Inhibitors of menin-MLL interaction

Abstract

The present disclosure relates to a compound of formula (0), or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, that is an inhibitor of the interaction of menin with MLL and MLL fusion proteins, pharmaceutical compositions containing same, and their use in the treatment of cancer and other diseases mediated by the menin-MLL interaction. JPEG2024517945000679.jpg59164

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 188,704, filed May 14, 2021, which is incorporated herein by reference in its entirety. [Background technology]

[0002] The mixed lineage leukemia (MLL) protein is a histone methyltransferase that is mutated in clinically and biologically distinct subsets of acute leukemia. Rearranged mixed lineage leukemia (MLL-r) involves recurrent translocations at the 11q23 chromosomal locus and causes an aggressive form of acute leukemia with limited therapeutic options. These translocations target the MLL gene, generating oncogenic fusion proteins containing the amino terminus of MLL fused in-frame with over 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 cofactor for oncogenic MLL-r fusion proteins. Disruption of this interaction results in selective growth inhibition and apoptosis of MLL-r leukemia cells both in vitro and in vivo.

[0003] The menin-MLL complex has been implicated in castration-resistant / advanced prostate cancer, and menin-MLL inhibitors have been shown to reduce tumor growth in vivo. Furthermore, menin-MLL inhibitors have been shown to increase human beta cell proliferation, supporting the role of inhibitors of the menin-MLL interaction in the treatment of diabetes. The interaction of menin with MLL or MLL fusion proteins is an attractive target for therapeutic intervention, and novel agents that inhibit the menin-MLL interaction are needed for the treatment of various diseases and conditions, including leukemia, other cancers, and diabetes.

[0004] Furthermore, the hERG potassium channel is essential for normal electrical activity of the heart. Genetic mutations in the hERG gene cause long QT syndrome, a condition that predisposes individuals to life-threatening arrhythmias. Arrhythmias can also be induced by blockade of the hERG channel by a surprisingly diverse group of drugs. This side effect is a common reason for drug failure in preclinical safety studies, and compounds that exhibit low off-target hERG binding are of paramount importance in drug design for high clinical need. Therefore, determining the potential of candidate compounds to block the hERG channel is crucial in drug development. However, this property cannot be easily determined from the compound's structure, and even closely related compounds can vary greatly in their potential to block the hERG channel. Therefore, there is an urgent need to develop effective compounds that minimize hERG channel blockade. Summary of the Invention

[0005] In one aspect, the present disclosure provides a compound of formula 0 [ka] or a pharmaceutically acceptable salt thereof (wherein W, X, Y, R1, R2, R3, R4, and R5 are as defined herein).

[0006] In some aspects, the present application relates to a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of the present application and a pharmaceutically acceptable carrier.

[0007] In some aspects, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0008] In some aspects, the present application relates to a pharmaceutical composition comprising a compound of the present application and a pharmaceutically acceptable carrier.

[0009] In some aspects, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present application and a pharmaceutically acceptable carrier.

[0010] The present disclosure further provides a method for inhibiting the interaction between menin and MLL, comprising contacting menin and MLL with a compound of Formula I, Ia, II, IIa, III, or IIIa, or a stereoisomer or pharmaceutically acceptable salt thereof.

[0011] 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 Formula 0, 0a, I, Ia, II, IIa, III, or IIIa, or a stereoisomer or pharmaceutically acceptable salt thereof.

[0012] The present disclosure further provides a method for inhibiting the interaction between menin and MLL, comprising contacting menin and MLL with a compound of Formula 0, 0a, I, Ia, II, IIa, III, or IIIa.

[0013] 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 Formula 0, 0a, I, Ia, II, IIa, III, or IIIa.

[0014] Details of the present 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, exemplary methods and materials are described below. In case of conflict, the present specification, including definitions, will control. Additionally, the materials, methods, and examples are merely illustrative and not intended to be limiting. Other features, objects, and advantages of the present disclosure will become apparent from the description and claims. In this specification and the appended claims, the singular forms include the plural forms 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.

[0015] The contents of all references cited throughout this application (including literature references, issued patents, published patent applications, and co-pending patent applications) are expressly incorporated herein by reference in their entirety. No reference cited herein is admitted to be prior art to this application. DETAILED DESCRIPTION OF THE INVENTION

[0016] In one aspect, the present disclosure provides a compound of formula 0 [ka] a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 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-C 12 Cycloalkyl, C6-C 10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted with 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; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be optionally substituted with one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted with C1-C6 alkyl, 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(R N )2, Each R N are independently H, C1-C6 alkyl, or C1-C6 haloalkyl; each R5 is independently H, C1-C6 alkyl, or C1-C6 haloalkyl).

[0017] In one aspect, the present disclosure provides a compound of formula 0a [ka] a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 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-C 12 Cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more of halo, OH, OBn, oxo, CN, N(R N)2, optionally substituted with 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; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be optionally substituted with one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted with C1-C6 alkyl, 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(R N )2, Each R N are independently H, C1-C6 alkyl, or C1-C6 haloalkyl; each R5 is independently H, C1-C6 alkyl, or C1-C6 haloalkyl).

[0018] In one aspect, the present disclosure provides a compound of formula I [ka] a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 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-C 12 Cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted with 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; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be optionally substituted with one or more of halo, OH, OBn, oxo, CN, N(R N)2, optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or aryl; R4 is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; Each R N are independently H, C1-C6 alkyl, or C1-C6 haloalkyl; each R5 is independently H, C1-C6 alkyl, or C1-C6 haloalkyl).

