genitourinary cancer, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer (e.g., castration resistant prostate cancer), renal cancer (e.g., renal cell carcinoma), skin cancer, thyroid cancer (e.g., papillary thyroid carcinoma), testicular cancer, sarcoma (e.g., Ewing’s sarcoma), and AIDS-related cancers. In some embodiments, the cancer is associated with a rearranged MLL gene. In some embodiments, the pathophysiology of the cancer is dependent on the MLL gene. In some embodiments, the cancer is associated with mutant p53 gain-of-function. In some embodiments, the specific cancers that may be treated by the compounds, compositions and methods described herein include cardiac cancers, such as for example, sarcoma (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; lung cancers, including, for example, bronchogenic carcinoma (e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma), alveolar and bronchiolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, bronchial adenomas / carcinoids, and pleuropulmonary blastoma; gastrointestinal cancer, including, for example, cancers of the esophagus (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma), cancers of the stomach (e.g., carcinoma, lymphoma, and leiomyosarcoma), cancers of the pancreas (e.g., ductal adenocarcinoma, insulinoma, glucagonoma gastrinoma carcinoid tumors and vipoma) cancers of the small bowel (eg adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma), cancers of the large bowel or colon, (e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma), and other cancers of the digestive tract (e.g., anal cancer, anorectal cancer, appendix cancer, cancer of the anal canal, cancer of the tongue, gallbladder cancer, gastrointestinal stromal tumor (GIST), colon cancer, colorectal cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, rectal cancer, and small intestine cancer); genitourinary tract cancers, including, for example, cancers of the kidney (e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, and leukemia), cancers of the bladder and urethra (e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma), cancers of the prostate (e.g., adenocarcinoma and sarcoma), cancers of the testis, (e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma), as well as transitional cell cancer, transitional cell cancer of the renal pelvis and ureter and other urinary organs, urethral cancer, and urinary bladder cancer; liver cancers, including, for example, hepatoma (e.g., hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; bone cancers, including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; nervous system cancers, including, for example, cancers of the skull (e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans); cancers of the meninges (e.g., meningioma, meningiosarcoma, and gliomatosis); cancers of the brain (e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors); cancers of the spinal cord (e.g., neurofibroma, meningioma, glioma, and sarcoma), and other nervous system cancers (e.g., brain stem glioma, diffuse intrinsic pontine glioma (DIPG), brain tumor, central nervous system cancer, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, primary central nervous system lymphoma, visual pathway and hypothalamic glioma, nervous system lymphoma, supratentorial primitive neuroectodeimal tumors pineoblastoma and supratentorial primitive neuroectodermal tumors); gynecological cancers, including, for example, cancers of the uterus (e.g., endometrial carcinoma), cancers of the cervix (e.g., cervical carcinoma, and pre tumor cervical dysplasia), cancers of the ovaries (e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa thecal cell tumors, Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma), cancers of the vulva (e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma), cancers of the vagina (e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma), and cancers of the fallopian tubes (e.g., carcinoma); other reproductive tract cancers, including, for example, endometrial cancer, endometrial uterine cancer, germ cell tumor, gestational trophoblastic tumor, gestational trophoblastic tumor glioma, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, penile cancer, vaginal cancer, vulvar cancer, extracranial germ cell tumor, extragonadal germ cell tumor, uterine cancer, uterine corpus cancer, uterine sarcoma; lymphatic and hematologic cancers, including, for example, cancers of the blood (e.g., acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin's lymphoma, non Hodgkin's lymphoma (malignant lymphoma) and Waldenstrom's macroglobulinemia), and other lymphatic or hematologic cancers including, for example, childhood leukemia, myeloproliferative disorders (e.g., primary myelofibrosis), plasma cell neoplasm / multiple myeloma, myelodysplasia, myelodysplastic syndrome, cutaneous T-cell lymphoma, lymphoid neoplasm, AIDS-related lymphoma, thymoma, thymoma and thymic carcinoma, mycosis fungoides, and Sézary Syndrome; skin cancers, including, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis, merkel cell carcinoma, merkel cell skin carcinoma, melanoma, and carcinoid tumor; adrenal gland cancers, including, for example, neuroblastoma; other cancers associated with the endocrine system including, for example, adrenocortical carcinoma, multiple endocrine neoplasia (e.g., multiple endocrine neoplasia type I), multiple endocrine neoplasia syndrome, parathyroid cancer, pituitary tumor, pheochromocytoma, islet cell pancreatic cancer, and islet cell tumors); connective tissue cancer (e.g., bone cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma); cancer associated with the head neck and mouth (eg head and neck cancer paranasal sinus and nasal cavity cancer, metastatic squamous neck cancer, mouth cancer, throat cancer, esophageal cancer, laryngeal cancer, pharyngeal cancer, hypopharyngeal cancer, lip and oral cavity cancer, nasopharyngeal cancer, oral cancer, oropharyngeal cancer, and salivary gland cancer); and cancer associated with the eye (e.g., ocular cancer, intraocular melanoma). In some embodiments, the cancer is Ewing’s sarcoma. In some embodiments, the cancer is a hematological cancer such as leukemia or lymphoma. Example leukemia and lymphomas treatable by the compounds of the disclosure include mixed lineage leukemia (MLL), MLL-related leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage leukemia (MLL-r), leukemia associated with a MLL rearrangement or a rearrangement of the MLL gene, acute leukemia, chronic leukemia, indolent leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, myelogenous leukemia, childhood leukemia, acute lymphocytic leukemia (ALL) (also referred to as acute lymphoblastic leukemia or acute lymphoid leukemia), acute myeloid leukemia (AML) (also referred to as acute myelogenous leukemia or acute myeloblastic leukemia), acute granulocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia (CLL) (also referred to as chronic lymphoblastic leukemia), chronic myelogenous leukemia (CML) (also referred to as chronic myeloid leukemia), therapy related leukemia, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD) (such as primary myelofibrosis (PMF)), myeloproliferative neoplasia (MPN), plasma cell neoplasm, multiple myeloma, myelodysplasia, cutaneous T-cell lymphoma, lymphoid neoplasm, AIDS-related lymphoma, thymoma, thymic carcinoma, mycosis fungoides, Alibert-Bazin syndrome, granuloma fungoides, Sézary Syndrome, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, meningeal leukemia, leukemic leptomeningitis, leukemic meningitis, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin’s lymphoma (malignant lymphoma), and Waldenstrom's macroglobulinemia. In some embodiments, the acute myeloid leukemia (AML) is abstract nucleophosmin (NPM1)-mutated acute myeloid leukemia (i.e., NPM1mutacute myloid leukemia). In particular embodiments, compounds of the disclosure are used to treat leukemia associated with a MLL rearrangement, acute lymphocytic leukemia associated with a MLL rearrangement, acute lymphoblastic leukemia associated with a MLL rearrangement, acute lymphoid leukemia associated with a MLL rearrangement acute myeloid leukemia associated with a MLL rearrangement, acute myelogenous leukemia associated with a MLL rearrangement, or acute myeloblastic leukemia associated with a MLL rearrangement. As used herein, “MLL rearrangement” means a rearrangement of the MLL gene. In some embodiments, diseases and conditions treatable with compounds of the disclosure include insulin resistance, pre-diabetes, diabetes (e.g., Type 2 diabetes or Type 1 diabetes), and risk of diabetes. In some embodiments, diseases and conditions treatable with compounds of the disclosure include hyperglycemia. In some embodiments, the hyperglycemia is associated with diabetes, such as Type 2 diabetes. In some embodiments, compounds of the disclosure are used to treat loss of response to other anti-diabetic agents and / or reduced beta cell function in a patient or subject. In some embodiments, compounds of the disclosure are used to restore response to other anti-diabetic agents and / or to restore beta cell function and / or to reduce the need for insulin in a patient or subject. In some embodiments, compounds of the disclosure are used to reduce insulin resistance, reduce the risk of diabetes, or reduce increases in blood glucose caused by a statin in a subject taking a statin. In some embodiments, compounds of the disclosure are used to treat diabetes in a subject taking a statin or to prevent diabetes in a subject taking a statin. Methods of the disclosure include decreasing, reducing, inhibiting, suppressing, limiting or controlling in the patient elevated blood glucose levels. In further aspects, methods of the disclosure include increasing, stimulating, enhancing, promoting, inducing or activating in the subject insulin sensitivity. Statins include, but are not limited to atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rousuvastatin and simvastatin. In some embodiments, a patient is treated with (e.g., administered) a compound of the present disclosure in an amount sufficient to treat or ameliorate one or more of the diseases and conditions recited above (e.g., a therapauetically effective amount). The compounds of the disclosure may also be useful in the prevention of one or more of the diseases recited therein. Combination Therapy The disclosure further relates to a combination therapy for treating a disease or a disorder described herein. In some embodiments, the combination therapy comprises administering at least one compound of the present disclosure in combination with one or more other pharmaceutically active agents for treating cancer or other disorders mediated by menin / MLL. In some embodiments the combination therapy comprises administering at least one compound of the present disclosure in combination with one or more other pharmaceutically active agents, such as for the treatment of cancer. The pharmaceutically active agents can be combined with a compound of the disclosure in a single dosage form, or the therapeutics can be administered simultaneously or sequentially as separate dosage forms. In some embodiments, the invention provides a combination therapy comprising a menin inhibitor of the present disclosure (e.g., a compound of Formula 0, Formula 0a, Formula I, Formula Ia, Formula II, Formula IIa, etc.) and a CYP3A4 inhibitor. In certain embodiments, the invention provides for a pharmaceutical composition comprising: (a) a menin inhibitor of the present disclosure (e.g., a compound of Formula 0, Formula 0a, Formula I, Formula Ia, Formula II, Formula IIa, etc.), and (b) a CYP3A4 inhibitor. In some embodiments, the invention is directed to a method for treating a patient comprising (a) administering a menin inhibitor of the present disclosure (e.g., a compound of Formula 0, Formula 0a, Formula I, Formula Ia, Formula II, Formula IIa, etc.), and (b) administering a CYP3A4 inhibitor. Some embodiments of this invention are directed to combination therapies designed to treat or manage cancer in a subject, wherein the combination therapies comprise administering a menin inhibitor of the present disclosure (e.g., a compound of Formula 0, Formula 0a, Formula I, Formula Ia, Formula II, Formula IIa, etc.) in combination with a CYP3A4 inhibitor. In particular, some embodiments of this invention are directed to methods of treating or managing cancer in a subject, comprising administering a menin inhibitor in combination with a therapeutically effective amount of a CYP3A4 inhibitor administered simultaneously, separately or sequentially. In some embodiments, the CYP3A inhibitor is: an antiarrhythmic; an antihistamine; an azole antifungal; a benzodiazepine; a calcium channel blocker; a HIV antiviral; a HMG CoA Reductase inhibitor; a macrolide antibiotic; a prokinetic; a protease inhibitor; or any combinations thereof. In some embodiments, the CYP3A inhibitor is: posaconazole, alprazolam; amiodarone; amlodipine; aprepitant; aripiprazole; astemizole; atorvastatin; boceprevir; buspirone; chloramphenicol; chlorpheniramine; cimetidine; ciprofloxacin; cisapride; clarithromycin; cobicistat (GS-9350); analogs or derivatives of cobicistat (GS-9350); cyclosporine; delaviridine; diazepamĺ3-OH; diethyl-dithiocarbamate; diltiazem; erythromycin; felodipine; fluconazole; fluvoxamine; gestodene; gleevec; grapefruit juice; haloperidol; imatinib; indinavir; itraconazole; ketoconazole; lovastatin; methadone; mibefradil; midazolam; mifepristone; nefazodone; nelfinavir; nifedipine; nisoldipine; nitrendipine; norfloxacin; norfluoxetine; pimozide; quinine; quinidineĺ3-OH; ritonavir; saquinavir; sildenafil; simvastatin; starfruit; tacrolimus (FK506); tamoxifen; telaprevir; telithromycin; trazodone; triazolam; verapamil; telaprevir; vincristine; voriconazole; or any combinations thereof. In some embodiments, the CYP3A4 inhibitor is posaconazole, cobicistat (GS-9350) or analogs or derivatives of cobicistat (GS-9350). In some embodiments, the CYP3A4 inhibitor is ketoconazole. In some embodiments, the CYP3A4 inhibitor is ritonavir. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are in separate dosage forms. In some embodiments, the pharmaceutical composition is in a combined dosage form. In some embodiments, the CYP3A4 inhibitor is posaconazole. In some embodiments, the pharmaceutical composition comprises an amount of the CYP3A4 inhibitor that is effective to increase the oral bioavailability of the menin inhibitor. The compounds according to the disclosure may also be used in combination with immunotherapies, including but not limited to cell-based therapies, antibody therapies and cytokine therapies, for the treatment of a disease or disorder disclosed herein. In certain embodiments, compounds according to the disclosure are used in combination with one or more passive immunotherapies, including but not limited to naked monoclonal antibody drugs and conjugated monoclonal antibody drugs. Examples of naked monoclonal antibody drugs that can be used include, but are not limited to, rituximab (Rituxan®), an antibody against the CD20 antigen; trastuzumab (Herceptin®), an antibody against the HER2 protein; alemtuzumab (Lemtrada®, Campath®), an antibody against the CD52 antigen; cetuximab (Erbitux®), an antibody against the EGFR protein; and bevacizumab (Avastin®) which is an anti- angiogenesis inhibitor of VEGF protein. Examples of conjugated monoclonal antibodies that can be used include, but are not limited to, radiolabeled antibody ibritumomab tiuxetan (Zevalin®); radiolabeled antibody tositumomab (Bexxar®); and immunotoxin gemtuzumab ozogamicin (Mylotarg®) which contains calicheamicin; BL22, an anti-CD22 monoclonal antibody-immunotoxin conjugate; radiolabeled antibodies such as OncoScint®and ProstaScint®; brentuximab vedotin (Adcetris®); ado- trastuzumab emtansine (Kadcyla®, also called TDM-1). Further examples of therapeutic antibodies that can be used include, but are not limited to, REOPRO®(abciximab), an antibody against the glycoprotein IIb / IIIa receptor on platelets; ZENAPAX®(daclizumab) an immunosuppressive humanized anti CD25 monoclonal antibody; PANOREX™, a murine anti-17-IA cell surface antigen IgG2a antibody; BEC2, a murine anti- idiotype (GD3 epitope) IgG antibody; IMC-C225, a chimeric anti-EGFR IgG antibody; VITAXIN™ a humanized anti-ĮVȕ3 integrin antibody; Campath 1H / LDP-03, a humanized anti CD52 IgG1 antibody; Smart M195, a humanized anti-CD33 IgG antibody; LYMPHOCIDE™, a humanized anti-CD22 IgG antibody; LYMPHOCIDE™ Y-90; Lymphoscan; Nuvion®(against CD3; CM3, a humanized anti-ICAM3 antibody; IDEC-114 a primatized anti-CD80 antibody; IDEC-131 a humanized anti-CD40L antibody; IDEC-151 a primatized anti-CD4 antibody; IDEC- 152 a primatized anti-CD23 antibody; SMART anti-CD3, a humanized anti-CD3 IgG; 5G1.1, a humanized anti-complement factor 5 (C5) antibody; D2E7, a humanized anti-TNF-Į antibody; CDP870, a humanized anti-TNF-Į Fab fragment; IDEC-151, a primatized anti-CD4 IgG1 antibody; MDX-CD4, a human anti-CD4 IgG antibody; CD20-streptdavidin (+biotin-yttrium 90); CDP571, a humanized anti-TNF-Į IgG4 antibody; LDP-02, a humanized anti-Į4ȕ7 antibody; OrthoClone OKT4A, a humanized anti-CD4 IgG antibody; ANTOVA™, a humanized anti- CD40L IgG antibody; ANTEGREN™, a humanized anti-VLA-4 IgG antibody; and CAT-152, a human anti-TGF-ȕ2 antibody. In certain embodiments, compounds according to the disclosure are used in combination with one or more targeted immunotherapies containing toxins but not an antibody, including but not limited to denileukin diftitox (Ontak®), IL-2 linked to diphtheria toxin. The compounds according to the disclosure may also be used in combination with adjuvant immunotherapies for the treatment of a disease or disorder disclosed herein. Such adjuvant immunotherapies include, but are not limited to, cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-1-alpha, interleukins (including IL-1, IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-18, IL-21, and IL-27), tumor necrosis factors (including TNF-alpha), and interferons (including IFN-alpha, IFN-beta, and IFN-gamma); aluminum hydroxide (alum); Bacille Calmette-Guérin (BCG); Keyhole limpet hemocyanin (KLH); Incomplete Freund's adjuvant (IFA); QS-21; DETOX; Levamisole; and Dinitrophenyl (DNP), and combinations thereof, such as, for example, combinations of interleukins, for example IL-2, with other cytokines, such as IFN-alpha. In certain embodiments, compounds according to the disclosure are used in combination with vaccine therapy including but not limited to autologous and allogeneic tumor cell vaccines antigen vaccines (including polyvalent antigen vaccines), dendritic cell vaccines, and viral vaccines. In another embodiment, the present disclosure comprises administering to a subject with cancer an effective amount of a compound of the disclosure and one or more additional anti-cancer therapies selected from: surgery, anti-cancer agents / drugs, biological therapy, radiation therapy, anti-angiogenesis therapy, immunotherapy, adoptive transfer of effector cells, gene therapy or hormonal therapy. Examples of anti-cancer agents / drugs are described below. In some embodiments, the anti-cancer agents / drug is, for example, adriamycin, aactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride; palbociclib; Yervoy®(ipilimumab); MekinistTM(trametinib); peginterferon alfa-2b, recombinant interferon alfa-2b; SylatronTM(peginterferon alfa-2b); Tafinlar®(dabrafenib); Zelboraf®(vemurafenib); or nivolumab. The compounds according to the present disclosure can be administered in combination with existing methods of treating cancers, for example by chemotherapy, irradiation, or surgery. Thus, there is further provided a method of treating cancer comprising administering an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt form thereof, to a subject in need of such treatment, wherein an effective amount of at least one additional cancer chemotherapeutic agent is administered to the subject. Examples of suitable cancer chemotherapeutic agents include any of: abarelix, ado-trastuzumab emtansine, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, emtansine, epirubicin, eribulin, erlotinib, estramustine, etoposide phosphate, etoposide, everolimus, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fruquintinib, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, ixabepilone lapatinib ditosylate lenalidomide letrozole leucovorin leuprolide acetate levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pertuzuma, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, sorafenib, streptozocin, sulfatinib, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, volitinib, vorinostat, and zoledronate. In particular embodiments, compounds according to the disclosure are used in combination with one or more anti-cancer agent selected from methotrexate, paclitaxel albumin-stabilized nanoparticle formulation, ado-trastuzumab emtansine, eribulin, doxorubicin, fluorouracil, everolimus, anastrozole, pamidronate disodium, exemestane, capecitabine, cyclophosphamide, docetaxel, epirubicin, toremifene, fulvestrant, letrozole, gemcitabine, gemcitabine hydrochloride, goserelin acetate, trastuzumab, ixabepilone, lapatinib ditosylate, megestrol acetate, tamoxifen citrate, pamidronate disodium, palbociclib, and pertuzumab for the treatment of breast cancer. Other anti-cancer agents / drugs include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors; castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclin-dependent kinase inhibitors; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9- dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate;fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1- based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N acetyldinaline; N substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitors; microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras- GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; zanoterone; zilascorb; zinostatin stimalamer; 5-fluorouracil; and leucovorin. In some embodiments, the anti-cancer agent / drug is an agent that stabilizes microtubules. As used herein, a "microtubulin stabilizer" means an anti-cancer agent / drug which acts by arresting cells in the G2-M phases due to stabilization of microtubules. Examples of microtubulin stabilizers include ACLITAXEL®and Taxol®analogues. Additional examples of microtubulin stabilizers include without limitation the following marketed drugs and drugs in development: Discodermolide (also known as NVP-XX-A-296); Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA); Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B); Epothilone E; Epothilone F; Epothilone B N-oxide; Epothilone A N-oxide; 16-aza-epothilone B; 21-aminoepothilone B (also known as BMS-310705); 21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone); FR-182877 (Fujisawa, also known as WS-9885B), BSF-223651 (BASF, also known as ILX-651 and LU-223651); AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCl); AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A); Fijianolide B; Laulimalide; Caribaeoside; Caribaeolin; Taccalonolide; Eleutherobin; Sarcodictyin; Laulimalide; Dictyostatin-1; Jatrophane esters; and analogs and derivatives thereof. In another embodiment, the anti-cancer agent / drug is an agent that inhibits microtubules. As used herein, a "microtubulin inhibitor" means an anti-cancer agent which acts by inhibiting tubulin polymerization or microtubule assembly. Examples of microtubulin inhibitors include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104); Dolastatin 10 (also known as DLS-10 and NSC-376128); Mivobulin isethionate (also known as CI-980); Vincristine; NSC-639829; ABT-751 (Abbott, also known as E-7010); Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C); Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9); Cemadotin hydrochloride (also known as LU- 103793 and NSC-D-669356); Auristatin PE (also known as NSC-654663); Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577); LS-4578 (Pharmacia, also known as LS-477-P); LS-4477 (Pharmacia), LS-4559 (Pharmacia); RPR-112378 (Aventis); Vincristine sulfate; DZ-3358 (Daiichi); GS-164 (Takeda); GS-198 (Takeda); KAR-2 (Hungarian Academy of Sciences); SAH 49960 (Lilly / Novartis); SDZ 268970 (Lilly / Novartis); AM 97 (Armad / Kyowa Hakko); AM-132 (Armad); AM-138 (Armad / Kyowa Hakko); IDN-5005 (Indena); Cryptophycin 52 (also known as LY-355703); Vitilevuamide; Tubulysin A; Canadensol; Centaureidin (also known as NSC-106969); T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067); COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261); H10 (Kansas State University); H16 (Kansas State University); Oncocidin A1 (also known as BTO-956 and DIME); DDE-313 (Parker Hughes Institute); SPA-2 (Parker Hughes Institute); SPA-1 (Parker Hughes Institute, also known as SPIKET-P); 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-569); Narcosine (also known as NSC-5366); Nascapine, D-24851 (Asta Medica), A-105972 (Abbott); Hemiasterlin; 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-191); TMPN (Arizona State University); Vanadocene acetylacetonate; T-138026 (Tularik); Monsatrol; Inanocine (also known as NSC-698666); 3-IAABE (Cytoskeleton / Mt. Sinai School of Medicine); A-204197 (Abbott); T-607 (Tularik, also known as T-900607); RPR-115781 (Aventis); Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin); Halichondrin B; D-64131 (Asta Medica); D-68144 (Asta Medica); Diazonamide A; A-293620 (Abbott); NPI-2350 (Nereus); TUB-245 (Aventis); A-259754 (Abbott); Diozostatin; (-)-Phenylahistin (also known as NSCL-96F037); D-68838 (Asta Medica); D-68836 (Asta Medica); Myoseverin B; D-43411 (Zentaris, also known as D-81862); A-289099 (Abbott); A-318315 (Abbott); HTI-286 (also known as SPA-110, trifluoroacetate salt) (Wyeth); D-82317 (Zentaris); D-82318 (Zentaris); SC-12983 (NCI); Resverastatin phosphate sodium; BPR- 0Y-007 (National Health Research Institutes); SSR-250411 (Sanofi); Combretastatin A4; eribulin (Halaven®); and analogs and derivatives thereof. In further embodiments, compounds according to the disclosure are used in combination with one or more alkylating agents, antimetabolites, natural products, or hormones. Examples of alkylating agents useful in the methods of the disclosure include but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites useful in the methods of the disclosure include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine cytarabine) and purine analogs (eg mercaptopurine thioguanine pentostatin) Examples of natural products useful in the methods of the disclosure include but are not limited to vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide, teniposide), antibiotics (e.g., actinomycin D, daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin) or enzymes (e.g., L-asparaginase). Examples of hormones and antagonists useful for the treatment of cancer include but are not limited to adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), and gonadotropin releasing hormone analog (e.g., leuprolide). Other agents that can be used in combination with the compounds of the disclosure for the treatment of cancer include platinum coordination complexes (e.g., cisplatin, carboblatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), and adrenocortical suppressant (e.g., mitotane, aminoglutethimide). Other anti-cancer agents / drugs that can be used in combination with the compounds of the disclosure include, but are not limited to, liver X receptor (LXR) modulators, including LXR agonists and LXR beta-selective agonists; aryl hydrocarbon receptor (AhR) inhibitors; inhibitors of the enzyme poly ADP ribose polymerase (PARP), including olaparib, iniparib, rucaparib, veliparib; inhibitors of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including cediranib; programmed cell death protein 1 (PD-1) inhibitors, including nivolumab (Bristol-Myers Squibb Co.) and pembrolizumab (Merck & Co., Inc.; MK-3475); MEK inhibitors, including cobimetinib; B-Raf enzyme inhibitors, including vemurafenib; cytotoxic T lymphocyte antigen (CTLA-4) inhibitors, including tremelimumab; programmed death-ligand 1 (PD-L1) inhibitors, including MEDI4736 (AstraZeneca); inhibitors of the Wnt pathway; inhibitors of epidermal growth factor receptor (EGFR) including AZD9291 (AstraZeneca), erlotinib, gefitinib, panitumumab, and cetuximab; adenosine A2A receptor inhibitors; adenosine A2B receptor inhibitors; colony-stimulating factor-1 receptor (CSF1R) inhibitors, including PLX3397 (Plexxikon), and inhibitors of CD73. The compounds of the disclosure can be used in combination with one or more therapeutic strategies including immune checkpoint inhibitors, including inhibitors of PD-1, PD-L1, and CTLA 4 The compounds of the disclosure can be used in combination with one or more anti-cancer agents selected from MCL-1 inhibitors, e.g., homoharringtonin (HHT) and omacetaxine; BCL-2 inhibitors, e.g., venetoclax (ABT-199), navitoclax (ABT-263), ABT-737, gossypol (AT-101), apogossypolone (ApoG2) and obatoclax; selective inhibitors of nuclear export (SINEs), e.g., selinexor (KPT-330). In particular embodiments, the compounds of the disclosure are used in combination with one or more anti-cancer agents selected from methotrexate (Abitrexate®; Folex®; Folex PFS®; Mexate®; Mexate-AQ®); nelarabine (Arranon®); blinatumomab (Blincyto®); rubidomycin hydrochloride or daunorubicin hydrochloride (Cerubidine®); cyclophosphamide (Clafen®; Cytoxan®; Neosar®); clofarabine (Clofarex®; Clolar®); cytarabine (Cytosar-U®; Tarabine PFS®); dasatinib (Sprycel®); doxorubicin hydrochloride; asparaginase Erwinia chrysanthemi (Erwinaze); imatinib mesylate (Gleevec®); ponatinib hydrochloride (Iclusig®); mercaptopurine (Purinethol; Purixan); pegaspargase (Oncaspar®); prednisone; vincristine sulfate (Oncovin®, Vincasar PFS®, Vincrex®); vincristine sulfate liposome (Marqibo®); hyper-CVAD (fractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone); arsenic trioxide (Trisenox®); idarubicin hydrochloride (Idamycin®); mitoxantrone hydrochloride; thioguanine (Tabloid®); ADE (cytarabine, daunorubicin, and etoposide); alemtuzumab (Lemtrada®, Campath®); chlorambucil (Ambochlorin®, Amboclorin®, Leukeran®, Linfolizin®); ofatumumab (Arzerra®); bendamustine hydrochloride (Treanda®); fludarabine phosphate (Fludara®); obinutuzumab (Gazyva®); ibrutinib (Imbruvica®); idelalisib (Zydelig®); mechlorethamine hydrochloride (Mustargen®); rituximab (Rituxan®); chlorambucil-prednisone; CVP (cyclophosphamide, vincristine, and prednisone); bosutinib (Bosulif®); busulfan (Busulfex®; Myleran®); omacetaxine mepesuccinate (Synribo®); nilotinib (Tasigna®); Intron®A (recombinant interferon Alfa-2b); DOT1L inhibitors, including EPZ-5676 (Epizyme, Inc.); and inhibitors of bromodomain and extra-terminal motif (BET) proteins (BET inhibitors), including MS417, JQ1, I-BET 762, and I-BET 151 for the treatment of leukemia. Compounds of the disclosure can be used in combination with one or more other agents or therapies for the treatment of insulin resistance, pre-diabetes, diabetes (e.g., Type 2 diabetes or Type 1 diabetes), and risk of diabetes, including but not limited to insulins and insulin analogues, such as Humulin®(EIi Lilly), Lantus® (Sanofi Aventis), Novolin®(Novo Nordisk), and Exubera®(Pfizer); Avandamet®(metformin HCI and rosiglitazone maleate GSK); Avandaryl®(glimepiride and rosiglitazone maleate, GSK); Metaglip®(glipizide and metformin HCI, Bristol Myers Squibb); Glucovance®(glyburide and metformin HCI, Bristol Myers Squibb); PPAR gamma agonists, such as Avandia®(rosiglitizone maleate, GSK) and Actos®(pioglitazone hydrochloride, Takeda / Eli Lilly); sulfonylureas, such as Amaryl®(glimepiride, Sanofi Aventis), Diabeta®(glyburide, Sanofi Aventis), Micronase® / Glynase®(glyburide, Pfizer), and Glucotrol® / Glucotrol XL®(glipizide, Pfizer); meglitinides, such as Prandin® / NovoNorm®(repaglinide, Novo Nordisk), Starlix®(nateglinide, Novartis), and Glufast®(mitiglinide, Takeda); biguanides, such as Glucophase® / Glucophase XR®(metformin HCI, Bristol Myers Squibb) and Glumetza®(metformin HCI, Depomed); thiazolidinediones; amylin analogs; GLP-1 analogs; DPP-IV inhibitors such as Januvia®(sitagliptin, Merck) and Galvus®(vildagliptin, Novartis); PTB-1 B inhibitors; protein kinase inhibitors (including AMP-activated protein kinase inhibitors); glucagon antagonists, glycogen synthase kinase-3 beta inhibitors; glucose-6-phoshatase inhibitors; glycogen phosphorylase inhibitors; sodium glucose co-transporter inhibitors; and alpha-glucosidase inhibitors, such as Glycet®(miglitol, Pfizer); statins, fibrates, and Zetia®(ezetimibe); alpha- blockers; beta-blockers; calcium channel blockers; diuretics; angiotensin converting enzyme (ACE) inhibitors; dual ACE and neutral endopeptidase (NEP) inhibitors; angiotensin-receptor blockers (ARBs); aldosterone synthase inhibitors; aldosterone-receptor antagonists; endothelin receptor antagonists; orlistat; phentermine; sibutramine; Acomplia®(rimonabant); thiazolidinediones (e.g., rosiglitazone, pioglitazone); SGLT 2 inhibitors (e.g., dapagliflozin, remogliflozin etabonate, sergliflozin, canagliflozin, and 1 -chloro-4-(ȕ-D- glucopyranos-1-yl)-2- [4-(('S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene); PPAR-gamma-agonists (e.g., Gl 262570) and antagonists; PPAR-gamma / alpha modulators (e.g., KRP 297); alpha-glucosidase inhibitors (e.g., acarbose, voglibose); DPPIV inhibitors (e.g., Januvia®(sitagliptin), Galvus® / Zomelis®(vildagliptin), Onglyza®(saxagliptin), Nesina® / Vipidia®(alogliptin), and Tradjenta® / Trajenta®(linagliptin)); alpha2-antagonists; glucagon-like protein-1 (GLP-1) receptor agonists and analogues (e.g., exendin-4); amylin; inhibitors of protein tyrosinephosphatase 1; substances that affect deregulated glucose production in the liver, e.g., inhibitors of glucose-6-phosphatase, or fructose-1 ,6- bisphosphatase, glycogen phosphorylase; glucagon receptor antagonists; inhibitors of phosphoenol pyruvate carboxykinase; glycogen synthase kinase and glucokinase activators; lipid lowering agents such as HMG-CoA-reductase inhibitors (e.g., simvastatin, atorvastatin); fibrates (eg bezafibrate fenofibrate) nicotinic acid and the derivatives thereof PPAR alpha agonists, PPAR-delta agonists; ACAT inhibitors (e.g., avasimibe); cholesterol absorption inhibitors such as ezetimibe; bile acid-binding substances such as cholestyramine; inhibitors of ileac bile acid transport; HDL-raising compounds such as CETP inhibitors and ABC1 regulators; active substances for treating obesity such as sibutramine and tetrahydrolipostatin; SDRIs; axokine; leptin; leptin mimetics; antagonists of the cannabinoid l receptor; and MCH-1 receptor antagonists; MC4 receptor agonists; NPY5 and NPY2 antagonists; beta3 adrenergic agonists such as SB- 418790 and AD-9677; agonists of the 5HT2c receptor; GABA-receptor antagonists; Na- channel blockers; topiramate; protein-kinase C inhibitors; advanced glycation end product inhibitors; and aldose reductase inhibitors. Pharmaceutical Formulations, Administration, and Dosage Forms When employed as pharmaceuticals, the compounds of the disclosure can be administered in the form of a pharmaceutical composition which refers to a combination of a compound of the disclosure, or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. This disclosure also includes pharmaceutical compositions which contain, as the active ingredient one or more of the compounds of the disclosure above in combination with one or more pharmaceutically acceptable carriers. In making the compositions of the disclosure, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. Compounds or compositions described herein may be administered to a patient using any amount and any route of administration effective for treating or lessening the severity of one or more of the diseases and conditions described herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, disease or disorder, the particular agent, its mode of administration, and the like. Provided compounds are preferably formulated in a particular unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. The therapeutic dosage of the compounds of the present disclosure can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the disclosure in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the disclosure can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. EXAMPLES As depicted in the Examples below, compounds of the disclosure were prepared and isolated according to the following general procedures. It will be appreciated that, although the general methods may depict the synthesis of certain compounds of the present disclosure, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