[0019] In one aspect, the present disclosure provides a compound of formula Ia [ka] a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 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-C 12 Cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more of halo, OH, OBn, oxo, CN, N(RN )2, optionally substituted with 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; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be optionally substituted with one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or aryl; R4 is H, halo, C1-C6 alkyl, or C1-C6 haloalkyl; Each R N are independently H, C1-C6 alkyl, or C1-C6 haloalkyl; each R5 is independently H, C1-C6 alkyl, or C1-C6 haloalkyl).

[0020] In one aspect, the present disclosure provides a compound of formula II [ka] a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C6-C 10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted with 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; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be optionally substituted with one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or aryl; Each R Nis independently H, C1-C6 alkyl, or C1-C6 haloalkyl).

[0021] In one aspect, the present disclosure provides a compound of formula IIa [ka] a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted with 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; R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12Cycloalkyl, NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be optionally substituted with one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or aryl; Each R N is independently H, C1-C6 alkyl, or C1-C6 haloalkyl).

[0022] In one aspect, the present disclosure provides a compound of formula III [ka] a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C6-C 10aryl, 5-10 membered heteroaryl, or 3-12 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-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; R6 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be optionally substituted with one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or aryl; Each R N is independently H, C1-C6 alkyl, or C1-C6 haloalkyl).

[0023] In one aspect, the present disclosure provides a compound of formula IIIa [ka] a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C6-C 10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be selected from the group consisting of one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted with 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; R6 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl may be optionally substituted with one or more of halo, OH, OBn, oxo, CN, N(R N )2, optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or aryl; Each R N is independently H, C1-C6 alkyl, or C1-C6 haloalkyl).

[0024] Embodiment For any of Formulas 0, 0a, I, Ia, II, IIa, III, or IIIa, where applicable, the following embodiments are contemplated alone and in conjunction with other embodiments that result in the formation of stable compounds.

[0025] In some embodiments, X is C=O, S(=O)(=NR), or S(=O). In some embodiments, X is C=O. In some embodiments, X is S(=O)(=NR). In some embodiments, X is S(=NR). In some embodiments, when X, each R is independently selected and may be the same or different. In some embodiments, X is S(=O). In some embodiments, X is C=O, or S(=O). In some embodiments, X is C=O, S(=O)(=NR), or S(=O). In some embodiments, X is S(=O)(=NR), or S(=O).

[0026] 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 R3 is 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, R1 is C1-C2 alkyl. In some embodiments, R1 is methyl. In some embodiments, R1 is ethyl. In some embodiments, R1 is propyl. In some embodiments, R1 is isopropyl. In some embodiments, R1 is butyl. In some embodiments, R1 is tert-butyl.

[0027] In some embodiments, R1 is methyl substituted with cyclopropane. In some embodiments, R1 is methyl substituted with cyclobutene. In some embodiments, R1 is 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 one halo, two halo, or three halo. In some embodiments, R1 is ethyl substituted with one or more halo. In some embodiments, R1 is ethyl substituted with one halo, two halo, or three halo.

[0028] In some embodiments, R1 is -CH2-CHF2.

[0029] In some embodiments, R1 is ethyl substituted with two halo atoms. In some embodiments, R1 is ethyl substituted with three halo atoms. In some embodiments, R1 is ethyl substituted with one fluorine atom. In some embodiments, R1 is ethyl substituted with two fluorine atoms. In some embodiments, R1 is ethyl substituted with three fluorine atoms. In some embodiments, R1 is -CH2-CF3. In some embodiments, R1 is -CF2-CF3. In some embodiments, R1 is difluoroethyl.

[0030] In some embodiments, R1 is cyclopropyl. In some embodiments, R1 is cyclobutyl. In some embodiments, R1 is oxetanyl. In some embodiments, R1 is 2-oxetanyl. In some embodiments, R1 is 3-oxetanyl.

[0031] In some embodiments, R1 is C2-C6 alkyl, wherein the alkyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy.

[0032] In some embodiments, R1 is C3-C6 alkyl, wherein the alkyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy.

[0033] In some embodiments, R1 is C1-C5 alkyl, wherein the alkyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy.

[0034] In some embodiments, R1 is C2-C5 alkyl, wherein the alkyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy.

[0035] In some embodiments, R1 is C3-C5 alkyl, wherein the alkyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy.

[0036] In some embodiments, R1 is C1-C4 alkyl, wherein the alkyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy.

[0037] In some embodiments, R1 is C2-C4 alkyl, wherein the alkyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy.

[0038] In some embodiments, R1 is C3-C4 alkyl, where the alkyl is optionally substituted with 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 alkyl, where the alkyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy.

[0039] In some embodiments, R1 is C2 alkyl, wherein the alkyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy.

[0040] In some embodiments, R1 is C3 alkyl, where alkyl is optionally substituted with 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, where cycloalkyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy.

[0041] In some embodiments, R1 is C3-cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy.

[0042] In some embodiments, R1 is C4-cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy.

[0043] In some embodiments, R1 is C5-cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more halo, OH, OBn, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy.

[0044] In some embodiments, R1 is a 4-, 5-, or 6-membered heterocyclyl having one or two heteroatoms, each selected from N or O, wherein the heterocyclyl 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.

[0045] In some embodiments, R1 is a 4- or 5-membered heterocyclyl having one or two heteroatoms, each selected from N or O, wherein the heterocyclyl 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.

[0046] In some embodiments, R1 is a 5- or 6-membered heterocyclyl having one or two heteroatoms, each selected from N or O, wherein the heterocyclyl 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.

[0047] In some embodiments, R1 is a 4-membered heterocyclyl having one or two heteroatoms each selected from N or O, wherein the heterocyclyl 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.

[0048] In some embodiments, R1 is a 5-membered heterocyclyl having one or two heteroatoms each selected from N or O, wherein the heterocyclyl 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.

[0049] In some embodiments, R1 is a 6-membered heterocyclyl having one or two heteroatoms each selected from N or O, wherein the heterocyclyl 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.

[0050] In some embodiments, R1 is C1-C6 alkyl or C3-C6 cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with 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 a 4-, 5-, or 6-membered heterocyclyl having one or two heteroatoms selected from N or O, respectively, where the alkyl or heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy.

[0051] In some embodiments, R1 is a C3-C6 cycloalkyl optionally substituted with one or more halo, C1-C6 alkoxy, or CN, or a 4-, 5-, or 6-membered heterocyclyl having one or two heteroatoms selected from N or O, respectively.

[0052] In some embodiments, R1 is C2-C6 alkenyl. In some embodiments, R1 is C2-C6 alkynyl. In some embodiments, R1 is C1-C6 alkoxy. In some embodiments, R1 is C1-C6 alkoxy substituted with one, two, or three halo. In some embodiments, R1 is C3-C6 alkoxy. 12In some embodiments, R1 is C3-C6 cycloalkyl. In some embodiments, R1 is C3-C5 cycloalkyl. In some embodiments, R1 is C3-C4 cycloalkyl.

[0053] In some embodiments, R1 is a C3-C6 substituted with one, two, or three halo. 12In some embodiments, R1 is C3-C6 cycloalkyl substituted with one, two, or three halo. In some embodiments, R1 is C3-C5 cycloalkyl substituted with one, two, or three halo. In some embodiments, R1 is C3-C4 cycloalkyl substituted with one, two, or three halo. In some embodiments, R1 is C3-C5 cycloalkyl substituted with C1-C6 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-C6 haloalkyl. In some embodiments, R1 is 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, R1 is cis-cyclobutyl substituted with CF3. In some embodiments, R1 is trans-cyclobutyl substituted with CF3. In some embodiments, R1 is 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, R1 is cyclobutyl substituted with fluorine. In some embodiments, R1 is cis-cyclobutyl substituted with fluorine. In some embodiments, R1 is 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, R1 is cis-cyclobutyl substituted with OH.In some embodiments, R1 is 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.

[0054] In some embodiments, R1 is oxabicyclo[3.1.0]hexan-6-yl.

[0055] In some embodiments, R1 is 2-oxaspiro[3.3]heptan-6-yl.

[0056] In some embodiments, R1 is oxabicyclo[2.2.1]heptan-2-yl.

[0057] In some embodiments, R1 is oxetanyl.

[0058] In some embodiments, R1 is tetrahydro-2H-pyran-4-yl.

[0059] In some embodiments, R1 is 3-hydroxycyclobutyl.

[0060] In some embodiments, R1 is 3,3-difluorocyclobutyl.

[0061] In some embodiments, R1 is (E1)-2-hydroxycyclobutyl.

[0062] In some embodiments, R1 is (E2)-2-hydroxycyclobutyl.

[0063] In some embodiments, R1 is (1R,2S)-2-hydroxycyclobutyl.

[0064] In some embodiments, R1 is (1r,3r)-3-hydroxycyclobutyl.

[0065] In some embodiments, R1 is (3R,5R)-3,5-dimethylmorpholinyl.

[0066] In some embodiments, R1 is (R)-tetrahydrofuran-3-yl.

[0067] In some embodiments, R1 is (S)-tetrahydrofuran-3-yl.

[0068] In some embodiments, R1 is cyanomethyl.

[0069] In some embodiments, R1 is 2-cyanoethyl.

[0070] In some embodiments, R1 is (1r,3r)-3-fluorocyclobutyl.

[0071] In some embodiments, R1 is (1s,3s)-3-fluorocyclobutyl.

[0072] In some embodiments, R1 is (1r,3r)-3-(difluoromethyl)cyclobutyl.

[0073] In some embodiments, R1 is (1s,3s)-3-(difluoromethyl)cyclobutyl.

[0074] In some embodiments, R is C-C 10 In some embodiments, R is C aryl. In some embodiments, R is C-C aryl substituted with one, two, or three halo. 10In some embodiments, R1 is a C6 aryl substituted with one, two, or three halo. In some embodiments, R1 is a 5- to 10-membered heteroaryl. In some embodiments, R1 is a 5- to 7-membered heteroaryl. In some embodiments, R1 is a 5- to 6-membered heteroaryl. In some embodiments, R1 is a 5-membered heteroaryl having two heteroatoms selected from N, O, and S. In some embodiments, R1 is a 6-membered heteroaryl having two heteroatoms selected from N, O, and S. In some embodiments, R1 is a 5-membered heteroaryl having two nitrogen heteroatoms. In some embodiments, R1 is a 6-membered heteroaryl having two nitrogen heteroatoms. In some embodiments, R1 is a 5-membered heteroaryl having one heteroatom selected from N, O, and S. In some embodiments, R1 is a 6-membered heteroaryl having one heteroatom selected from N, O, and S. In some embodiments, R1 is a 3- to 10-membered heterocyclyl.