[0005] LCMS Instrument names: Shimadzu LC2020 Nexera Series; Shimadzu MS2020 N-Series; Agilent 1290 Method A: Mobile Phase A: 10 mM Ammonium Bicarbonate in water; Mobile Phase B: ACN; Flow Rate: 0.8 mL / min; Column: X Bridge C8 (50 x 4.6 mm), 3.5 um Method B: Mobile Phase: 0.1% HCOOH in water / ACN (95:5); Flow Rate: 0.8 mL / min; Column: ZORBAX ECLIPSE PLUS C18 (50 x 2.1 mm), 1.8 um Method C: Mobile Phase: 10mM NH4OAc in water / ACN (95:5); Flow Rate: 0.6 mL / min; Column: Acquity UPLC BEH C18 (2.1 x 50 mm), 1.7 um Method D: Mobile phase: A: 0.1% TFA in water, B: ACN; Column: Acquity UPLC BEH C18 (2.1 x 50)mm,1.7 Pm. Method E: Mobile Phase: A: 10 mM NH4HCO3 in water, B: ACN; Column: Phenomenex Kinetex EVO C18 (3.0 x 50 mm), 2.6 Pm. Method F: Mobile Phase: A: 0.1% TFA in water, B: ACN; Column: ZORBAX ECLIPSE PLUS C18 (50 x 2.1 mm), 1.8 Pm. HPLC Instrument names: Shimadzu LC; Prominence-I series instruments as followed using % with UV detection (Maxplot) Method A: Mobile Phase: A-10 mM NH4HCO3in water, B: ACN; flow rate: 2.0 mL / min; Column: X-Bridge C8 (150 x 4.6 mm, 5 μm). Method B: Mobile Phase: A; 0.1% TFA in water, B: ACN; flow rate: 2.0 mL / min; Column: X-Bridge C8 (50 x 4.6 mm, 3.5 μm). Method C: Mobile Phase: A-0.1% TFA in water, B: ACN; flow rate: 1.0 mL / min; Column: Atlantis column C18 (4.6 x 250 mm, 5 μm). Method D: Mobile Phase: A- 10mm NH4OAc in water, B: ACN; flow rate: 1.5 mL / min; Column: Gemini NX C18 (4.6X150mm, 3 ^m). Method E: Mobile Phase A: 0.1% HCOOH in water, B: ACN; Flow Rate: 2.0 mL / min; Column: X-Select C18 (4.6X150mm, 5 ^m). Method F: Mobile Phase A: 0.1% HCOOH in water, B: ACN; Flow Rate: 2.0 mL / min; Column: X-Select C18 (4.6X150mm, 5 ^m). Method G: Mobile Phase A: 0.1% TFA in water, B: ACN; Flow Rate: 2.0 mL / min; Column: X-Select C18 (4.6X150mm, 5 ^m). Prep-HPLC Instrument names: Agilent Technologies 1260 Infinity II Series LC / 6125 Quadrupole MSD Shimadzu Nexera Prep HPLC with LCMS 2020 Method A: Mobile phase A: 10 mM NH4HCO3 in water; mobile Phase B: ACN; Flow Rate: 15 mL / min; Column: XBridge C18 (150 x 19 mm), 5 um Prep-HPLC Instrument names: Agilent Technologies 1260 Infinity II Series LC / 6125 MSD; Shimadzu P HPLC MS2020 Method A: Mobile phase A: 10 mm NH4HCO3 in water; mobile Phase B: ACN; Flow Rate: 15.0 mL / min; Column: ZORBAX C 18 (50 x 21.2 mm), 5 μm. Method B: Mobile phase A: 10 mm NH4HCO3in water; mobile Phase B: ACN; Flow Rate: 15.0 mL / min; Column: X-Bridge C18 (150 x 19.0 mm), 5 μm. Method C: Mobile phase A: 10 mm NH4HCO3 in water; mobile Phase B: ACN; Flow Rate: 15.0 mL / min; Column: SHIMPACK GIST C18 (150 x 20.0 mm) 5 μm. Method D: Mobile phase A: 10 mm NH4HCO3in water; mobile Phase B: ACN; Flow Rate: 15.0 mL / min; Column: SHIMPACK GIST C18 (250 x 20.0 mm) 5 μm. Method E: Mobile phase A: 10 mm NH4HCO3in water; mobile Phase B: ACN; Flow Rate: 15.0 mL / min; Column: SHIMPACK SCEPTER C8 (150 x 20.0 mm) 5 μm. Method F: Mobile phase A: 10 mm NH4HCO3 in water; mobile Phase B: ACN; Flow Rate: 15.0 mL / min; Column: SHIMPACK SCEPTER C8 (250 x 20.0 mm) 5 μm. Method G: Mobile phase A: 10 mm NH4HCO3in water; mobile Phase B: ACN; Flow Rate: 15.0 mL / min; Column: Gemini -NX-C18 ((250 x 21.2 mm), 5 μm. Method H: Mobile phase A: 0.1% Formic acid in water, mobile phase B: ACN; Flow Rate: 15.0 mL / min; Column: X-Select - C18 (250 x 19.0 mm), 5 μm. Method I Mobile phase A: 10 mm NH4HCO3in water; mobile Phase B: ACN; Flow Rate: 15.0 mL / min; Column: X-Bridge C18 (250 x 19.0 mm), 5 μm. Method J: Mobile phase A: 10 mm NH4HCO3in water; mobile Phase B: ACN; Flow Rate: 15.0 mL / min; Column: ZORBAX C18 (50 x 21.2 mm), 5 μm. Method K: Mobile phase A: 0.1% Formic acid in water, mobile phase B: ACN; Flow Rate: 15.0 mL / min; Column: ZORBAX C 18 (250 x 21.2 mm), 5 μm. Method L: Mobile phase A: 10 mm NH4HCO3in water; mobile Phase B: ACN; Flow Rate: 15.0 mL / min; Column: YMC C18 (250 x 20.0 mm), 5 μm. Chiral SFC Instrument names: SFC Analytical - PIC 10-20 and Shimadzu Analytical with MS and ELSD detectors. Method A: Mobile Phase A: CO2; Co-solvent - 0.5% isopropylamine in IPA:MeOH (50:50); Flow Rate: 4.0 mL / min; % Co-Solvent : 35%, Column: Lux-A1 (250 x 4.6), 5 ^m. Method B: Mobile Phase A: CO2; Co-solvent - 0.5% isopropylamine in IPA; Flow Rate: 5.0 mL / min; % Co-Solvent : 40%, Column: Lux-A1 (250 x 4.6), 5 ^m. Method C: Mobile Phase A: CO2; Co-solvent - 0.5% isopropylamine in MeOH; Flow Rate: 5.0 mL / min; % Co-Solvent : 40%, Column: Lux-A1(250 x 4.6), 5 ^m. Method D: Mobile Phase A: CO2; Co-solvent - 0.5% isopropylamine in MeOH; Flow Rate: 5.0 mL / min; % Co-Solvent : 40%, Run time: 12 min; Column: LUX-C4, (250 x 4.6), 5 ^m. Method E: Mobile Phase A: CO2; Co-solvent - 0.5% isopropylamine in MeOH; Flow Rate: 4.0 mL / min; % Co-Solvent : 40%, Run time: 12 min; Column: LUX-C4, (250 x 4.6), 5 ^m. Method F: Mobile Phase A: CO2; Co-solvent - 0.5% isopropylamine in MeOH; Flow Rate: 5.0 mL / min; % Co-Solvent : 50%, Run time: 12 min; Column: LUX-C4, (250 x 4.6), 5 ^m. Method G: Mobile Phase A: CO2; Co-solvent - 0.5% isopropylamine in IPA; Flow Rate: 4.0 mL / min; % Co-Solvent : 40%; Column: I-Cellulose B (250 x 4.6), 5 ^m. Method H: Mobile Phase A: CO2; Co-solvent - 0.5% isopropylamine in IPA; Flow Rate: 5.0 mL / min; % Co-Solvent : 50%; Column: I-Cellulose B (250 x 4.6), 5 ^m. Method I: Mobile Phase A: CO2; Co-solvent - 0.5% isopropylamine in MeOH; Flow Rate: 4.0 mL / min; % Co-Solvent : 40%; Column: I-Cellulose B (250 x 4.6), 5 ^m. Method J: Mobile Phase A: CO2; Co-solvent - 0.5% isopropylamine in MeOH; Flow Rate: 4.0 mL / min; % Co-Solvent : 40%, Column: Whelk-01_(R,R) (250 x 4.6), 5 ^m. Method K: Mobile Phase A: CO2; Co-solvent - 0.1 % NH3in IPA:MeOH (50:50); Flow Rate: 4.0 mL / min; % Co-Solvent : 20%, Column: Reflect I-Amylose A (250 x 4.6), 5 ^m. Method L: Mobile Phase A: CO2; Co-solvent - 0.5% isopropylamine in IPA; Flow Rate: 4.0 mL / min; % Co-Solvent : 40%, Column: YMC Amylose-SA (250 x 4.6), 5 ^m. Method M: Mobile Phase A: CO2; Co-solvent - 0.5% isopropylamine in MeOH; Flow Rate: 5.0 mL / min; % Co-Solvent : 50%, Column: Chiralpak AS-H, (250 x 4.6), 5 ^m. Method K: Mobile Phase A: CO2; Co-solvent - 0.5% isopropylamine in IPA; Flow Rate: 5.0 mL / min; % Co-Solvent : 35%, Column: Lux-A3, (250 x 4.6), 5 ^m. Method L: Mobile Phase A: CO2; Co-solvent - 0.5% isopropylamine in MeOH; Flow Rate: 5.0 mL / min; % Co-Solvent: 30%; Column: I-Cellulose B (250 x 4.6), 5 ^m. Prep-SFC Instrument names SFC Preparative PIC 175 Method A: Mobile Phase: CO2: 0.5% Isopropylamine in IPA: ACN (70:30); Flow Rate: 100 mL / min; Column: Lux Amylose-1 (250*30) mm, 5 ^m. Method B: Mobile Phase: CO2: 0.5% Isopropylamine in IPA (65:35); Flow Rate: 100 mL / min; Column: YMC Amylose-SA (250*30) mm, 5 ^m. Method C: Mobile Phase: CO2: 0.5% isopropylamine in IPA:ACN(1:1) [65:35]; Flow Rate: 100 mL / min; Column: Lux Amylose-3(250*30)mm, 5 ^m. Synthesis of Intermediates Intermediate 1. 2-((4-(2,7-Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5- fluoro-N-isopropylbenzamide, hydrochloride Step 1.5-(2-Bromo-4-fluorophenoxy)pyrimidine In a dried, 1000 mL three-necked round bottom flask under nitrogen atmosphere, 2-bromo- 4-fluorophenol (50 g, 262 mmol) was dissolved in DMA (300 mL). To this reaction mixture cesium carbonate (111 g, 340 mmol) and 5-bromopyrimidine (42.9 g, 270 mmol) were added at 25oC under nitrogen atmosphere. The reaction mixture was stirred at 120oC for 64 h under nitrogen atmosphere. Reaction progress was monitored by LCMS (Method B; 58% product, 20.7% bromopyridine, 14.5% phenolic compound). After this time, the reaction was cooled to 25oC and reverse-quenched in water (1000 mL). The aqueous layer was then extracted with MTBE (3 x 300 mL). The combined organic layer was washed with 2 N sodium hydroxide solution (250 mL), followed by 0.5 M citric acid solution (250 mL), and finally with 5 wt% sodium bicarbonate solution (250 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator under reduced pressure (bath temperature 45oC) to obtain crude compound as yellow oil (51.4 g). The crude compound was purified on Isolera column chromatography using 100-200 silica and eluting with ethyl acetate in hexane (the desired product eluted with 20% ethyl acetate in hexane) to obtain 5-(2-bromo-4-fluorophenoxy)pyrimidine (38 g, 117 mmol, 44.8 % yield) as pale yellow oil: Rf = 0.52 (20% EtOAc in petroleum ether;1H NMR (400 MHz, DMSO- d6): į 8.99 (s, 1H), 8.57 (s, 2H), 7.82-7.79 (m, 1H), 7.45-7.37 (m, 2H); LCMS (Method B): Rt =1.97 min, 271.9 (M+2)+. Step 2. Methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate In a 250 mL tiny clave charged with 5-(2-bromo-4-fluorophenoxy)pyrimidine (9 g, 33.4 mmol) and methanol (125 mL) purged with nitrogen, was added triethylamine (23.34 mL, 167 mmol) followed by 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (2.447 g, 3.34 mmol). The reaction was stirred under 100 psi carbon monoxide gas (Caution: toxic gas) at 80oC for 48 hr. The reaction was monitored by TLC (30 % EtOAc in hexane; at 36 hr, LCMS Method B showed 34 % product, 30 % SM). After completion of the reaction, the reaction mixture was cooled to 25oC, and filtered over a Celite^ pad to remove the palladium catalyst. The Celite^ pad was washed with methanol (2 x 50 mL). The organic layers were dried over sodium sulfate and concentrated on a rotary evaporator under reduced pressure (bath temperature 45oC) to afford crude product (12 g, brown-colored liquid). The crude product was purified by column chromatography (Isolera), using ethyl acetate and hexane as an eluting solvent system (the product eluted at 20 % ethyl acetate in hexane) to afford pure methyl 5-fluoro- 2-(pyrimidin-5-yloxy)benzoate (3.6 g, 41.5% yield) as a colorless liquid:1H NMR (400 MHz, CDCl3): į ppm 8.96 (s, 1H), 8.39 (s, 2H), 7.75 (dd, J = 2.8, 8.6 Hz, 1H), 7.36-7.33 (m, 1H), 7.15 (dd, J = 4.4, 9.0 Hz, 1H), 3.83 (s, 3H); LCMS (Method B): Rt = 1.77 min, 249.2 (M+H)+. Step 3.5-Fluoro-2-(pyrimidin-5-yloxy)benzoic acid In 500 mL three necked round bottom flask methyl 5-fluoro-2-(pyrimidin-5- yloxy)benzoate (16 g, 64.5 mmol) was dissolved in MeOH (112 mL) and water (48 mL). To this reaction mixture was added NaOH (10.31 g, 258 mmol) and the reaction mixture was stirred at 25 consumption of the ester, the reaction mixture was concentrated on a rotary evaporator under reduced pressure (bath temperature 45oC) and diluted with water (200 mL). The reaction mixture was extracted with ethyl acetate (3 x 100 mL). These organic extracts were discarded. The remaining aqueous layer was acidified by dropwise addition of 6N HCl (100 mL) and extracted with ethyl acetate (3 x 100 mL). Combined organic layers were dried over sodium sulfate and concentrated on a rotary evaporator under reduced pressure (bath temperature 45oC) to obtain 5- fluoro-2-(pyrimidin-5-yloxy)benzoic acid (14.1 g, 91%) as an off-white solid:1-NMR (400 MHz, DMSO-d6): į 8.92 (s, 1H), 8.47 (s, 2H), 7.70 (dd, J = 3.20, 8.80 Hz, 1H), 7.58-7.53 (m, 1H), 7.40 (dd, J = 4.80, 9.00 Hz, 1H); LCMS (Method B): Rt = 1.49 min, 235.2 (M + H)+. In a dried, 500 mL two-necked round bottom flask under nitrogen atmosphere 5-fluoro-2- (pyrimidin-5-yloxy) benzoic acid (14 g, 59.8 mmol) was dissolved in DMF (140 mL). To this solution, N-ethylpropan-2-amine (7.96 mL, 65.8 mmol), HATU (27.3 g, 71.7 mmol) and TEA (16.67 mL, 120 mmol) were added at 25oC under nitrogen atmosphere and the reaction mixture was stirred at 25oC for 11 h. The reaction progress was monitored by TLC (100% EtOAc). After completion of the reaction, the reaction mixture was quenched with water (500 mL) and the aqueous layer was extracted with ethyl acetate (3 x 150 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated on a rotary evaporator (bath temperature 40oC) to afford the crude compound. The crude compound was purified by column chromatography (Isolera) using 100-200 silica gel eluting with ethyl acetate in hexane (desired product eluted in 55-60 % EtOAc in hexane). The fractions containing the required product were concentrated under reduced pressure to obtain N-ethyl-5-fluoro-N-isopropyl-2- (pyrimidin-5-yloxy)benzamide (16.1 g, 86.0 % yield) as an oily mass:1H NMR (400 MHz, DMSO-d6): į 8.95 (s, 1H), 8.52 (d, J = 8.80 Hz, 2H), 7.37-7.34 (m, 3H), 4.27-3.74 (m, 1H), 3.38- 3.36 (m, 1H), 3.19-3.12 (m, 1H), 1.14-0.96 (m, 9H). LCMS (Method B): Rt = 1.85 min, 304.0 (M+H)+. In a dried, 250 mL three-necked round bottom flask was added N-ethyl-5-fluoro-N- isopropyl-2-(pyrimidin-5-yloxy)benzamide (16 g, 52.7 mmol) in tetrahydrofuran (160 mL). The resulting mixture was cooled to 0oC and urea-hydrogen peroxide (1 / 1; 9.92 g, 105 mmol) was added, followed by dropwise addition of TFAA (15.17 mL, 108 mmol), maintaining the reaction temperature below 10oC. The reaction mixture was then stirred at 0 to 10oC for 1 h, and the reaction progress was monitored by TLC (100 % ethyl acetate). After 1 h, the reaction was quenched by adding 5% NaHCO3 (60 mL), maintaining the temperature below 10oC. The product was extracted with DCM (2 x 150 mL) and the organic layer was washed with 5% NaHCO3(2 x 60 mL). To the organic layer 1M Na2S2O3 solution (70 mL) was added and the mixture was stirred for 15 min. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated on a rotary evaporator under reduced pressure (bath temperature 30oC) to approximately one volume remaining in the flask. Ethyl acetate (2 x 60 mL) was added to the one volume solution remaining in the flask and concentrated on a rotary evaporator again to one volume remaining in the flask (Note: do not dry the mass completely). Hexane (250 mL) was added to the flask containing the concentrate. The precipitate obtained was stirred for 30 min at 25oC. The solid was collected by filtration and suction-dried to obtain 5-(2- (ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine 1-oxide (16.0 g, 77.0% yield) as an off- white solid: LCMS (Method B): Rt = 1.58 min, 320.0 (M+H)+. To a dried, 500 mL three-necked round bottom flask under nitrogen atmosphere, 5-(2- (ethyl-(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine 1-oxide (16 g, 50.1 mmol) was added to ethyl acetate (200 mL). DIPEA (43.6 mL, 251 mmol) was added at 0oC. The reaction mixture was stirred for 10 min at 0oC and then phosphoryl trichloride (5.62 mL, 60.1 mmol) was added dropwise at 0oC. After complete addition, the reaction mixture was stirred for 30 min at 0oC, slowly allowed to warm to 25oC, and stirred for 2 h. The reaction progress was monitored by TLC (100% EtOAc). After completion of the reaction, the reaction mixture was quenched with cold water (25 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated on a rotary evaporator under reduced pressure (bath temperature 45oC) to afford the crude compound. The crude compound was purified by column chromatography (Isolera) by using 100-200 mesh silica gel and eluting with ethyl acetate in hexane (the desired product eluted in 25% ethyl acetate in hexane). The fractions containing the required product were concentrated under reduced pressure to obtain 2-((4-chloropyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (5.82 g, 30.0% yield) as a brown gummy liquid: LCMS (Method B): Rt = 1.96 min, 338.0 (M+H)+. In a dried, 250 mL three-necked round bottom flask, 2-((4-chloropyrimidin-5-yl)oxy)-N- ethyl-5-fluoro-N-isopropylbenzamide (5.82 g, 17.23 mmol) was dissolved in 2-propanol (50 mL). To this solution, TEA (7.20 mL, 51.7 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7- carboxylate hydrochloride (5.43 g, 20.68 mmol) were added at 25oC under nitrogen atmosphere, and the resulting reaction was heated at 80oC for 18 h. The reaction progress was monitored by TLC (100% EtOAc). After complete consumption of the amine, the solvent was distilled off and the residue was quenched with ice water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated on a rotary evaporator under reduced pressure (bath temperature 45oC) to afford the crude product. The crude product was purified by column chromatography (Isolera) by using 100-200 mesh silica gel and eluting with ethyl acetate in hexane (the desired product eluted in 30- 70 % ethyl acetate in hexane) The fractions containing the desired product were concentrated under reduced pressure to obtain tert-butyl 2-(5-(2-(ethyl(isopropyl)carbamoyl)-4- fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (6.1g, 61.5% yield) as a semi-solid:1H NMR (400 MHz, CDCl3): į 8.40 (s, 1H), 7.81 (s, 1H), 7.05-7.01 (m, 2H), 6.77- 6.74 (m, 1H), 4.00-3.85 (m, 5H), 3.50-3.20 (m, 6H), 1.72 (t, J = 6.80 Hz, 3H), 1.47 (s, 9H), 1.29- 1.15 (m, 9H).); LCMS (Method C): Rt = 2.12 min, 528.2 (M+H)+. Step 8. 2-((4-(2,7-Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N- isopropylbenzamide, hydrochloride In a dried, 250 mL three-necked round bottom flask under nitrogen atmosphere was charged tert-butyl 2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7- diazaspiro [3.5] nonane-7-carboxylate (6.8 g, 12.89 mmol) in 2,2,2-triflouroethanol (40 mL). To this solution, TMS-Cl (6.59 mL, 51.6 mmol) was added dropwise at 0oC, and then the reaction mixture was stirred for 2 h at 25oC. The reaction progress was monitored by TLC (10% MeOH in DCM). After 2 h, the solvent was removed under reduced pressure on a rotary evaporator and the residue was co-distilled with ethyl acetate (2 x 20 mL). The residue was triturated with hexane to obtain 2-((4-(2,7-diazaspiro[3.5] nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N- isopropylbenzamide, hydrochloride (5.9 g, 86.0% yield) as an off-white solid: LCMS (Method A): Rt =1.54 min, 428.3 (M+H)+. Intermediate 1 (large-scale preparation). 2-((4-(2,7-diazaspiro[3.5]nonan-2- yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide, bis-tosylate salt Step 1.5-(2-Bromo-4-fluorophenoxy)pyrimidine Step 1 was performed in three batches, an 8.00 kg batch (4.00 kg and 4.00 kg from in one reactor and divided into two reactors for workup) and a 3.00 kg batch. In a 100-L, cylindrical reactor, 2-bromo-4-fluorophenol (8.00 kg, 41.9 mol, 1.00 equiv), 5- bromopyrimidine (6.86 kg, 43.1 mol, 1.03 equiv), cesium carbonate (17.7 kg, 54.5 mol, 1.3 equiv), and DMAc (48 L, 6 vol) were charged. The batch was heated to 119oC over 9 h and held at temperature for 82 h. The batches were then cooled to 34oC and an IPC sample was taken, which indicated 82.2% conversion by NMR from the phenol. The internal temperature of the batch was adjusted to 25oC and the batch was split into two 100-L reactors. To each batch, MTBE (10.6 L, 2.66 vol) and deionized water (48 L, 12 vol), were added and agitated 15 min. The extraction of the resulting aqueous phase was repeated on each batch 5 times with MTBE (5 × 10.6 L, 5 × 2.66 vol for each). The MTBE extracts were combined and washed sequentially with 2 N sodium hydroxide (8 L, 2 vol, 50% NaOH), 0.5 M citric acid (4 L, 1 vol, solid), and finally by 5 wt % sodium bicarbonate (4 L, 1 vol). The MTBE solutions were combined and concentrated via rotary evaporation (bath temperature 55oC). The residue from the combined batch was then stored in a carboy prior to wiped film evaporation purification. Similarly, a 3.00 kg batch was completed and the crude oil was stored in a carboy at ambient temperature until purification (3.50 kg). A 4” Pope wiped-film evaporator (WFE) was used to purify 8.17 kg crude 5-(2-bromo-4- fluorophenoxy)pyrimidine through multiple passes. The conditions for WFE distillation first pass were as follows: vacuum 10–12 Torr (empty), wiper speed 328–333 rpm, jacket temperature 160oC, condenser temperature 85oC, addition rate §4 mL / min. The conditions for WFE distillation second pass were as follows: vacuum 0.8 Torr (empty), wiper speed 320–330 rpm, jacket temperature 150oC, condenser temperature 50oC, addition rate §10 mL / min. A third pass was completed to re-pass pot fractions that contained large amounts of products. The conditions for WFE distillation third pass were as follows: vacuum 0.8 Torr (empty), wiper speed 320–330 rpm, jacket temperature 130oC, condenser temperature 50oC, addition rate §15 mL / min. After the third pass, the product spontaneously crystallized upon cooling. All the material was collected and combined in several jars with the purified material (6.58 kg, 43% yield combined, 95.9% AUC 912 t % 1H NMR) Steps 2 and 3.5-Fluoro-2-(pyrimidin-5-yloxy)benzoic acid A 22-gal, jacketed, stainless steel pressure vessel was charged with [1,1’- bis(diphenylphosphino) ferrocene]dichloro-palladium(II) dichloromethane adduct (Pd(dppf)Cl2 DCM complex, 0.989 kg, 1.21 moles, 0.05 equiv), 5-(2-bromo-4-fluorophenoxy)pyrimidine (6.52 kg, 24.2 moles, 1.00 equiv), triethylamine (4.93 kg, 48.4 moles, 2.00 equiv), and methanol (32.6 L, 5 vol). The reactor was purged with nitrogen (3 times up to 60 psig of nitrogen pressure) and then with carbon monoxide gas [3 times up to 50 psig of carbon monoxide]. The reactor internal temperature was adjusted to 70 ± 5oC over 1 h and the internal pressure was adjusted to 40 ± 5 psig with carbon monoxide gas. The batch was stirred at 70 ± 5oC for 13 h, cooled to 25oC, and purged with nitrogen three times with 50 psig pressure. The batch was filtered over a Celite^ pad to remove the palladium catalyst, which was rinsed with MeOH (6.5 L, 1 vol). The solution containing methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate was transferred to a100-L, jacketed, glass reactor and diluted with water (13 L, 2 vol). 50 wt % sodium hydroxide aqueous solution (7.8 kg, 96.9 moles, 4 equiv) was added keeping the batch internal temperature <45oC (max temperature 42.4oC). The batch was stirred for 14 h then concentrated under reduced pressure (28.5 in Hg, 42oC) to 4 vol (24 L). The batch was diluted with water (34 L, 7 vol), cooled to 25oC, and filtered through a Celite^ pad to remove the remaining catalyst. The pad was washed with water (6.5 L, 1 vol). The batch was extracted with MTBE (13 L, 2 vol) two times for 30 min each time. The batch was acidified to pH §2 using 6 M hydrochloric acid (about 13 L, 2.3 vol; conc. HCl), maintaining an internal batch temperature of 20oC. Once the acid addition was complete, the batch was stirred for 20 h, then filtered over a polypropylene cloth using a filter / dryer. The filter cake was washed three times with water (3 × 13 L, 3 × 2 vol) and dried under stream of nitrogen at 40–45oC over five days until the water level was 0.3 wt % by KF analysis. The product was isolated in 98% yield (, 5.58 kg, 98.8% AUC). Step 4. N-Ethyl-5-fluoro-N-isopropyl-2-(pyrimidin-5-yloxy)benzamide Step 4 was performed following the same procedure in two batches, a 2.80 kg batch and a 5.00 kg batch. A 100-L, cylindrical, glass jacketed reactor was inerted by flow-through with N2and connected to a 2 N NaOH scrubber. 5-Fluoro-2-(pyrimidin-5-yloxy)benzoic acid (5.00 kg, 21.3 mol, 1.00 equiv) and DCM (50 L, 10 vol) were charged to the reactor. Agitation began to form a light beige suspension and the batch was cooled to <10oC. DMF (100 mL, 1.28 mol, 0.06 equiv,) was charged, followed by oxalyl chloride (470 mL, 5.55 mol, 0.26 equiv) over 20 min. Triethylamine (2.71 L, 19.4 mol) and oxalyl chloride (1.88 L, 22.2 mol, 1.04 equiv) were charged simultaneously over 90 min with the oxalyl chloride rate of addition slightly faster than that of triethylamine. The temperature was adjusted to 15oC and held for 80 min. The batch was sampled for IPC, which indicated 94.6% conversion to the acid chloride (an aliquot of the reaction mixture was quenched with benzylamine prior to analysis). After holding for 1 h at 15oC, the batch was cooled to <5oC and a solution of N-ethyl-2-propanamine (5.16 L, 42.7 mol, 2.00 equiv) and triethylamine (3.27 L, 23.5 mol, 1.10 equiv.) was charged in small portions over 3 h, maintaining batch temperature <10oC. After warming to 15oC over 1 h, the reaction was held at 15–20oC for 12 h at which point HPLC indicated 97.2% conversion (an aliquot of the reaction mixture was quenched with benzylamine). The batch was washed sequentially with 1 N HCl (20.0 L, 4 vol, concentrated HCl) and 2 N NaOH (20.0 L, 4 vol, 50% NaOH), stirring each for 20 min, and allowing layers to separate for 10 min. The batch was then concentrated to near-dryness via rotary evaporation to 1.6 vol (8 L) and MTBE (6 L, 1.2 vol) was added in portions. The batch was then distilled again to near-dryness (6.25 L) via rotovap, at which time the batch started to crash out, indicating low levels of DCM. The batch was transferred back into the reactor using 3 L of MTBE as a rinse and cooled to 0oC. Once at 0oC, heptanes (9.3 L, 1.9 vol, with 0.005% Statsafe 6000) was charged slowly over 1 h to obtain an approximate 1:1 ratio of MTBE / heptanes. The batch initially oiled and became a thick slurry with a thin shell along the reactor walls after 1 h at 20oC. While cooling to 0–5oC, the remaining heptanes (60 L) were slowly added over 70 min and the shell was physically scraped off the reactor wall The batch was aged at 0oC for 13 h and then filtered through a Nutsche filter equipped with a polypropylene cloth. The reactor was rinsed once with heptanes (5 L, 1 vol) and the rinse was applied to the filer cake. The isolated solids were dried in a vacuum oven at 30–40oC over five days to yield N-ethyl-5-fluoro-N-isopropyl-2- (pyrimidin-5-yloxy)benzamide as a tan solid ( 5.60 kg, 87% yield, 96.4% AUC, 89.0% by weight). Step 5 was performed following the same procedure in two batches, a 3.40 kg batch and a 4.65 kg batch. N-Ethyl-5-fluoro-N-isopropyl-2-(pyrimidin-5-yloxy)benzamide (4.65 kg, 15.3 mol, 1.00 equiv.) and DCM (23 L, 4.9 vol) were charged to a 100-L, cylindrical, jacketed reactor and cooled to 5oC over 15 min. Urea hydrogen peroxide (UHP, 2.16 kg, 23.0 mol, 1.50 equiv.) was charged followed by DCM (5 L, 1.1 vol) as a rinse. Trifluoroacetic anhydride (TFAA, 1.6 L, 11.5 mol, 0.75 equiv.) was added over 2 h, maintaining batch temperature <10oC. Then, the reactor was purged with N2for 30 min, to ensure the atmosphere was free from O2that may have been produced. This was followed by addition of a second portion of TFAA (1.6 L, 11.5 mol, 0.75 equiv) over 2 h. The reactor was again inerted with N2 for 30 min. After stirring for 17 h, conversion was 92.0% by HPLC. To drive conversion further, UHP (288 g, 3.06 mol, 0.2 equiv) was charged and TFAA (426 mL, 3.06 mol, 0.2 equiv,) was added over 15 min. After stirring for 1 h, conversion reached 96.7% by HPLC. The reaction was quenched with a solution of 1 M sodium sulfite (12.4 L, 2.6 vol, 0.8 equiv), which was stirred for 30 min prior to charging 5% NaHCO3(23.2 L, 5.0 vol, solid NaHCO3), while maintaining <20oC over 30 min. The mixture was stirred for 2 h due to residual bubbling that indicated ongoing neutralization. The layers were separated, and the organic phase tested negative for peroxides using KI-starch test paper. The batch was washed a second time with 5% NaHCO3(32.9 L, 5 vol) for 15 min. The organic phase was distributed into two glass carboys and 4Å molecular sieves (3.0 kg, 10 % w / v) were charged to the carboys and held at ambient temperature. The batch was periodically stirred and checked by KF. After 135 h, the water content was 416 ppm. The batch was filtered into a 100-L, cylindrical, jacketed reactor. The sieves were washed with DCM (9.3 L, 2 vol) and the wash charged to the reactor. The batch (88.5% AUC, 7.6 wt % by qNMR corresponding to 3.58 kg, 73% yield,) was held at 0oC for 18 h prior to performing Step 6. Step 6 was performed following the same procedure in two batches, a 2.86 kg batch and a 3.58 kg batch. To a 100-L, cylindrical, jacketed reactor was charged a solution of 5-(2- (ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine 1-oxide in DCM (total volume §36 L). The amount of 5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine 1-oxide in the DCM solution was 3.58 kg (11.2 mol, 1 equiv) by 1H qNMR weight assay. The batch temperature was adjusted from 4oC to 11oC and triethylamine (2.34 L, 16.8 mol, 1.5 equiv) was added while maintaining a batch temperature <15oC. Oxalyl chloride (1.23 L, 14.6 mol, 1.3 equiv) was charged in small increments over 3 h to control the vigorous gas evolution. The batch was adjusted to 30oC over 1 h and held at 30–35oC for 1 h, after which 2.6% of 5-(2-(ethyl(isopropyl)carbamoyl)-4- fluorophenoxy)pyrimidine 1-oxide remained, so additional charges of triethylamine (90 mL, 0.65 mol, 0.06 equiv) and oxalyl chloride (71 g, 0.56 mol, 0.05) were added, and the batch was stirred an additional 15 h. 1 N HCl (17.9 L, 5 vol, concentrated HCl) was charged over 30 min maintaining batch temperature <20oC and then stirred for 2 h while sparging with 10 psi N2 gas through the bottom outlet valve (BOV). The opaque dark brown phases were separated, and the organic phase was held overnight before washing with 5% NaHCO3solution (17.9 L, 5 vol). The batch was sparged again with N2 gas through the BOV for 30 min. Both phases were again dark brown and opaque. The phases separated and the organic phase was stripped to dryness via rotary evaporation (bath temp 35oC) to produce 4.92 kg of crude 2-((4-chloropyrimidin-5-yl)oxy)-N- ethyl-5-fluoro-N-isopropylbenzamide as a thick dark brown oil (2.96 kg adjusted for purity, 78% adjusted yield, 81.8% AUC, 60.1% potency by 1H qNMR) which was held in IPAc (19.6 L, 6.6 vol relative to 2-((4-chloropyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide) at 0oC prior to use. Step 7. tert-butyl 2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)- 2,7-diazaspiro[3.5]nonane-7-carboxylate Step 7 was performed following the same procedure in two batches, a 2.06 kg batch and a 2.96 kg batch. Crude 2-((4-chloropyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (2.96 kg adjusted input based on weight potency, 8.8 mol), tert-butyl 2,7-diazaspiro[3.5]nonane-7- carboxylate HCl (2.5 g, 9.6 mol, 0.3 equiv.) and IPAc (29.6 L, 6.0 vol) were charged to a 100-L, cylindrical, jacketed reactor. DIPEA (6.1 L, 35.1 mol) was charged and the batch was heated to 75–80oC over 3 h and stirred at temperature for 8 h. HPLC analysis of the reaction indicated 95.0% conversion, so another 0.1 equiv of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate HCl (230 g, 0.88 mol, 0.1 equiv) was charged. Conversion reached 96.5% after 3 h of heating, so the batch was cooled to 50oC. A 0.5 M citric acid solution (14.8 L, 5 vol) was charged over 10 min maintaining temperature >40oC and agitated at 40oC for 20 min. The dark opaque brown phases were separated and 0.5 M citric acid solution (14.8 L, 5 vol) was charged, stirred for 20 min, and the phases separated. The batch was cooled and held at 20oC overnight, then 5 wt % NaHCO3(29.6 L, 5 vol) was charged over 45 min maintaining batch temperature 35–40oC. After agitating for 20 min, the phases were separated. The organic phase was rotovapped over 1 h to 4 vol (§20 L). The batch spontaneously solidified in the rotovap bulb, and was transferred into the reactor, then the brown suspension was cooled to 20oC, and n-heptane (35.5 L, 12 vol) was charged over 1 h. The light brown suspension was stirred at §20oC for 13 h, cooled to 5oC over 1 h, and held at 5oC for 2 h prior to filtering. The filtrate was analyzed by HPLC to confirm that no further precipitation occurred after an additional hour and then the batch was filtered over 2 h through a Nutsche funnel equipped with a polypropylene cloth. n-Heptane (5.9 L, 2 vol) was then used to wash the reactor and the wash was pulled through the wet cake over 20 min. The wet cake was conditioned for 42 h prior to drying under high vacuum at 40–45oC to produce crude tert-butyl 2- (5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane- 7-carboxylate as an off-white to light tan solid (3.99 kg, 92.2% AUC, 88.2 wt % by 1H qNMR, 76% yield adjusted for potency of product). tert-Butyl 2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7- diazaspiro[3.5]nonane-7-carboxylate was purified in one batch. Crude tert-butyl 2-(5-(2- (ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7- carboxylate (7.04 kg) was charged to a 100-L, cylindrical, jacketed reactor. IPAc (31.7 L, 4.5 vol,) and MTBE (31.7 L, 4.5 vol) were charged, and the batch was heated to 70 ± 5oC and held for 1 h. After cooling to 5oC (target 0oC) over 4.5 h, the batch was held for 16 h and filtered using a Nutche filter with polypropylene cloth. Two portions of MTBE (2 × 14 L, 2 × 2 vol) were used to rinse the reactor, cooled to 5oC, and washed through the wet cake. The pale brown solid was dried under high vacuum at 40oC to produce purified tert-butyl 2-(5-(2-(ethyl(isopropyl)carbamoyl)-4- fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (4.54 kg, 76% yield, 98.9% AUC UV-HPLC, 97.4 wt % 1H qNMR, 99.4% AUC CAD-HPLC). Step 8. 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N- isopropylbenzamide, bis-tosylate salt In a 100-L, cylindrical, jacketed reactor, tert-butyl 2-(5-(2-(ethyl(isopropyl)carbamoyl)-4- fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (3.50 kg, 6.63 mol, 1.0 equiv.) was dissolved in THF (36 L, 10 vol). The solution was transferred to a glass carboy, then p-toluene sulfonic acid monohydrate (pTSA, 3.90 kg, 19.9 mol, 3.0 equiv) was dissolved in THF (18 L, 5 vol) and purified water (540 mL, 0.15 vol), and the solution was heated to 55 ± 5oC. The tert-butyl 2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7- diazaspiro[3.5]nonane-7-carboxylate solution was transferred to the reactor over 4 h while maintaining the batch at 55 ± 5oC. After 16 h, the batch was cooled to 20 ± 5oC over 1.5 h and held for 2 h prior to filtration. The wet cake was washed three times with THF (3 × 18 L, 3 × 5 vol) The filtration and washes were completed in 175 h then the wet cake was conditioned under vacuum for 17.5 h prior to drying under reduced pressure at 45 ± 5oC. 2-((4-(2,7- Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide, bis- tosylate salt was isolated in 94% yield (4.80 kg). Intermediate 2. ((2S,5R)-5-((tert-Butoxycarbonyl)amino)tetrahydro-2H-pyran-2- yl)methyl 4-methylbenzenesulfonate In a dried, 100 mL three-necked round bottom flask, tert-butyl ((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate (500 mg, 2.16 mmol) was dissolved in CH2Cl2(20 mL) and the solution was cooled to 0oC over 5 min. To this solution was added DIPEA (1.15 mL, 6.49 mmol) followed by DMAP (31.7 mg, 0.25 mmol) and 4- methylbenzenesulfonyl chloride (495 mg, 2.59 mmol) at 0oC. The reaction mixture was then brought to 25oC over a period of 30 min and stirred at 25oC for 16 h. The reaction progress was monitored by TLC (100% EtOAc). After 16 h, the reaction was quenched with water (50 mL) and extracted with DCM (2 x 50 mL). The organic layer was washed with brine (2 x 25 mL) followed by aqueous NaHCO3 (2 x 50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated on a rotary evaporator (bath temperature 40oC) to afford the crude product (810 mg). The crude product was purified by column chromatography (SepaBean) using 100-200 silica gel and eluting with ethyl acetate in hexane (required product eluted in 40% ethyl acetate in hexane). The fractions containing the required product were concentrated under reduced pressure to obtain ((2S,5R)-5-((tert- butoxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (680 mg, 81% yield) as a white solid:1H NMR (400 MHz, DMSO-d6): į 7.78 (d, J = 8.00 Hz, 2 H), 7.49 (d, J = 8 Hz, 2H), 6.76-6.74 (m, 1 H), 4.00-3.98 (m, 1 H), 3.92-3.88 (m, 1 H), 3.73-3.71 (m, 1 H), 3.39-3.37 (m, 1 H), 3.32-3.24 (m, 1 H), 2.90-2.85 (m, 1 H), 2.43 (s, 3 H), 1.82-1.80 (m, 1 H), 1.56- 1.52 (m, 1 H), 1.37 (s, 9 H), 1.37-1.21 (m, 2 H). LCMS (Method B): Rt = 2.92 min, 330.2 (M-56). Intermediate 3: 2-((4-(2,7-Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-diisopropyl benzamide, hydrochloride