[0075] In some embodiments, R1 is a 3- to 9-membered heterocyclyl. In some embodiments, R1 is a 3- to 8-membered heterocyclyl. In some embodiments, R1 is a 3- to 7-membered heterocyclyl. In some embodiments, R1 is a 3- to 6-membered heterocyclyl. In some embodiments, R1 is a 3- to 5-membered heterocyclyl. In some embodiments, R1 is a 3-membered heterocyclyl. In some embodiments, R1 is a 4-membered heterocyclyl. In some embodiments, R1 is a 3-membered heterocyclyl optionally substituted with one, two, or three halo. In some embodiments, R1 is a 4-membered heterocyclyl optionally substituted with one, two, or three halo. In some embodiments, R1 is a 5-membered heterocyclyl optionally substituted with one, two, or three halo. In some embodiments, R1 is a 6-membered heterocyclyl optionally substituted with one, two, or three halo. In some embodiments, R1 is a 3-membered heterocyclyl substituted with one, two, or three halo. In some embodiments, R1 is a 4-membered heterocyclyl substituted with one, two, or three halo. In some embodiments, R1 is a 5-membered heterocyclyl substituted with one, two, or three halo. In some embodiments, R1 is a 6-membered heterocyclyl substituted with one, two, or three halo.

[0076] 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, R1 is 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, R1 is 2-oxetanyl optionally substituted with -CF3. In some embodiments, R1 is 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, R1 is tetrahydrofuranyl. In some embodiments, R1 is 2-tetrahydrofuranyl. In some embodiments, R1 is 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, R1 is tetrahydrofuranyl optionally substituted with -CF3. In some embodiments, R1 is 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, R1 is 3-tetrahydrofuranyl optionally substituted with haloalkyl.In some embodiments, R1 is 3-tetrahydrofuranyl optionally substituted with -CHF2. In some embodiments, R1 is 3-tetrahydrofuranyl optionally substituted with -CF3. In some embodiments, R1 is a 7- to 10-membered spirocyclic heterocyclyl. In some embodiments, R1 is a 7-membered spirocyclic heterocyclyl. In some embodiments, R1 is a 7-membered bicyclic heterocyclyl. In some embodiments, R1 is 2-oxaspiro[3.3]heptanyl.

[0077] In some embodiments, R1 and R2 form a 4-, 5-, or 6-membered heterocyclyl having one or two heteroatoms each selected from N, O, or S, where the heterocyclyl is optionally substituted with one or more alkyl groups. In some embodiments, R1 and R2 form a 5-membered heterocyclyl having one or two heteroatoms each selected from N, O, or S, where the heterocyclyl is optionally substituted with one or more alkyl groups. In some embodiments, R1 and R2 form a 5-membered heterocyclyl having one heteroatom selected from N, O, or S, where the heterocyclyl is optionally substituted with one or more alkyl groups. In some embodiments, R1 and R2 form a 5-membered heterocyclyl having two heteroatoms each selected from N, O, or S, where the heterocyclyl is optionally substituted with one or more alkyl groups. In some embodiments, R1 and R2 form a 6-membered heterocyclyl having one or two heteroatoms selected from N, O, or S, respectively, where the heterocyclyl is optionally substituted with one or more alkyl groups. In some embodiments, R1 and R2 form a 6-membered heterocyclyl having one heteroatom selected from N, O, or S, where the heterocyclyl is optionally substituted with one or more alkyl groups. In some embodiments, R1 and R2 form a 6-membered heterocyclyl having two heteroatoms selected from N or O, respectively, where the heterocyclyl is optionally substituted with one or more alkyl groups. In some embodiments, R1 and R2 form a 4-, 5-, or 6-membered heterocyclyl having one or two heteroatoms selected from N or O, respectively, where the heterocyclyl is substituted with two alkyl groups. In some embodiments, R 1 and R 2 form a 5-membered heterocyclyl having one or two 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 having one heteroatom selected from N or O, where the heterocyclyl is substituted by two alkyl groups. In some embodiments, R1 and R2 form a 5-membered heterocyclyl having two heteroatoms each selected from N or O, where the heterocyclyl is substituted by two alkyl groups. In some embodiments, R1 and R2 form a 6-membered heterocyclyl having one or two heteroatoms each selected from N or O, where the heterocyclyl is substituted by two alkyl groups. In some embodiments, R1 and R2 form a 6-membered heterocyclyl having one heteroatom selected from N or O, where the heterocyclyl is substituted by two alkyl groups. In some embodiments, R1 and R2 form a 6-membered heterocyclyl having two heteroatoms each selected from N or O, where the heterocyclyl is substituted by two alkyl groups.

[0078] In some embodiments, R3 is a 3-6 membered heterocyclyl having 1 or 2 heteroatoms each selected from C1-C6 alkyl, C3-C6 cycloalkyl, NH—C1-C6 alkyl, N—(C1-C6 alkyl)2, phenyl, N, O, or S, where the alkyl, cycloalkyl, or heterocyclyl is optionally substituted with C1-C6 alkyl or C1-C6 alkoxy. In some embodiments, R3 is a C1-C6 alkyl, where the alkyl is optionally substituted with C3-C6 cycloalkyl or C1-C6 alkoxy. In some embodiments, R3 is a C1-C6 alkyl, where the alkyl is optionally substituted with C3-C6 cycloalkyl. In some embodiments, R3 is a C1-alkyl, where the alkyl is optionally substituted with C3-cycloalkyl. In some embodiments, R3 is a C2-alkyl, where the alkyl is optionally substituted with C3-cycloalkyl. In some embodiments, R3 is C3-alkyl, where the alkyl is optionally substituted with C3-cycloalkyl. In some embodiments, R3 is C4-alkyl, where the alkyl is optionally substituted with C3-cycloalkyl. In some embodiments, R3 is C5-alkyl, where the alkyl is optionally substituted with C3-cycloalkyl. In some embodiments, R3 is C6-alkyl, where the alkyl is optionally substituted with C3-cycloalkyl. In some embodiments, R3 is C1-C2 alkyl, where the alkyl is optionally substituted with C3-cycloalkyl. In some embodiments, R3 is C1-C3 alkyl, where the alkyl is optionally substituted with C3-cycloalkyl. In some embodiments, R3 is C1-C4 alkyl, where the alkyl is optionally substituted with C3-cycloalkyl.In some embodiments, R3 is C1-C5 alkyl, where the alkyl is optionally substituted with C3-cycloalkyl. In some embodiments, R3 is C1-C6 alkyl, where the alkyl is optionally substituted with C3-cycloalkyl. In some embodiments, R3 is C1-C6 alkyl, where the alkyl is C. 1- In some embodiments, R3 is C1-C6 alkyl, where the alkyl is optionally substituted with C1-C6 alkoxy. In some embodiments, R3 is C1-C6 alkyl, where the alkyl is optionally substituted with C1-C6 alkoxy. In some embodiments, R3 is C3-C6 cycloalkyl, where the cycloalkyl is optionally substituted with C3-C6 cycloalkyl or C1-C6 alkoxy. In some embodiments, R3 is C3-C6-heterocyclyl having one or two heteroatoms each selected from N or O, where the heterocyclyl is optionally substituted with 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, R1 and R2 together form a 3,5-dimethylmorpholino ring. In some embodiments, R1 is ethyl optionally substituted with one or more halo or C1-C6 alkoxy, and R2 is isopropyl optionally substituted with one or more halo or C1-C6 alkoxy.