[0006] Step 1.5-Fluoro-N,N-diisopropyl-2-(pyrimidin-5-yloxy)benzamide In a 500 mL two-necked dried round bottom flask under nitrogen atmosphere, 5-fluoro-2- (pyrimidin-5-yloxy) benzoic acid (10 g, 42.7 mmol) was dissolved in DMF (100 mL). To this solution, diisopropylamine (9.00 mL, 64.1 mmol), HATU (19.48 g, 51.2 mmol) and DIPEA (38.1 mL, 214 mmol) were added at 25oC under nitrogen atmosphere, and the reaction was stirred at 25oC for 20 h. The reaction progress was monitored by TLC (50% EtOAc in hexane). After completion of the reaction, the reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated on a rotary evaporator (bath temperature 40oC) to obtain the crude product. The crude product was purified by column chromatography (Isolera) using 100-200 mesh silica gel and eluting with ethyl acetate in hexane (desired product eluted in 25% EtOAc in hexane). The fractions containing the desired product were concentrated under reduced pressure to obtain 5-fluoro-N, N-diisopropyl-2-(pyrimidin-5-yloxy) benzamide (7.2 g, 48.9 % yield) as an off-white solid:1H NMR (400 MHz, DMSO-d6): į 8.94 (s, 1 H), 8.51 (s, 2 H), 3.73-3.63 (m, 1 H), 3.56-3.46 (m, 1 H), 1.39 (d, J = 6.80 Hz, 3H), 1.17 (d, J = 6.80 Hz, 3H), 1.09 (d, J = 6.40 Hz, 3H); LCMS (Method B): Rt = 1.99 min, 318.2 (M+H)+. Step 2.5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine 1-oxide In a dried, 250 mL three-necked round bottom flask under nitrogen atmosphere, 5-fluoro- N,N-diisopropyl-2-(pyrimidin-5-yloxy)benzamide (6.0 g, 18.91 mmol) was dissolved in tetrahydrofuran (60 mL). The resulting solution was cooled to 0oC and urea hydrogen peroxide (3.56 g, 37.8 mmol) was added, followed by the dropwise addition of TFAA (5.42 mL, 38.4 mmol) while maintaining the temperature below 10oC. The reaction was stirred at 0oC to 10oC for 1 h, and the reaction progress was monitored by TLC (100 % EtOAc). After complete consumption of the starting material, the reaction was quenched by adding 5% NaHCO3 (50 mL), maintaining the temperature below 10oC. The reaction was extracted with DCM (2 x 100 mL) and the combined organic layer was sequentially washed with 5% NaHCO3(2 x 50 mL) and 1M Na2S2O3solution (60 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was minimized on a rotary evaporator (bath temperature 30oC) up to one volume remaining in RBF. This was co-distilled with ethyl acetate (2 x 60 mL) and the organic layer was again minimized to one volume remaining in RBF (Note: Do not evaporate to dryness). Hexane (250 mL) was added slowly to the remaining reaction volume in the evaporation flask. The precipitate obtained was stirred for 30 min at 25oC, filtered and suction-dried to obtain 5-(2- (diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine 1-oxide (6 g, 77.64% yield) as an off-white solid:1H NMR (400 MHz, DMSO-d6): į 8.87 (d, J = 1.60 Hz, 1H), 8.39 (t, J = 1.60 Hz, 1H), 8.05 (d, J = 2.40 Hz, 1H), 7.45-7.42 (m, 1H), 7.37-7.36 (m, 1H), 7.35-7.30 (m, 1H), 3.67-3.64 (m, 1H), 3.55-3.51 (m, 1H), 1.40 (d, J = 6.40 Hz, 3H), 1.40 (d, J = 6.40 Hz, 3H), 1.09 (d, J = 6.40 Hz, 3H), 1.06 (d, J = 6.80 Hz, 3H); LCMS (Method B): Rt = 1.64 min, 334.0 (M+H)+. S In a 250 mL three-necked round bottom flask under nitrogen atmosphere, 5-(2- (diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine-1-oxide (5.0 g, 15.00 mmol) was dissolved in ethyl acetate (50 mL). To this solution, DIPEA (43.6 mL, 251 mmol) was added at -5oC and then stirred for 10 min. After that, POCl3 (1.678 mL, 18.00 mmol) was added dropwise at -5oC. The reaction mixture was stirred for 30 min at 0oC and then allowed to warm slowly to 25oC and stirred for 1 h, monitoring the reaction progress by TLC (30 % EtOAc in Hexane). After completion of the reaction, the reaction mixture was quenched with cold water (20 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated on a rotary evaporator under reduced pressure (bath temperature 45oC) to obtain the crude product. The crude product was purified by column chromatography (Isolera) using 100-200 mesh silica gel and eluting with ethyl acetate in hexane (the desired product eluted in 22% ethyl acetate in hexane). The fractions containing the required product were concentrated under reduced pressure to obtain 2-((4-chloropyrimidin-5-yl)oxy)-5- fluoro-N,N-diisopropylbenzamide (2.4 g, 39.0% yield) as a yellow solid:1H NMR (400 MHz, DMSO-d6): į 8.79 (s, 1 H), 8.26 (s, 1 H), 7.40-7.33 (m, 3 H), 3.68-3.64 (m, 1 H), 3.55-3.51 (m, 1 H), 1.39 (d, J = 6.80 Hz, 3H), 1.21 (d, J = 6.80 Hz, 3H), 1.10 (d, J = 6.80 Hz, 6H); LCMS (Method B): Rt = 2.54 min, 352.3 (M+H)+. Step 4. tert-Butyl 2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7- diazaspiro[3.5]nonane-7-carboxylate In a 100 mL three-necked dried round bottom flask under nitrogen atmosphere, 2-((4- chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (2.4 g, 6.82 mmol) was dissolved in 2-propanol (25 mL). To this solution, TEA (2.85 mL, 20.47 mmol) and tert-butyl 2,7- diazaspiro[3.5]nonane-7-carboxylate hydrochloride (2.151 g, 8.19 mmol) were added at 25oC under nitrogen atmosphere. The resulting reaction was heated at 80oC for 13 h, monitoring the reaction progress by TLC (100% EtOAc). After 13 h, the solvent was distilled off and the residue was dissolved in ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated on a rotary evaporator under reduced pressure (bath temperature 45oC) to obtain the crude product. The crude product was purified by column chromatography (Isolera) using 100-200 silica gel and eluting with ethyl acetate in hexane (the required product eluted in 67-70 % ethyl acetate in hexane). The fractions containing the required product were concentrated under reduced pressure to obtain tert-butyl 2- (5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7- carboxylate (2.7 g, 70.0% yield) as a foam:1H NMR (400 MHz, DMSO-d6): į 8.27 (s, 1 H), 7.74 (s, 1 H), 7.32-7.14 (m, 2 H), 7.13-7.02 (m, 1 H), 4.05-3.84 (m, 4H), 3.70-3.67 (m, 1H), 3.55-3.49 (m, 1H), 3.26 (s, 4H), 1.63 (t, J = 4.80 Hz, 4H), 1.44 (d, J = 6.80 Hz, 3H), 1.40 (s, 9H), 1.34 (d, J = 6.80 Hz, 3H), 1.09 (d, J = 6.40 Hz, 3H), 1.00 (d, J = 6.40 Hz, 3H); LCMS (Method B): Rt = 2.25 min, 542.4 (M+H)+. Step 5. 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N- diisopropylbenzamide, hydrochloride In a 100 mL three-necked dried round bottom flask under nitrogen atmosphere, tert-butyl 2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7- carboxylate (2.7 g, 4.98 mmol) was dissolved in 2,2,2-triflouroethanol (27 mL). To this solution, TMS-Cl (2.230 mL, 17.45 mmol) was added dropwise at 10oC and the reaction mixture was stirred for 1 h at 25oC. The reaction progress was monitored by TLC (10% MeOH in DCM). After 1 h, the solvent was distilled off under reduced pressure on a rotary evaporator and the residue was co- distilled with ethyl acetate (2 x 20 mL). The residue obtained was triturated with hexane and dried under vacuum to obtain 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N- diisopropylbenzamide hydrochloride (2.5 g, 99.0% yield) as a light brown solid:1H NMR (400 MHz, DMSO-d6): į 9.05 (br s, 2H), 8.62 (s, 1H), 7.90 (s, 1H), 7.36-7.32 (m, 3H), 4.04-3.84 (m, 4H), 3.71-3.68 (m, 1H), 3.56-3.53 (m, 1H), 3.03 (s, 4H), 1.98 (t, J = 9.20 Hz, 4H), 1.43 (d, J = 6.40 Hz, 3H), 1.33 (d, J = 6.80 Hz, 3H), 1.11 (d, J = 6.40 Hz, 3H), 0.95 (d, J = 6.40 Hz, 3H); LCMS (Method B): Rt = 0.94 min, 442.2 (M+H)+. Intermediate 4. 2-((4-(7-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide, hydrochloride Step 1. tert-Butyl ((3R,6S)-6-((2-(5-(2-(ethyl(isopropyl)carbamoyl)-4- fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)tetrahydro-2H-pyran-3- yl)carbamate In a dried, 250 mL two-necked round bottom flask under nitrogen atmosphere, 2-((4-(2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide, bis- tosylate salt (1.3 g, 1.68 mmol) was dissolved in N-methyl-2-pyrrolidinone (5 mL). To this solution, K2CO3 (0.93 g, 6.74 mmol), KI (0.308 g, 1.853 mmol) and ((2S,5R)-5-((tert- butoxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (0.649 g, 1.68 mmol) were added at 25oC under nitrogen atmosphere. The resulting reaction was heated at 70oC for 17 h and the reaction progress was monitored by TLC (5% MeOH in DCM). After completion of the reaction, the reaction mixture was cooled to 25oC and quenched with water (100 mL). The aqueous layer was extracted with ethyl acetate (2 x 150 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated on a rotary evaporator (bath temperature 40oC) to afford the crude product (1.2 g). The crude product was purified by column chromatography (Isolera) using 100-200 mesh silica gel and eluting with methanol in DCM (desired product eluted in 45% methanol in DCM) The fractions containing the desired product were concentrated under reduced pressure to obtain tert-butyl ((3R,6S)-6-((2- (5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7- yl)methyl)tetrahydro-2H-pyran-3-yl)carbamate (650 mg, 59.7% yield) as a light brown syrup:1H NMR (400 MHz, DMSO-d6): į 8.27-8.26 (m, 1H), 7.72-7.67 (m, 1H), 7.30-7.23 (m, 2H), 7.05- 7.02 (m, 1H), 6.74 (d, J = 8.00 Hz, 1H), 3.85-3.73 (m, 6H), 3.43-3.21 (m, 4H), 2.95-2.88 (m, 1H), 2.28-2.18 (m, 6H), 1.84-1.81 (m, 1H), 1.65 (t, J = 8.00 Hz, 4H), 1.37 (s, 9H), 1.26-1.16 (m, 4H), 1.01-0.98 (m, 7H); LCMS (Method B): Rt.1.49 min, 641.4 (M+H)+. Step 2. 2-((4-(7-(((2S,5R)-5-Aminotetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide, hydrochloride In a dried, 100 mL three-necked round bottom flask under nitrogen atmosphere was added tert-butyl ((3R,6S)-6-((2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)- 2,7-diazaspiro[3.5]nonan-7-yl)methyl)tetrahydro-2H-pyran-3-yl)carbamate (300 mg, 0.468 mmol) in trifluoroethanol (2 mL). The resulting mixture was cooled to 10oC and chlorotrimethylsilane (153 mg, 1.40 mmol) was added. The reaction mixture was then stirred at 26oC for 2.5 h and the reaction progress was monitored by TLC (10 % Methanol in DCM). After complete consumption of the starting material, the reaction was concentrated on a rotary evaporator (bath temperature 40oC) to afford the crude product. The crude product was stirred with ethyl acetate (10 mL), filtered through a Buchner funnel, and washed with ethyl acetate (5 mL). The solid obtained was dried under vacuum to afford 2-((4-(7-(((2S,5R)-5-aminotetrahydro- 2H-pyran-2-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N- isopropylbenzamide, hydrochloride (230 mg, 90.0% yield) as an off-white solid: LCMS (Method B): Rt = 0.321 min, 541.40 (M+H)+. Intermediate 5. 2-((4-(7-(((2S,5R)-5-Aminotetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide, hydrochloride Step 1. tert-Butyl ((3R,6S)-6-((2-(5-(2-(diisopropylcarbamoyl)-4- fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)tetrahydro-2H-pyran-3- yl)carbamate In a dried, 100 mL two-necked round bottom flask under nitrogen atmosphere, 2-((4-(2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide, hydrochloride (2.5 g, 5.23 mmol) was dissolved in N-methyl-2-pyrrolidinone (5 mL). To this solution, K2CO3(2.89 g, 20.92 mmol), KI (0.868 g, 5.23 mmol) and ((2S,5R)-5-((tert- butoxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (2.419 g, 6.28 mmol) were added at 25oC under nitrogen atmosphere. The resulting reaction was heated at 70oC for 12 h, monitoring the reaction progress by TLC (10% MeOH in DCM). After completion of reaction, the reaction mixture was cooled to room temperature and quenched with water (500 mL). The aqueous layer was extracted with ethyl acetate (2 x 150 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated on a rotary evaporator (bath temperature 40oC) to obtain the crude product. The crude compound was purified by column chromatography (Isolera) using 100-200 silica and eluting with methanol in DCM (the desired product was eluted at 8-9% methanol in DCM). The fractions containing the i d d t t t d d d d t bt i t t B t l ((3R6S) 6 ((2 (5 (2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7- yl)methyl)tetrahydro-2H-pyran-3-yl)carbamate (3.5 g, 73.6% yield) as a light brown syrup: LCMS (Method A): Rt = 2.08 min, 655.8 (M+H)+. Step 2. 2-((4-(7-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide, hydrochloride In a dried, 100 mL three-necked round bottom flask under nitrogen atmosphere, tert-butyl ((3R,6S)-6-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7- diazaspiro[3.5]nonan-7-yl)methyl)tetrahydro-2H-pyran-3-yl)carbamate (3.5 g, 5.34 mmol) was dissolved in 2,2,2 trifluoroethanol (35 mL). The resulting solution was cooled to 10oC and TMS- Cl (2.391 mL, 18.71 mmol) was added to it. The reaction was stirred at 25oC for 1 h, monitoring the reaction progress by TLC (10 % methanol in DCM). After 1 h, the reaction mixture was concentrated on a rotary evaporator (bath temperature 40oC) to obtain the crude compound. The crude compound was stirred with ethyl acetate (50 mL). The solid obtained was filtered, washed with ethyl acetate (5 mL), and dried under vacuum to obtain 2-((4-(7-(((2S,5R)-5- aminotetrahydro-2H-pyran-2-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5- fluoro-N,N-diisopropylbenzamide, hydrochloride (2.9 g, 75.0% yield) as a light pink solid: LCMS (Method A): Rt = 1.76 min, 555.2 (M+H)+. Intermediate 6. tert-Butyl 2-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4- yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

[0007] Step 1.5-(2-Bromo-4-fluorophenoxy)pyrimidine To a mixture of 2-bromo-4-fluorophenol (350 g, 1.83 mol, 1.00 eq) in DMA (2.10 L) was added Cs2CO3(776 g, 2.38 mol, 1.30 eq) and 5-bromopyrimidine (335 g, 2.11 mol, 1.15 eq) at 25oC under nitrogen atmosphere. The mixture was stirred at 140oC for 64 hours under nitrogen. LCMS_IPC showed that most starting material was consumed. The reaction mixture was cooled to 20a25oC. Multiple reactions (1 x 300 g and 8 x 350 g) were combined and worked up together. The combined mixture was poured into water (61.4 L) and extracted with MTBE (18.6 L x 3). The combined organic layer was washed with sodium hydroxide solution (15.4 L, 2 N), citric acid solution (15.4 L, 0.50 M) and sodium bicarbonate solution (15.4 L, 5%) dried with anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel chromatography (100- 200 mesh silica gel, petroleum ether / ethyl acetate = 50 / 1, 10 / 1, TLC(petroleum ether / ethyl acetate = 8 / 1, Rf (product = 0.3)) to give 5-(2-bromo-4-fluorophenoxy)pyrimidine (2.00 kg, 4.79 mol, 29.5% yield, 64.5% purity) as a yellow oil, and crude 5-(2-bromo-4-fluorophenoxy)pyrimidine (1.10 kg):1H NMR (400 MHz, DMSO-d6) į 8.98 (d, 1H, J = 2.4 Hz), 8.55 (s, 2H), 7.80-7.77 (m, 1H), 7.44-7.36(m, 2H). Step 2. Methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate To a solution of 5-(2-bromo-4-fluorophenoxy)pyrimidine (100, 372 mmol, 1.00 eq) in MeOH (700 mL) was added TEA (188 g, 1.86 mol, 259 mL, 5.00 eq) and Pd(dppf)Cl2.CH2Cl2(911 112 l 003 ) d N Th i d d d d d with CO three times. The mixture was stirred under CO (40 psi) at 80oC for 48 hours. LCMS_IPC showed that the starting material was consumed completely. The reaction mixture was cooled to 20a25oC. Fifteen reactions (15 x 100 g) were combined and filtered over a Celite^ pad to remove the palladium catalyst. The Celite^ pad was washed with methanol (200 mL, 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (100-200 mesh silica gel, petroleum ether / ethyl acetate = 20 / 1 to 8 / 1, TLC(petroleum ether / ethyl acetate = 3 / 1, Rf(product) = 0.3)) to give methyl 5-fluoro-2- (pyrimidin-5-yloxy)benzoate (427 g, 1.54 mol, 43.0% yield, 89.7% purity) as a light yellow solid, and crude methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate (500 g, 37.3% yield, 66.5% purity):1H NMR (400 MHz CDCl3) į 8.96 (s, 1H), 8.39 (s, 2H), 7.73 (dd, J = 3.6, 8.8 Hz, 1H), 7.33-7.30 (m, 1H), 7.13 (dd, J = 4.4, 8.8 Hz, 1H), 3.82 (s, 3H). Step 3.5-(4-Fluoro-2-(methoxycarbonyl)phenoxy)pyrimidine 1-oxide To a solution of methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate (190 g, 765 mmol, 1.00 eq) in THF (1.90 L) was added UHP (144 g, 1.53 mol, 2.00 eq) and TFAA (322 g, 1.53 mol, 213 mL, 2.00 eq) under N2at 0a10oC. The mixture was stirred at 0a10oC for 1 hour. LCMS_IPC showed that the starting material was consumed completely. The reaction was quenched by adding 5% NaHCO3(950 mL), maintaining temperature below 10oC. Two reactions (2 x 190 g) were combined. The product was extracted with DCM (2 x 1.90 L). Organic layer was washed with 5% NaHCO3 (2 x 1.90 L). The organic layer was treated with 5% NaHCO3 (2.30 L) and 1M Na2S2O3solution (1.90 L) and stirred for 15 min at 20oC. The organic layer was separated, dried with anhydrous Na2SO4, filtered, and concentrated in vacuo at 45oC to give the residue. Three reactions (1 x 200 g and 2 x 190 g) were combined. The crude product was triturated with n- heptane (8.0 L)) and stirred at 25oC for 30 min. The mixture was filtered, the filter cake was washed with n-heptane (800 mL) and dried under vacuum to give 5-(4-fluoro-2- (methoxycarbonyl)phenoxy)pyrimidine 1-oxide (552 g, 1.89 mol, 80.7% yield, 90.3% purity) as a white solid:1H NMR (400 MHz DMSO-d6) į 8.86 (s, 1H), 8.44 (t, J = 1.60 Hz, 1H), 8.01 (d, J = 2.40 Hz, 1H), 7.74 (dd, J = 3.6, 9.2 Hz, 1H), 7.62-7.61 (m, 1H), 7.52-7.50 (m, 1H), 3.76 (s, 3H). To a solution of 5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidine 1-oxide (268 g, 1.01 mol, 1.00 eq) in EtOAc (2.70 L) was added DIPEA (655 g, 5.07 mol, 883 mL, 5.00 eq) under N2 at -5oC. POCl3 (187 g, 1.22 mol, 113 mL, 1.2 eq) was added the reaction mixture under N2 at 0oC. Reaction mixture was stirred at 20a25oC for 1.5 hours under N2. LCMS_IPC showed that the starting material was consumed completely. The reaction mixture was concentrated in vacuo at 45oC give the crude product (834 g). Multiple reactions (54.0 g crude product from 2 x 9.5 g; 300 g crude product from 1 x 100 g; 12.0 g crude product from 1 x 4.00 g; 1.30 kg crude product from 2 x 224 g; 834 g crude product from 1 x 268 g) were combined and purified together. The crude product (2.5 kg) was purified through a silica pad and the silica pad was eluted by a pre- mixed solution (petroleum ether / ethyl acetate = 2 / 1) to give the product as yellow solid (575 g). The crude product (575 g) was triturated with n-heptane / ethyl acetate (2 / 1, 3 V) and stirred at 25oC for 12 hours to give a yellow suspension. The mixture was filtered, the filter cake was washed with n-heptane / ethyl acetate (2 / 1, 0.2 V) and dried under vacuum to give methyl 2-((4- chloropyrimidin-5-yl)oxy)-5-fluorobenzoate (415 g, 1.45 mol, 45.7% yield, 98.8% purity) as a white solid:1H NMR (400 MHz CDCl3) į 8.72 (s, 1H), 8.01 (s, 1H), 7.76 (dd, J = 3.20, 8.40 Hz, 1H), 7.34-7.31 (m, 1H), 7.15-7.11 (m, 1H), 3.82 (s, 3H). Step 5. tert-Butyl 2-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7- diazaspiro[3.5]nonane-7-carboxylate To a mixture of methyl 2-((4-chloropyrimidin-5-yl)oxy)-5-fluorobenzoate (80.0 g, 283 mmol, 1.00 eq) in IPA (800 mL) was added TEA (85.9 g, 849 mmol, 118 mL, 3.00 eq) and tert- butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (89.2 g, 340 mmol, 1.20 eq, HCl) at 25oC under it t h Th i t ti d t 80 C f 3 h d it HPLC IPC and LCMS_IPC showed that the starting material was consumed completely. The reaction mixture was cooled to 25oC and concentrated in vacuo at 50oC. Multiple reactions (10.0 g crude product from 1 x 5.00 g; 80.0 g crude product from 2 x 20.0 g; crude product from 2 x 80.0 g) were combined. The crude product (410 g) was triturated with n-heptane (600 mL) and stirred at 25oC for 12 hour. The mixture was filtered, the filter cake was washed with n-heptane (60.0 mL) and dried under vacuum give crude product (330 g). The crude product (330 g) was triturated with water (3.30 L) and stirred at 25oC for 12 hour to remove the residual TEA.HCl. The mixture was filtered, the filter cake was washed with water (300 mL) and dried under vacuum give crude product (300 g). The crude product (300 g) was dissolved in dichloromethane (300 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give tert-butyl 2-(5-(4-fluoro-2- (methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (265 g, 558 mmol, 76.9% yield, 99.5% purity) as a white solid:1H NMR (400 MHz DMSO-d6) į 8.27 (s, 1H), 7.67-7.64 (m, 2H), 7.49-7.46 (m, 1H), 7.14-7.11 (m, 1H), 3.91 (s, 4H), 3.79 (s, 3H), 3.26 (s, 4H), 1.66 (t, J = 5.20 Hz, 4H), 1.38 (s, 9H). Intermediate 7. (2-((4-(7-(((2S,5R)-5-Aminotetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophenyl)((3S,5R)-3,5- dimethylmorpholino)methanone, hydrochloride In a 250 mL three-necked reaction flask was added tert-butyl 2-(5-(4-fluoro-2- (methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (20 g, 42.3 mmol) in MeOH (50 mL) and THF (50 mL). To this reaction mixture was added a solution of LiOH (1.216 g, 50.8 mmol) in water (25 mL) at 25oC and the reaction mixture was stirred at 25oC for 18 h. The reaction progress was monitored by TLC (20% MeOH in DCM). After complete consumption of the ester, the reaction was concentrated to dryness on a rotary evaporator. The residue was azeotroped with toluene (3 x 25 mL) to remove traces of water, and dried under vacuum to obtain the desired lithium 2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-2- yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate (19.5 g, 99% yield) as a white solid:1H NMR (400 MHz, DMSO-d6): į 8.12 (s, 1H), 7.36 (s, 1H), 7.17 (dd, J = 3.20, 9.20 Hz, 1H), 7.00-6.97 (m, 1H), 6.93- 6.89 (m, 1H), 4.01-4.00 (m, 4H), 3.29 ( br s, 4H), 1.67 (t, J = 5.60 Hz, 4H), 1.40 (s, 9H); LCMS (Method B): Rt = 1.4 min, 459.2 (M+H)+. Step 2. tert-Butyl 2-(5-(2-((3S,5R)-3,5-dimethylmorpholine-4-carbonyl)-4- fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate In a 50 mL three-necked reaction flask under nitrogen atmosphere was added lithium 2- ((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5- fluorobenzoate (2.5 g, 5.38 mmol) in DMF (10 mL). To the resulting solution, HATU (3.07 g, 8.07 mmol) and DIPEA (3.13 g, 24.22 mmol) were added. After that (3S,5R)-3,5- dimethylmorpholine hydrochloride (1.224 g, 8.07 mmol) was added at 25oC under nitrogen atmosphere and the reaction mixture stirred at 25oC for 18 h. The reaction progress was monitored by TLC (5% MeOH in DCM). After 18 h, the reaction was quenched with water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layer was washed with water (3 x 100 mL), brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated on a rotary evaporator under reduced pressure to obtain tert-butyl 2-(5-(2-((3S,5R)- 3,5-dimethylmorpholine-4-carbonyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7- diazaspiro[3.5]nonane-7-carboxylate (2.9 g, 70.8% yield) as a yellow gummy solid: LCMS (Method B): Rt = 1.48 min, 556.2 (M+H)+. Step 3. (2-((4-(2,7-Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5- fluorophenyl)((3S,5R)-3,5-dimethylmorpholino)methanone, hydrochloride In a 50 mL three-necked round bottom flask under nitrogen atmosphere, tert-butyl 2-(5-(2- ((3S,5R)-3,5-dimethylmorpholine-4-carbonyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7- diazaspiro[3.5]nonane-7-carboxylate (2.9 g, 5.22 mmol) was added to dioxane (10 mL). To the resulting solution, 4M HCl in dioxane (7.83 mL, 31.3 mmol) was added at 25oC. The reaction mixture was then stirred at 25oC for 2 h, monitoring the reaction progress by TLC (10% MeOH in DCM). After 2 h, the reaction was concentrated to dryness on a rotary evaporator to obtain the crude residue. The crude residue was triturated with ethyl acetate. The supernatant layer was decanted and the remaining solid was dried under vacuum to obtain (2-((4-(2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophenyl)((3S,5R)-3,5- dimethylmorpholino)methanone, hydrochloride (2.5 g, 64% yield) as a yellow solid: LCMS (Method A): Rt = 1.23 min, 456.2 (M+H)+. Step 4. tert-Butyl ((3S,6R)-6-((2-(5-(2-((3S,5R)-3,5-dimethylmorpholine-4-carbonyl)-4- fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)tetrahydro-2H-pyran-3- yl)carbamate In a dried, 50 mL three-necked round bottom flask under nitrogen atmosphere, (2-((4-(2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophenyl)((3S,5R)-3,5- dimethylmorpholino)methanone, hydrochloride (2.5 g, 5.08 mmol), K2CO3 (2.81 g, 20.33 mmol) and KI (0.844 g, 5.08 mmol) were suspended in NMP (10 mL). To this suspension was added ((2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)methyl 4- methylbenzenesulfonate (1.959 g, 5.08 mmol) at 25oC. The reaction mixture was then stirred at 75oC for 18 h, monitoring the reaction progress by TLC (10% MeOH in DCM). After 18 h, the reaction was quenched with water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layer was washed with water (3 x 100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated on a rotary evaporator under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (Isolera) eluting with methanol in DCM (the desired product eluted in 0 to 6%). The fractions containing the desired product were concentrated under reduced pressure to obtain tert-butyl ((3S,6R)-6-((2-(5-(2-((3S,5R)-3,5-dimethylmorpholine-4- carbonyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)tetrahydro- 2H-pyran-3-yl)carbamate (2.0 g, 58.82% yield) as a yellow gummy solid: LCMS (Method B): Rt = 1.14 min, 669.4 (M+H)+. Step 5. (2-((4-(7-(((2S,5R)-5-Aminotetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophenyl)((3S,5R)-3,5- dimethylmorpholino)methanone, hydrochloride In a 50 mL three necked round bottom flask under nitrogen atmosphere, tert-butyl ((3S,6R)-6-((2-(5-(2-((3S,5R)-3,5-dimethylmorpholine-4-carbonyl)-4-fluorophenoxy)pyrimidin- 4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)tetrahydro-2H-pyran-3-yl)carbamate (2.5 g, 3.74 mmol) was dissolved in 2,2,2-trifluoroethanol (25 mL). To this solution was added TMS-Cl (1.911 mL, 14.95 mmol) at 10oC. The reaction was stirred at 25oC for 2 h, monitoring the reaction progress by TLC (10% MeOH in DCM). After 2 h, the reaction was concentrated to dryness under d d t t t bt i th d d t Th d id triturated with ethyl acetate. The supernatant layer was decanted and remaining solid was dried under vacuum to obtain (2-((4-(7-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophenyl)((3S,5R)-3,5- dimethylmorpholino)methanone, hydrochloride (2.5 g, 92% yield) as a yellow solid: LCMS (Method A): Rt = 1.28 min, 569.2 (M+H)+. Intermediate 8. (2-((4-(7-(((2S,5R)-5-Aminotetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophenyl)((3R,5R)-3,5- dimethylmorpholino)methanone, hydrochloride Step 1. tert-Butyl 2-(5-(2-((3R,5R)-3,5-dimethylmorpholine-4-carbonyl)-4- fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate In a dried, 100 mL three-necked round bottom flask under nitrogen atmosphere, lithium 2- ((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5- fluorobenzoate (4 g, 8.61 mmol), HATU (4.91 g, 12.92 mmol) and DIPEA (5.01 g, 38.8 mmol) were added to DMF (40 mL). To this solution, (3R,5R)-3,5-dimethylmorpholine hydrochloride (1.959 g, 12.92 mmol) was added at 25oC and the reaction mixture stirred at 25oC for 18 h. The reaction progress was monitored by TLC (10% MeOH in DCM). After 18 h, the reaction was quenched with water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layer was washed with water (3 x 100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated on a rotary evaporator d d d t bt i t t b t l 2 (5 (2 ((3R5R) 35 di th l h li 4 carbonyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (4.4 g, 74.5% yield) as a yellow gummy solid:1H NMR (400 MHz, CDCl3) į 8.29 (s, 1H), 7.78-7.70 (m, 1H), 7.38-7.27 (m, 2H), 7.07-7.04 (m, 1H), 4.04-3.89 (m, 8H), 3.30 (br s, 4H), 2.90-2.74 (m, 2H), 1.65 (t, J = 5.20 Hz, 4H), 1.39 (s, 9H), 1.28-1.16 (m, 6H); LCMS (Method B): Rt = 1.59 min, 556.3 (M+H)+. Step 2. (2-((4-(2,7-Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5- fluorophenyl)((3R,5R)-3,5-dimethylmorpholino)methanone, hydrochloride In a dried, 100 mL three-necked round bottom flask under nitrogen atmosphere, tert-butyl 2-(5-(2-((3R,5R)-3,5-dimethylmorpholine-4-carbonyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7- diazaspiro[3.5]nonane-7-carboxylate (4.4 g, 7.92 mmol) was dissolved in dioxane (20 mL). To this solution, hydrochloric acid (4M in dioxane, 19.80 mL, 79 mmol) was added slowly at 25oC. The reaction mixture was then stirred at 25oC for 1 h, monitoring the reaction progress by TLC (10% MeOH in DCM). After 1 h, the reaction was concentrated to dryness on a rotary evaporator. The resulting gummy solid was triturated with ethyl acetate twice. The supernatant layer was decanted and the solid obtained was dried under reduced pressure to afford (2-((4-(2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophenyl)((3R,5R)-3,5- dimethylmorpholino)methanone, hydrochloride (3.8 g, 73.6% yield) as yellow solid: LCMS (Method A): Rt = 1.17 min, 456.2 (M+H)+Step 3. tert-Butyl ((3R,6S)-6-((2-(5-(2-((3R,5R)-3,5-dimethylmorpholine-4-carbonyl)-4- fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)tetrahydro-2H-pyran-3- yl)carbamate