[0079] In some embodiments, R1 is isopropyl optionally substituted with one or more halo or C1-C6 alkoxy, and R2 is isopropyl optionally substituted with one or more halo or C1-C6 alkoxy. In some embodiments, R1 is tetrahydrofuranyl and R2 is isopropyl. In some embodiments, R1 is tetrahydrofuranyl and R2 is ethyl. In some embodiments, R1 is cyclopropyl and R2 is isopropyl. In some embodiments, R1 is cyclopropyl and R2 is ethyl. In some embodiments, R1 and R2 together form a methylmorpholino ring. In some embodiments, R1 and R2 together form a (3R,5R)-3,5-dimethylmorpholine ring. In some embodiments, R1 and R2 together form a (3S,5R)-3,5-dimethylmorpholine ring. In some embodiments, R1 and R2 together form a (3R,5S)-3,5-dimethylmorpholine ring. In some embodiments, R1 and R2 together form a (3S,5S)-3,5-dimethylmorpholine ring.

[0080] In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is propyl. In some embodiments, R2 is isopropyl. In some embodiments, R2 is butyl. In some embodiments, R2 is tert-butyl. In some embodiments, R2 is methyl substituted with cyclopropane. In some embodiments, R2 is methyl substituted with cyclobutene. In some embodiments, R2 is CH2-O-OH3. In some embodiments, R2 is ethyl substituted with methoxy. In some embodiments, R2 is ethyl substituted with one or more halo. In some embodiments, R2 is ethyl substituted with one halo, two halo, or three halo. In some embodiments, R2 is -CH2-CHF2. In some embodiments, R2 is ethyl substituted with two halo. In some embodiments, R2 is ethyl substituted with three halo. In some embodiments, R2 is ethyl substituted with one fluorine. In some embodiments, R2 is ethyl substituted with two fluorines. In some embodiments, R2 is ethyl substituted with three fluorines. In some embodiments, R2 is -CH2-CF3. In some embodiments, R2 is propyl substituted with two halo. In some embodiments, R2 is propyl substituted with three halo. In some embodiments, R2 is propyl substituted with one fluorine. In some embodiments, R2 is propyl substituted with two fluorines. In some embodiments, R2 is propyl substituted with three fluorines. In some embodiments, R2 is isopropyl substituted with two halos. In some embodiments, R2 is isopropyl substituted with three halos. In some embodiments, R2 is isopropyl substituted with one fluorine.In some embodiments, R2 is isopropyl substituted by two fluorines. In some embodiments, R2 is isopropyl substituted by three fluorines. In some embodiments, R2 is cyclopropyl. In some embodiments, R2 is cyclobutyl. In some embodiments, R2 is oxetanyl. In some embodiments, R2 is 2-oxetanyl or 3-oxetanyl. In some embodiments, R2 is tetrahydrofuranyl.

[0081] In some embodiments, R1 and R2 are the same. In some embodiments, R1 and R2 are different.

[0082] In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl. In some embodiments, R3 is propyl. In some embodiments, R3 is isopropyl. In some embodiments, R3 is butyl. In some embodiments, R3 is tert-butyl. In some embodiments, R3 is methyl substituted with cyclopropane. In some embodiments, R3 is methyl substituted with cyclobutene. In some embodiments, R3 is CH2-O-OH3. In some embodiments, R3 is ethyl substituted with methoxy. In some embodiments, R3 is ethyl substituted with one or more halo. In some embodiments, R3 is ethyl substituted with one halo, two halo, or three halo. In some embodiments, R3 is -CH2-CHF2. In some embodiments, R3 is ethyl substituted with two halo. In some embodiments, R3 is ethyl substituted with three halo. In some embodiments, R3 is ethyl substituted with one fluorine. In some embodiments, R3 is ethyl substituted with two fluorines. In some embodiments, R3 is ethyl substituted with three fluorines. In some embodiments, R3 is -CH2-CF3. In some embodiments, R3 is cyclopropyl.

[0083] In some embodiments, R3 is dialkylamino. In some embodiments, R3 is dimethylamino. In some embodiments, R3 is NH-C1-C6 alkyl. In some embodiments, R3 is NH-C1-C3 alkyl. In some embodiments, R3 is NH-C1-C2 alkyl. In some embodiments, R3 is NH-methyl. In some embodiments, R3 is NH-ethyl. In some embodiments, R3 is NH-propyl. In some embodiments, R3 is NH-i-propyl. In some embodiments, R3 is NH-butyl. In some embodiments, R3 is NH-i-butyl. In some embodiments, R3 is NH-sec-butyl. In some embodiments, R3 is NH-t-butyl.