[0008] In a 50 mL three-necked round bottom flask under nitrogen atmosphere, (2-((4-(2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophenyl)((3R,5R)-3,5- dimethylmorpholino)methanone, hydrochloride (3.8 g, 7.72 mmol), K2CO3(4.27 g, 30.9 mmol) and KI (1.282 g, 7.72 mmol) were suspended in NMP (25 mL). To this suspension was added ((2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)methyl 4- methylbenzenesulfonate (2.98 g, 7.72 mmol) at 25oC. The reaction mixture was then stirred at 75oC for 18 h, monitoring the reaction progress by TLC (10% MeOH in DCM). After 18 h, the reaction was quenched with water (250 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layer was washed with water (3 x 150 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain the crude product. The crude product was purified by flash column chromatography (Isolera) using methanol in DCM (the desired product eluted in 0 to 6% MeOH in DCM). The fractions containing the required product were concentrated under reduced pressure to obtain tert- butyl ((3R,6S)-6-((2-(5-(2-((3R,5R)-3,5-dimethylmorpholine-4-carbonyl)-4- fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)tetrahydro-2H-pyran-3- yl)carbamate (4.1 g, 66% yield) as a yellow gummy solid: LCMS (Method B): Rt = 1.15 min, 669.4 (M+1)+. Step 4. (2-((4-(7-(((2S,5R)-5-Aminotetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophenyl)((3R,5R)-3,5- dimethylmorpholino)methanone, hydrochloride