[0084] In some embodiments, R3 is a 4-membered heterocyclyl. In some embodiments, R3 is a 4-membered N-heterocycle. In some embodiments, R3 is azetane. In some embodiments, R3 is N-azetane. In some embodiments, R3 is a 5-membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R3 is a 6-membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R3 is morpholinyl. In some embodiments, R3 is N-morpholinyl. In some embodiments, R3 is 2-oxaspiro[3.3]heptanyl.

[0085] In some embodiments, R3 is a 5-membered heteroaryl optionally substituted with C1-C6 alkyl. In some embodiments, R3 is a 6-membered heteroaryl optionally substituted with C1-C6 alkyl. 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.

[0086] In some embodiments, R3 is 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 diazolyl optionally substituted with C1-C6 alkyl. In some embodiments, R3 is pyrazolyl optionally substituted with C1-C6 alkyl. In some embodiments, R3 is diazolyl optionally substituted with one or more methyl. In some embodiments, R3 is diazolyl optionally substituted with one or more C1-C6 alkyl. In some embodiments, R3 is diazolyl optionally substituted with methyl and ethyl. In some embodiments, R3 is diazolyl optionally substituted with heterocyclic N-C1-C6 alkyl. In some embodiments, R3 is diazolyl optionally substituted with heterocyclic N-C1-C2 alkyl.

[0087] In some embodiments, R3 is a 5- to 10-membered heteroaryl. In some embodiments, R3 is a 5- to 7-membered heteroaryl. In some embodiments, R3 is a 5- to 6-membered heteroaryl. In some embodiments, R3 is a 5-membered heteroaryl having two heteroatoms selected from N, O, and S. In some embodiments, R3 is a 6-membered heteroaryl having two heteroatoms selected from N, O, and S. In some embodiments, R3 is a 5-membered heteroaryl having two nitrogen heteroatoms. In some embodiments, R3 is a 6-membered heteroaryl having two nitrogen heteroatoms. In some embodiments, R3 is a 5-membered heteroaryl having one heteroatom selected from N, O, and S. In some embodiments, R3 is a 6-membered heteroaryl having one heteroatom selected from N, O, and S. In some embodiments, R3 is a 3- to 10-membered heterocyclyl.

[0088] 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, R3 is 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-CHF2. In some embodiments, R3 is a diazoyl ring substituted with N-CHF2. In some embodiments, R3 is 1-methyl-1H-pyrazolyl. In some embodiments, R3 is 1-methyl-1H-pyrazolyl attached at the 3-position. In some embodiments, R3 is 1-methyl-1H-pyrazolyl attached at the 4-position. In some embodiments, R3 is 1-methyl-1H-pyrazolyl attached at the 5-position. In some embodiments, R3 is oxa-6-azaspiro[3.3]heptane. In some embodiments, R3 is azaspiro[3.3]heptane. In some embodiments, R3 is azaspiro[3.3]heptane with an oxygen heteroatom in the ring.

[0089] In some embodiments, R3 is cyclobutyl. In some embodiments, R3 is oxetanyl. In some embodiments, R3 is 2-oxetanyl or 3-oxetanyl. In some embodiments, R3 is tetrahydrofuranyl.

[0090] In some embodiments, R3 is aryl, wherein the aryl is optionally substituted.

[0091] In some embodiments, R3 is phenyl.

[0092] In some embodiments, R3 is pyrazolyl.

[0093] In some embodiments, R3 is 1-methyl-1H-pyrazolyl.

[0094] In some embodiments, R3 is thiazolyl.

[0095] In some embodiments, R3 is 2-methylthiazolyl.

[0096] In some embodiments, R3 is morpholinyl.

[0097] In some embodiments, R3 is tetrahydro-2H-pyranyl.

[0098] In some embodiments, R3 is azetidinyl.

[0099] In some embodiments, R3 is 3,3-difluoroazetidiyl.

[0100] In some embodiments, R3 is oxazolyl.

[0101] In some embodiments, R3 is 2-methyloxazolyl.

[0102] In some embodiments, R3 is 3-methyloxazolyl.

[0103] In some embodiments, R3 is 4-methyloxazolyl.

[0104] In some embodiments, R3 is 1-methyl-6-oxo-1,6-dihydropyridinyl.

[0105] In some embodiments, R3 is 4-methyl-6-oxo-1,6-dihydropyridinyl.

[0106] In some embodiments, R3 is 5-chloro-1-methyl-1H-pyrazolyl.

[0107] In some embodiments, R3 is 1-cyclopropyl-1H-pyrazolyl.

[0108] In some embodiments, R3 is 1-(difluoromethyl)-1H-pyrazolyl.

[0109] In some embodiments, R3 is N-isopropyl-N-methyl.

[0110] In some embodiments, R3 is 1,5-dimethyl-1H-pyrazolyl.

[0111] In some embodiments, R3 is 1-ethyl-1H-pyrazolyl.

[0112] In some embodiments, R3 is tetrahydro-2H-pyran-3-yl.

[0113] In some embodiments, R3 is (R)-2-methylpyrrolidinyl.

[0114] In some embodiments, R3 is (S)-2-methoxypyrrolidinyl.

[0115] In some embodiments, R3 is (R)-2-methoxypyrrolidinyl.

[0116] In some embodiments, R3 is (S)-2-methylpyrrolidinyl.

[0117] In some embodiments, R3 is (R)-3-methylpyrrolidinyl.

[0118] In some embodiments, R3 is (S)-3-methylpyrrolidinyl.

[0119] In some embodiments, R3 is (R)-3-methoxypyrrolidinyl.

[0120] In some embodiments, R3 is (S)-3-methoxypyrrolidinyl.

[0121] In some embodiments, R3 is (R)-2-(methoxymethyl)pyrrolidinyl.

[0122] In some embodiments, R3 is (S)-2-(methoxymethyl)pyrrolidinyl.

[0123] In some embodiments, R3 is N-(3-hydroxypropyl)-N-methyl.

[0124] In some embodiments, R3 is 2-methyl-6-oxo-1,6-dihydropyridinyl.

[0125] In some embodiments, R3 is 5-methyl-6-oxo-1,6-dihydropyridinyl.

[0126] In some embodiments, R3 is 2,7-diazaspiro[3.5]nonan-2-yl.

[0127] In some embodiments, R3 is 2-oxa-6-azaspiro[3.3]heptanyl.

[0128] In some embodiments, R3 is 6-oxa-2-azaspiro[3.4]octanyl.

[0129] In some embodiments, R3 is hexahydro-1H-furo[3,4-c]pyrrolyl.

[0130] In some embodiments, R3 is 3-(benzyloxy)azetidinyl.

[0131] In some embodiments, R3 is 3-hydroxyazetidinyl.

[0132] In some embodiments, R3 is N-(2-hydroxyethyl)-N-methyl.

[0133] In some embodiments, R3 is 4-fluoro-1-methyl-1H-pyrazolyl.

[0134] In some embodiments, R3 is a diazoyl ring optionally substituted with cyclopropyl. In some embodiments, R3 is a pyrazolyl ring optionally substituted with cyclopropyl.

[0135] In some embodiments, R3 is thiazolyl. In some embodiments, R3 is optionally substituted thiazolyl. In some embodiments, R3 is thiazolyl optionally substituted with a methyl group. In some embodiments, R3 is thiazolyl optionally substituted with a 2-methyl group. In some embodiments, R3 is phenyl. In some embodiments, R3 is tolyl. In some embodiments, R3 is ortho-tolyl. In some embodiments, R3 is meta-tolyl. In some embodiments, R3 is para-tolyl. In some embodiments, R3 is phenyl optionally substituted with methyl. In some embodiments, R3 is phenyl optionally substituted with halo. In some embodiments, R3 is phenyl optionally substituted with chloro. In some embodiments, R3 is phenyl optionally substituted with 2-chloro. In some embodiments, R3 is phenyl optionally substituted with 3-chloro. In some embodiments, R3 is phenyl optionally substituted with 4-chloro. In some embodiments, R3 is pyridyl. In some embodiments, R3 is ortho-pyridyl. In some embodiments, R3 is meta-pyridyl. In some embodiments, R3 is para-pyridyl. In some embodiments, R3 is anisolyl. In some embodiments, R3 is ortho-anisolyl. In some embodiments, R3 is meta-anisolyl. In some embodiments, R3 is para-anisolyl.

[0136] In some embodiments, R3 is -CDH-CD3. In some embodiments, R3 is -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, R3 is -CD2-CD3.

[0137] In some embodiments, R4 is H, halo, or C1-C6 alkyl. In some embodiments, R4 is H. In some embodiments, R4 is halo. In some embodiments, R4 is fluorine. In some embodiments, R4 is CH3. In some embodiments, R4 is ethyl. In some embodiments, R4 is propyl.

[0138] In some embodiments, R5 is H or C1-C6 alkyl. In some embodiments, R5 is H. In some embodiments, R5 is CH3. In some embodiments, R5 is ethyl. In some embodiments, R5 is propyl.

[0139] In some embodiments, X is absent.

[0140] In some embodiments, Y is absent.

[0141] In some embodiments, X and Y are both absent.

[0142] In some embodiments, X and Y are both absent and R3 is H.

[0143] 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.

[0144] In some embodiments, R 1 is methyl, ethyl, or propyl, and R 2 is methyl, ethyl, or propyl, wherein the methyl, ethyl, or propyl is optionally substituted with 1, 2, or 3 halogens.

[0145] In some embodiments, R is C 1-3 alkyl, and R2 is C 1-3 alkyl, where the alkyl is optionally substituted with two or three fluorines.

[0146] In some embodiments, R1 is C3 alkyl and R2 is ethyl optionally substituted with two or three fluorines.

[0147] In some embodiments, R1 is isopropyl and R2 is ethyl optionally substituted with two or three fluorines.

[0148] In some embodiments, R1 is isopropyl and R2 is ethyl substituted with two or three fluorines.

[0149] In some embodiments, R1 is isopropyl and R2 is ethyl substituted with two fluorines.

[0150] In some embodiments, R1 is isopropyl and R2 is ethyl substituted with three fluorines.

[0151] In some embodiments, R1 is C1-C6 alkyl, or C3-C 12R is H, C-C alkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, where the alkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, C-C alkyl, R is H, and each R is H.

[0152] In some embodiments, R1 is C1-C6 alkyl, or C3-C 12 R is ethyl, propyl, or isopropyl; R and R optionally form a 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with two C-C alkyl or halo; R ​​is C-C alkyl, a 5-membered heteroaryl, a 5-membered heterocyclyl, where 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.

[0153] In some embodiments, R1 is C1-C6 alkyl, or C3-C 12R is ethyl, propyl, or isopropyl; R and R optionally form a 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with two C-C alkyl or halo; R ​​is C-C alkyl, 5-membered heteroaryl, where the alkyl, heteroaryl is optionally substituted with one or more halo or C-C alkyl; R is H; and each R is H.