[0009] In a 25 mL three-necked round bottom flask, tert-butyl ((3R,6S)-6-((2-(5-(2-((3R,5R)-3,5- dimethylmorpholine-4-carbonyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7- yl)methyl)tetrahydro-2H-pyran-3-yl)carbamate (4 g, 5.98 mmol) was dissolved in 2,2,2- trifluoroethanol (30 mL). To this solution, TMS-Cl (7.64 mL, 59.8 mmol) was added slowly at 25oC and the reaction mixture was stirred at 25oC for 1 h. The reaction progress was monitored by TLC (10% MeOH in DCM). After 1 h, the reaction was concentrated to dryness on a rotary evaporator under reduced pressure to obtain the crude residue. The crude residue was triturated with ethyl acetate. The supernatant layer was decanted and the remaining solid dried under vacuum to afford (2-((4-(7-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophenyl)((3R,5R)-3,5- dimethylmorpholino)methanone, hydrochloride (3.1 g, 75% yield) as a yellow solid: LCMS (Method A): Rt = 1.28 min, 569.3 (M+H)+. Intermediate 9. 2-((4-(7-(((2S,5R)-5-(Ethylsulfonamido)tetrahydro-2H-pyran-2- yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoic acid Step 1. Methyl 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5- fluorobenzoate, hydrochloride In a dried, 500 mL three-necked round bottom flask under nitrogen atmosphere was charged tert-butyl 2-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7- diazaspiro[3.5]nonane-7-carboxylate (25 g, 52.9 mmol) in 2,2,2-triflouroethanol (200 mL). To this solution, TMS-Cl (20.29 mL, 159 mmol) was added dropwise at 10oC. The reaction mixture was then stirred for 1 h at 25oC, monitoring the progress by TLC (10% MeOH in DCM). After 1 h, the solvent was distilled off under reduced pressure on a rotary evaporator and the residue was co-distilled with ethyl acetate (2 x 100 mL). The residue obtained was triturated with hexane to afford methyl 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate, hydrochloride (20.1 g, 93% yield) as an off-white solid:1H NMR (400 MHz, DMSO-d6): į 9.17 (br s, 2H), 8.62 (s, 1H), 7.78-7.75 (m, 1H), 7.70 (s, 1H), 7.66-7.62 (m, 1H), 7.50-7.47 (m, 1H), 4.29-3.84 (m, 4H), 3.81 (s, 3H), 3.04 (s, 4H), 2.02 (t, J = 5.20 Hz, 4H); LCMS (Method A): Rt = 1.33 min, 373.1 (M+H)+. Step 2. Methyl 2-((4-(7-(((2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2- yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate In a dried, 250 mL two-necked round bottom flask under nitrogen atmosphere, methyl 2- ((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate, hydrochloride (5 g, 12.23 mmol) was dissolved in N-methyl-2-pyrrolidinone (50 mL). To this solution, K2CO3(6.76 g, 48.9 mmol), KI (2.233 g, 13.45 mmol) and ((2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro- 2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (5.66 g, 14.68 mmol) were added at 25oC under nitrogen atmosphere. The resulting reaction was heated at 70oC for 12 h, monitoring the reaction progress by TLC (10% MeOH in DCM). After 12 h, the reaction mixture was cooled to room temperature, quenched with water (200 mL), and extracted with ethyl acetate (2 x 150 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated on a rotary evaporator (bath temperature 40oC) to obtain the crude product. The crude product was purified by column chromatography (Isolera) using 100-200 silica gel eluting with methanol in DCM (desired product was eluted at 4% methanol in DCM). The fractions containing the desired product were concentrated under reduced pressure to obtain methyl 2-((4- (7-(((2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate (5 g, 59.1% yield) as a light brown solid:1H NMR (400 MHz, DMSO-d6): į 8.28 (s, 1H), 7.67-7.64 (m, 2H), 7.50-7.45 (m, 1H), 7.12-7.09 (m, 1H), 6.74 (d, J = 7.60 Hz, 1H), 3.86-3.73 (m, 8H), 3.31-3.28 (m, 2H), 2.93- 2.88 (m, 1H), 2.33-2.27 (m, 3H), 2.20-2.16 (m, 3H), 1.87-1.81 (m, 1H), 1.68-1.64 (m, 5H), 1.37 (s, 9H), 1.33-1.22 (m, 2H); LCMS (Method B): Rt = 1.10 min, 586.4 (M+H)+. Step 3. Methyl 2-((4-(7-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate, hydrochloride In a dried, 500 mL three-necked round bottom flask under nitrogen atmosphere was charged methyl 2-((4-(7-(((2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2- yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate (5 g, 8.54 mmol) in 2,2,2-triflouro ethanol (50 mL). To this solution, TMS-Cl (3.27 mL, 25.6 mmol) was added dropwise at 10oC. The reaction was then stirred for 1 h at 25oC, monitoring the progress by TLC (10% MeOH in DCM). After 1 h, the solvent was distilled off under reduced pressure on a rotary evaporator and the residue was co-distilled with ethyl acetate (2 x 50 mL). The residue obtained was triturated with hexane and dried to afford methyl 2-((4-(7-(((2S,5R)-5-aminotetrahydro-2H- pyran-2-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate, hydrochloride (4.2 g, 76 % yield) as an off-white solid: LCMS (Method A): Rt = 1.290 min, 486.2 (M+H)+. Step 4. Methyl 2-((4-(7-(((2S,5R)-5-(ethylsulfonamido)tetrahydro-2H-pyran-2-yl)methyl)- 2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate In a dried, 25 mL three-necked round bottom flask under nitrogen atmosphere, methyl 2- ((4-(7-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2,7-diazaspiro[3.5]nonan-2- yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate, hydrochloride (4.2 g, 8.65 mmol) was dissolved in CH2Cl2 (50 mL) and cooled to 0oC. To this solution, TEA (12.16 mL, 86 mmol) was added and the reaction was stirred at 0oC for 30 min. After that ethanesulfonyl chloride (4.12 mL, 43.2 mmol) was added slowly and the reaction was stirred at 25oC for 16 h, monitoring the reaction progress by TLC (10 % Methanol in DCM). After 16 h, the reaction was quenched with water (10 mL) and extracted with DCM (2 x 15 mL). The organic layer was washed with aq. NaHCO3 (2 x 10 mL) and brine (2 x 10 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated on a rotary evaporator (bath temperature 40oC) to obtain the crude product. The crude product was purified by column chromatography (Isolera) using 100-200 silica and eluting with methanol in DCM (desired product was eluted at 5% methanol in DCM). The fractions containing the pure product were concentrated under reduced pressure to obtain methyl 2-((4-(7-(((2S,5R)-5-(ethylsulfonamido)tetrahydro-2H-pyran- 2-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate (3.8 g, 64.6 % yield) as a yellow solid:1H NMR (400 MHz, DMSO-d6): į 8.28 (s, 1H), 7.67-7.64 (m, 2H), 7.49- 7.47 (m, 1H), 7.11-7.09 (m, 2H), 3.86-3.80 (m, 7H), 3.09-2.98 (m, 6H), 2.29-2.21 (m, 5H), 1.95- 1.93 (m, 1H), 1.74-1.69 (m, 5H), 1.43-1.24 (m, 3H), 1.18 (t, J = 7.20 Hz, 3H); LCMS (Method B): Rt = 0.889 min, 578.3 (M+H)+. Step 5. 2-((4-(7-(((2S,5R)-5-(Ethylsulfonamido)tetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoic acid

[0010] In a dried, 250 mL three-necked round bottom flask under nitrogen atmosphere, methyl 2- ((4-(7-(((2S,5R)-5-(ethylsulfonamido)tetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate (3.8 g, 6.58 mmol) was dissolved in THF (20 mL), MeOH (16.00 mL) and H2O (4 mL). To the resulting solution, LiOH (0.315 g, 13.16 mmol) was added at 25oC and the reaction mixture was stirred at 25oC for 16 h. The reaction progress was monitored by TLC (10 % MeOH in DCM). After 16 h, the solvent was distilled off under reduced pressure on a rotary evaporator to obtain the crude product. The crude residue was co distilled with ethyl acetate (2 x 25 mL) to obtain 2-((4-(7-(((2S,5R)-5- (ethylsulfonamido)tetrahydro-2H-pyran-2-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin- 5-yl)oxy)-5-fluorobenzoic acid (3.5 g, 92 % yield) as a light brown solid:1H NMR (400 MHz, DMSO-d6): į 8.12 (s, 1H), 7.35 (s, 1H), 7.21 (dd, J = 3.20, 8.80 Hz, 1H), 7.04-6.99 (m, 1H), 6.93- 6.90 (m, 1H), 3.99-3.88 (m, 4H), 3.66 (d, J = 5.20 Hz, 1H), 3.26-3.17 (m, 3H), 2.85 (d, J = 6.40 Hz, 2H), 2.57-2.51 (m, 2H), 2.36-2.26 (m, 5H), 1.82-1.79 (m, 1H), 1.71-1.58 (m, 5H), 1.24-0.14 (m, 3H), 1.06 (t, J = 2.40 Hz, 3H); LCMS (Method A): Rt = 1.05 min, 564.2 (M+H)+. Intermediate 10. Lithium 2-((4-(7-(((2S,5R)-5-((tert- butoxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)methyl)-2,7-diazaspiro[3.5]nonan-2- yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate In 100 mL three necked round bottom flask methyl 2-((4-(7-(((2S,5R)-5-((tert- butoxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)methyl)-2,7-diazaspiro[3.5]nonan-2- MeOH (8 mL), and water (4 mL). To the resulting mixture LiOH (0.196 g, 8.20 mmol) was added at 25oC, and the reaction mixture was stirred at 25oC for 16 h.. Reaction progress was monitored by TLC (10 % MeOH in DCM). The solvent was evaporated on a rotary evaporator completely to obtain a crude mass, which was co-distilled with ethyl acetate (2 x 25 mL) to obtain lithium 2- ((4-(7-(((2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate (3.8 g, 87%) as a yellow solid): LCMS: (Method C) Rt.1.354 min, 572.4 (M+H)+. The crude product was used without any further purification Intermediate 1 Lithium 2-((4-(7-(((2S,5R)-5- (cyclopropanesulfonamido)tetrahydro-2H-pyran-2-yl)methyl)-2,7-diazaspiro[3.5]nonan-2- yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate Step 1. Methyl 2-((4-(7-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate, hydrochloride In a dried, 100 mL single-necked round bottom flask under nitrogen atmosphere, methyl 2-((4-(7-(((2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate (1.49 g, 2.188 mmol) was added to trifluoroethanol (8 mL). The resulting reaction mixture was cooled to 0oC and TMS-Cl (1.11 mL, 8.75 mmol) was added to it. The reaction was then stirred at 25oC for 1.5 h, monitoring the reaction progress by TLC (10 % methanol in dichloromethane) After 15 h the reaction mixture was concentrated on a rotary evaporator under reduced pressure to obtain the crude product. The crude product was co-distilled with ethyl acetate to obtain methyl 2-((4-(7-(((2S,5R)-5- aminotetrahydro-2H-pyran-2-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5- fluorobenzoate, hydrochloride (1.5 g, 1.695 mmol, 77 % yield) as a light brown semi-solid: LCMS (Method C): Rt = 1.462 min, m / z: 486.2 (M+H)+. This was taken as such to the next step without further purification. Step 2. Methyl 2-((4-(7-(((2S,5R)-5-(cyclopropanesulfonamido)tetrahydro-2H-pyran-2- In a dried, 100 mL three-necked round bottom flask under nitrogen atmosphere, methyl 2- ((4-(7-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2,7-diazaspiro[3.5]nonan-2- yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate, hydrochloride (1.5 g, 2.87 mmol)) was dissolved in DCM (30 mL) and the resulting solution was cooled to 0oC. Triethylamine (4.01 mL, 28.7 mmol) was added to the reaction mixture and stirred at 0oC for 5 min. After this, cyclopropanesulfonyl chloride (0.585 mL, 5.75 mmol) was added and then the reaction was stirred at 26oC for 16 h, monitoring the reaction progress by TLC (10 % methanol in dichloromethane). After 16 h, the reaction was concentrated on a rotary evaporator (bath temperature 40oC) under reduced pressure to obtain the crude compound. The crude compound was purified by prep HPLC (Method A). The fractions containing the desired product were lyophilized to obtain methyl 2-((4-(7-(((2S,5R)- 5-(cyclopropanesulfonamido)tetrahydro-2H-pyran-2-yl)methyl)-2,7-diazaspiro[3.5]nonan-2- yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate (0.06 g, 0.097 mmol, 3.36 % yield) as an off white solid: LCMS (Method C): Rt = 1.685 min, m / z: 590.4 (M+H)+. Step 3. Lithium 2-((4-(7-(((2S,5R)-5-(cyclopropanesulfonamido)tetrahydro-2H-pyran-2- yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate

[0011] In a dried, 25 mL two-necked round bottom flask under nitrogen atmosphere, methyl 2- ((4-(7-(((2S,5R)-5-(cyclopropanesulfonamido)tetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate (0.06 g, 0.102 mmol) was dissolved in THF (2.67 mL), methanol (2 mL) and water (0.667 mL). To this reaction mixture, lithium hydroxide (9.75 mg, 0.407 mmol) was added at 25oC under nitrogen atmosphere and the reaction mixture stirred at 25oC for 16 h, monitoring the reaction progress by TLC. After 16 h, the reaction mixture was concentrated on a rotary evaporator (bath temperature 45oC) under reduced pressure to obtain the crude lithium 2-((4-(7-(((2S,5R)-5- (cyclopropanesulfonamido)tetrahydro-2H-pyran-2-yl)methyl)-2,7-diazaspiro[3.5]nonan-2- yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate (0.066 g, 0.107 mmol, 105 % yield) as a light yellow solid: LCMS (Method C): Rt = 1.33 min, m / z: 576.5 (M+H)+. This was taken as such to next step without purification. Intermediate 12. 2-((4-(7-(((2S,5R)-5-Aminotetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-(2- methoxyethyl)benzamide, hydrochloride Step 1. tert-Butyl ((3R,6S)-6-((2-(5-(4-fluoro-2-(isopropyl(2- methoxyethyl)carbamoyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7- yl)methyl)tetrahydro-2H-pyran-3-yl)carbamate In a dried, 50 mL two-necked round bottom flask under nitrogen atmosphere, lithium 2- ((4-(7-(((2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate (1.0 g, 1.749 mmol) was dissolved in DMF (10 mL). To this solution, TEA (0.975 mL, 7.00 mmol), HATU (0.998 g, 2.62 mmol) and N-(2-methoxyethyl)propan-2-amine (0.246 g, 2.099 mmol) were added at 25oC under nitrogen atmosphere. The reaction was stirred at 25oC for 19 h, monitoring the reaction progress by TLC (10% methanol in dichloromethane). After 19 h, the reaction mixture was quenched with water (50 mL) and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated on a rotary evaporator (bath temperature 40oC) under reduced pressure to obtain crude tert-butyl ((3R,6S)-6-((2-(5-(4-fluoro-2-(isopropyl(2-methoxyethyl)carbamoyl)phenoxy)pyrimidin-4-yl)- 2,7-diazaspiro[3.5]nonan-7-yl)methyl)tetrahydro-2H-pyran-3-yl)carbamate (1.1 g, 1.185 mmol, 67.8 % yield) as an oily mass: LCMS (Method C): Rt = 2.085 min, m / z: 671.2 (M+H)+. This was taken as such to next step without further purification. Step 2. 2-((4-(7-(((2S,5R)-5-Aminotetrahydro-2H-pyran-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-(2- methoxyethyl)benzamide, hydrochloride In a dried, 50 mL two-necked round bottom flask under nitrogen atmosphere, tert-butyl ((3R,6S)-6-((2-(5-(4-fluoro-2-(isopropyl(2-methoxyethyl)carbamoyl)phenoxy)pyrimidin-4-yl)- 2,7-diazaspiro[3.5]nonan-7-yl)methyl)tetrahydro-2H-pyran-3-yl)carbamate (1.1 g, 1.640 mmol) was dissolved in 2,2,2 trifluoroethanol (10 mL). The resulting solution was cooled to 0oC and TMS-Cl (0.734 mL, 5.74 mmol) was added to it. The reaction was then stirred at 25oC for 1 h, monitoring the reaction progress by TLC (10 % methanol in dichloromethane). After 1 h, the reaction was concentrated on a rotary evaporator (bath temperature 40oC) under reduced pressure to obtain the crude product. The crude produc...

Claims

1. Compound according to formula 0, its stereoisomer or its pharmaceutically acceptable salt, where W represents N or CH; X represents C=O, S(=O)(=NR5) or S(=O)2; Y represents NH, O or bond; R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl is optionally substituted with one or more halogens, OH, O(benzyl), oxo, CN, N(RN)2, C1-C6 alkyls, C1-C6 haloalkyls, C3-C6 cycloalkyls or C1-C6 alkoxy; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl is optionally substituted with one or more halogens, OH, O(benzyl), oxo, CN, N(RN)2, C1-C6 alkyls, C1-C6 haloalkyls, C3-C6 cycloalkyls or C1-C6 alkoxy; R1 and R2 optionally form a 3-12 membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more C1-C6 alkyl, halogen, OH, CN or C1-C6 alkoxy; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, C6-C10 aryl, 5-10-membered heteroaryl, 3-12-membered heterocyclyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5-10-membered heteroaryl or 3-12-membered heterocyclyl is optionally substituted with one or more halogens, OH, O(benzyl), oxo, CN, N(RN)2, C1-C6 alkyls, C1-C6 haloalkyls, C3-C6 cycloalkyl, C1-C6 alkoxy or C6-C10 aryl; R4 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or N(RN)2; each RN is independently H, C1-C6 alkyl or C1-C6 haloalkyl; i each R5 is independently H, C1-C6 alkyl or C1-C6 haloalkyl, wherein each heteroaryl or heterocyclyl independently contains from 1 to 4 heteroatoms, each of which is independently selected from N, O and S.

2. Compound according to formula 0, its stereoisomer or its pharmaceutically acceptable salt, where W represents N or CH; X represents C=O, S(=O)(=NR5) or S(=O)2; Y represents NH, O or bond; R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl is optionally substituted with one or more halogens, OH, O(benzyl), oxo, CN, N(RN)2, C1-C6 alkyls, C1-C6 haloalkyls, C3-C6 cycloalkyls or C1-C6 alkoxy; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5-10-membered heteroaryl or 3-12-membered heterocyclyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5-10-membered heteroaryl or 3-12-membered heterocyclyl is optionally substituted with one or more halogens, OH, O(benzyl), oxo, CN, N(RN)2, C1-C6 alkyls, C1-C6 haloalkyls, C3-C6 cycloalkyls or C1-C6 alkoxy; R1 and R2 optionally form a 3-12-membered heterocyclyl, wherein the 3-12-membered heterocyclyl is optionally substituted with one or more C1-C6 alkyls, halogens, OH, CN or C1-C6 alkoxy; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, C6-C10 aryl, 5-10-membered heteroaryl, 3-12-membered heterocyclyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5-10-membered heteroaryl or 3-12-membered heterocyclyl is optionally substituted with one or more halogens, OH, O(benzyl), oxo, CN, N(RN)2, C1-C6 alkyls, C1-C6 haloalkyls, C3-C6 cycloalkyl, C1-C6 alkoxy or C6-C10 aryl; R4 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or N(RN)2; each RN is independently H, C1-C6 alkyl or C1-C6 haloalkyl; i each R5 is independently H, C1-C6 alkyl or C1-C6 haloalkyl, wherein each heteroaryl or heterocyclyl independently contains from 1 to 4 heteroatoms, each of which is independently selected from N, O and S.

3. The compound according to claim 1 or 2, wherein W is N.

4. The compound according to claim 1 or 2, wherein W is CH.

5. A compound according to any one of claims 1 to 4, wherein X is C=O or S(=O)2.

6. A compound according to any one of claims 1 to 5, wherein X is S(=O)2.

7. A compound according to any one of the preceding claims 1 to 6, wherein Y is NH, O or a bond.

8. A compound according to any one of claims 1 to 7, wherein Y is NH or a bond.

9. A compound according to any one of claims 1 to 8, wherein Y is NH.

10. A compound according to any one of claims 1 to 9, wherein R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy is optionally substituted with one or more halogens, OH, O(benzyl), oxo, CN or C3-C6 cycloalkyls.

11. A compound according to any one of claims 1 to 10, wherein R1 is C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted with one or more halogens, OH, oxo, CN or C3-C6 cycloalkyls.

12. A compound according to any one of claims 1 to 11, wherein R1 is C1-C6 alkyl optionally substituted with one or more halogens, OH, oxo, CN or C3-C6 cycloalkyls.

13. A compound according to any one of claims 1 to 12, wherein R1 is C1-C4 alkyl optionally substituted with one or more halogens, OH, oxo, CN or C3-C6 cycloalkyls.

14. A compound according to any one of claims 1 to 13, wherein R1 is C1-C4 alkyl optionally substituted with one or more halogens.

15. A compound according to any one of claims 1 to 14, wherein R1 is C1-C4 alkyl.

16. A compound according to any one of claims 1 to 14, wherein R1 is ethyl substituted with one or more halogens.

17. The compound according to claim 16, wherein R1 is -CH2-CHF2 or -CH2-CF3.

18. A compound according to any one of claims 1 to 15, wherein R1 is isopropyl.

19. A compound according to any one of claims 1 to 9, wherein R1 is C3-C12 cycloalkyl, C6-C10 aryl, 5-10-membered heteroaryl or 3-12-membered heterocyclyl, wherein the C3-C12 cycloalkyl, C6-C10 aryl, 5-10-membered heteroaryl or 3-12-membered heterocyclyl is optionally substituted with one or more halogens, OH, oxo, CN, C1-C6 alkyls, C1-C6 haloalkyls, C3-C6 cycloalkyls or C1-C6 alkoxy.

20. A compound according to any one of claims 1 to 9, wherein R1 is C3-C12 cycloalkyl, 5-10-membered heteroaryl or 3-12-membered heterocyclyl, wherein the C3-C12 cycloalkyl, 5-10-membered heteroaryl or 3-12-membered heterocyclyl is optionally substituted with one or more halogens, OH, oxo, CN, C1-C6 alkyls, C1-C6 haloalkyls, C3-C6 cycloalkyls or C1-C6 alkoxy.

21. A compound according to any one of claims 1 to 9, wherein R1 is C3-C12 cycloalkyl, wherein the C3-C12 cycloalkyl is optionally substituted with one or more halogens, OH, oxo, CN, C1-C6 alkyls, C1-C6 haloalkyls, C3-C6 cycloalkyls or C1-C6 alkoxy.

22. A compound according to any one of claims 1 to 9, wherein R1 is 3-6 membered heterocyclyl optionally substituted with one or more halogens, OH, oxo, CN, C1-C6 alkyls, C1-C6 haloalkyls, C3-C6 cycloalkyls or C1-C6 alkoxy.

23. A compound according to any one of claims 1 to 9, wherein R1 is 3-6 membered heterocyclyl optionally substituted with one or more halogens, C1-C6 alkyls or C1-C6 haloalkyls.

24. A compound according to any one of claims 1 to 9, wherein R1 is 3-6 membered heterocyclyl optionally substituted with one or more C1-C6 alkyl or OH.

25. A compound according to any one of claims 1 to 9, wherein R1 is 3-5 membered heterocyclyl optionally substituted with one or more C1-C6 alkyl or OH.

26. A compound according to any one of claims 1 to 9, wherein R1 is 3-5-membered heterocyclyl substituted with one or more C1-C6 alkyl or OH.

27. A compound according to any one of claims 1 to 26, wherein R2 is C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted with one or more halogens, OH, oxo, CN, C1-C6 alkyls, C1-C6 haloalkyls, C3-C6 cycloalkyls or C1-C6 alkoxy.

28. A compound according to any one of claims 1 to 27, wherein R2 is C1-C4 alkyl optionally substituted with one or more halogens.

29. A compound according to any one of claims 1 to 28, wherein R2 is C1-C3 alkyl optionally substituted with one or more halogens.

30. A compound according to any one of claims 1 to 29, wherein R2 is ethyl.

31. A compound according to any one of claims 1 to 29, wherein R2 is propyl.

32. The compound according to claim 31, wherein R2 is isopropyl.

33. A compound according to any one of claims 1 to 32, wherein R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, NH2, NH-C1-C6 alkyl or N-(C1-C6 alkyl)2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy is optionally substituted with one or more halogens, OH, oxo, CN, C1-C6 alkyls, C1-C6 haloalkyls, C3-C6 cycloalkyls or C1-C6 alkoxy.

34. A compound according to any one of claims 1 to 32, wherein R3 is C1-C6 alkyl, NH-C1-C6 alkyl or N-(C1-C6 alkyl)2, wherein C1-C6 alkyl is optionally substituted with one or more halogens, OH, oxo, CN, C1-C6 alkyls, C1-C6 haloalkyls, C3-C6 cycloalkyls or C1-C6 alkoxy.

35. A compound according to any one of claims 1 to 32, wherein R3 is C1-C6 alkyl, NH-C1-C6 alkyl or N-(C1-C6 alkyl)2, wherein C1-C6 alkyl is optionally substituted with one or more halogens.

36. A compound according to any one of claims 1 to 32, wherein R3 is C1-C6 alkyl, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2 or 5-10-membered heteroaryl, wherein the C1-C6 alkyl, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2 or 5-10-membered heteroaryl is optionally substituted with one or more halogens, C1-C6 alkyls, C1-C6 haloalkyls, C3-C6 cycloalkyls or C1-C6 alkoxy.

37. A compound according to any one of claims 1 to 32, wherein R3 is C3-C12 cycloalkyl, C6-C10 aryl, 5-10-membered heteroaryl, 3-12-membered heterocyclyl, wherein C3-C12 cycloalkyl, C6-C10 aryl, 5-10-membered heteroaryl, 3-12-membered heterocyclyl is optionally substituted with one or more halogens, OH, oxo, CN, C1-C6 alkyls, C1-C6 haloalkyls, C3-C6 cycloalkyls or C1-C6 alkoxy.

38. A compound according to any one of claims 1 to 32, wherein R3 is 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more halogens, C1-C6 alkyls, C1-C6 haloalkyls, C3-C6 cycloalkyls or C1-C6 alkoxy.

39. A compound according to any one of claims 1 to 32, wherein R3 is 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with one or more halogens or C1-C6 alkyls.

40. A compound according to any one of claims 1 to 32, wherein R3 is a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted with one or more halogens or C1-C6 alkyls.

41. A compound according to any one of claims 1 to 32, wherein R3 is a 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with one or more halogens or C1 alkyls.

42. A compound according to any one of claims 1 to 32, wherein R3 is C1-C3 alkyl, NH-C1-C3 alkyl, N-(C1-C3 alkyl)2 or 5-6-membered heteroaryl, wherein the C1-C3 alkyl or 5-6-membered heteroaryl is optionally substituted with one or more halogens, C1-C6 alkyls, C1-C6 haloalkyls, C3-C6 cycloalkyls or C1-C6 alkoxy.

43. A compound according to any one of claims 1 to 32, wherein R3 is C1-C3 alkyl, NH-C1-C3 alkyl, N-(C1-C3 alkyl)2 or 5-6-membered heteroaryl, wherein the C1-C3 alkyl or 5-6-membered heteroaryl is substituted with one or more halogens, C1-C6 alkyls, C1-C6 haloalkyls, C3-C6 cycloalkyls or C1-C6 alkoxy.

44. A compound according to any one of claims 1 to 43, wherein R4 is H or halogen.

45. A compound according to any one of claims 1 to 44, wherein R4 is H.

46. ​​A compound according to any one of claims 1 to 45, wherein each R5 is independently H or C1-C6 alkyl.

47. A compound according to any one of claims 1 to 46, wherein each R5 is H.

48. A compound selected from: or its stereoisomer or its pharmaceutically acceptable salt.

49. A compound selected from: or a pharmaceutically acceptable salt thereof.

50. A compound selected from:

51. The use of a compound according to any one of claims 1 to 50 for the treatment of cancer, wherein the compound minimizes hERG binding.

52. A pharmaceutical composition comprising a compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

53. A pharmaceutical composition comprising a crystalline form of a compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

54. A method for inhibiting the interaction between menin and MLL, comprising contacting menin and MLL with a compound according to any one of claims 1 to 51 or a pharmaceutical composition according to claim 52 or 53.

55. A method of treating cancer in a patient, comprising administering to the patient a compound according to any one of claims 1-51 or a pharmaceutical composition according to claim 52 or 53.

56. The method according to claim 55, characterized in that the cancer is hematological cancer.

57. The method according to paragraph 55 or 56, characterized in that the cancer is leukemia.

58. The method according to paragraph 55 or 56, characterized in that the cancer is lymphoma.

59. The method according to claim 55 or 56, characterized in that the cancer is leukemia of mixed origin (MLL), leukemia associated with MLL, leukemia associated with MLL, MLL-positive leukemia, MLL-induced leukemia, rearranged leukemia of mixed origin (MLL-r), leukemia associated with MLL rearrangement or MLL gene rearrangement, acute leukemia, chronic leukemia, indolent leukemia, lymphoblastic leukemia, lymphocytic leukemia, myelogenous leukemia, myelogenous leukemia, childhood leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute granulocytic leukemia, acute non-lymphocytic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), therapy-associated leukemia, myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), myeloproliferative neoplasia (MPN), plasma cell neoplasm, multiple myeloma, myelodysplasia, cutaneous T-cell lymphoma, lymphoid neoplasm, AIDS-associated lymphoma,thymoma, thymic carcinoma, mycosis fungoides, Alibert-Bazin syndrome, granuloma fungoides, Sezary syndrome, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocyte leukemia, meningeal leukemia, leukemic leptomeningitis, leukemic meningitis, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma (malignant lymphoma), or Waldenstrom macroglobulinemia.

60. The method according to claim 55 or 56, wherein the cancer is acute myeloid leukemia with an abstract nucleophosmin (NPM1) mutation (i.e., acute myeloid leukemia NPM1mut).

61. The method according to claim 55 or 56, characterized in that the cancer is a rearranged leukemia of mixed origin (MLL-r).

62. The use of a compound according to any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 52 or 53, for the treatment or prevention of a disease caused by or associated with the expression, activity and / or function of menin.

63. The use of a compound according to any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 52 or 53, for the preparation of a medicament for the treatment or prevention of a disease caused by or associated with the expression, activity and / or function of menin.

64. The use of a compound according to any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 52 or 53, for the treatment or prevention of cancer.

65. The use of a compound according to any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 52 or 53, for the preparation of a medicament for the treatment or prevention of cancer.

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