[0154] In some embodiments, R1 is C1-C6 alkyl, or C3-C 12 R is ethyl, propyl, or isopropyl; R and R optionally form a 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with two methyl groups or halo; R ​​is C-C alkyl, a 5-membered heteroaryl, or a 5-membered heterocyclyl, where 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.

[0155] In some embodiments, R1 is C1-C4 alkyl or C3-C4 cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with one or more halo, OH, C1-C6 haloalkyl, or C1-C6 alkoxy; R2 is ethyl, propyl, or isopropyl; R1 and R2 optionally form a 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with two methyl groups or halo; R3 is C1-C6 alkyl, a 5-membered heteroaryl, or a 5-membered heterocyclyl, where 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.

[0156] In some embodiments, Y is NH or a bond, and R is C-C alkyl, or C-C 12 R is H, C-C alkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, where the alkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, C-C alkyl, R is H, and each R is H.

[0157] In some embodiments, Y is NH and R is C-C alkyl, or C-C 12R is ethyl, propyl, or isopropyl; R and R optionally form a 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with two C-C alkyl or halo; R ​​is C-C alkyl, a 5-membered heteroaryl, a 5-membered heterocyclyl, where 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.

[0158] In some embodiments, Y is NH and R is C-C alkyl, or C-C 12 R is ethyl, propyl, or isopropyl; R and R optionally form a 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with two C-C alkyl or halo; R ​​is C-C alkyl, 5-membered heteroaryl, where the alkyl, heteroaryl is optionally substituted with one or more halo or C-C alkyl; R is H; and each R is H.

[0159] In some embodiments, Y is NH and R is C-C alkyl, or C-C 12R is ethyl, propyl, or isopropyl; R and R optionally form a 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with two methyl groups or halo; R ​​is C-C alkyl, a 5-membered heteroaryl, or a 5-membered heterocyclyl, where 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.

[0160] In some embodiments, Y is NH, R1 is C1-C4 alkyl or C3-C4 cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with one or more halo, OH, C1-C6 haloalkyl, or C1-C6 alkoxy, R2 is ethyl, propyl, or isopropyl, R1 and R2 optionally form a 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with two methyl groups or halo, R3 is C1-C6 alkyl, a 5-membered heteroaryl, or a 5-membered heterocyclyl, where 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.

[0161] In some embodiments, X is C=O or S(=O), Y is NH or a bond, and R is C-C alkyl or C-C 12R is H, C-C alkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, where the alkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, C-C alkyl, R is H, and each R is H.

[0162] In some embodiments, X is S(=O)2, Y is NH, and R1 is C1-C6 alkyl, or C3-C 12 R is ethyl, propyl, or isopropyl; R and R optionally form a 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with two C-C alkyl or halo; R ​​is C-C alkyl, a 5-membered heteroaryl, a 5-membered heterocyclyl, where 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.

[0163] In some embodiments, X is S(=O)2, Y is NH, and R1 is C1-C6 alkyl, or C3-C 12R is ethyl, propyl, or isopropyl; R and R optionally form a 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with two C-C alkyl or halo; R ​​is C-C alkyl, 5-membered heteroaryl, where the alkyl, heteroaryl is optionally substituted with one or more halo or C-C alkyl; R is H; and each R is H.

[0164] In some embodiments, X is S(=O)2, Y is NH, and R1 is C1-C6 alkyl, or C3-C 12 R is ethyl, propyl, or isopropyl; R and R optionally form a 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with two methyl groups or halo; R ​​is C-C alkyl, a 5-membered heteroaryl, or a 5-membered heterocyclyl, where 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.

[0165] In some embodiments, X is S(=O)2, Y is NH, R1 is C1-C4 alkyl or C3-C4 cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with one or more halo, OH, C1-C6 haloalkyl, or C1-C6 alkoxy, R2 is ethyl, propyl, or isopropyl, R1 and R2 optionally form a 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with two methyl groups or halo, R3 is C1-C6 alkyl, a 5-membered heteroaryl, or a 5-membered heterocyclyl, where 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.

[0166] In some embodiments, W is CH, X is C=O or S(=O), Y is NH or a bond, and R is C-C alkyl or C-C 12 R is H, C-C alkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, where the alkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, C-C alkyl, R is H, and each R is H.

[0167] In some embodiments, W is CH, X is S(=O), Y is NH, and R is C-C alkyl, or C-C 12R is ethyl, propyl, or isopropyl; R and R optionally form a 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with two C-C alkyl or halo; R ​​is C-C alkyl, a 5-membered heteroaryl, a 5-membered heterocyclyl, where 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.

[0168] In some embodiments, W is CH, X is S(=O), Y is NH, and R is C-C alkyl, or C-C 12 R is ethyl, propyl, or isopropyl; R and R optionally form a 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with two C-C alkyl or halo; R ​​is C-C alkyl, 5-membered heteroaryl, where the alkyl, heteroaryl is optionally substituted with one or more halo or C-C alkyl; R is H; and each R is H.

[0169] In some embodiments, W is CH, X is S(=O), Y is NH, and R is C-C alkyl, or C-C 12R is ethyl, propyl, or isopropyl; R and R optionally form a 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with two methyl groups or halo; R ​​is C-C alkyl, a 5-membered heteroaryl, or a 5-membered heterocyclyl, where 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.

[0170] In some embodiments, W is CH, X is S(=O), Y is NH, R is C-C alkyl or C-C cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with one or more halo, OH, C-C haloalkyl, or C-C alkoxy, R is ethyl, propyl, or isopropyl, R and R optionally form a 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with two methyl groups or halo, R is C-C alkyl, a 5-membered heteroaryl, or a 5-membered heterocyclyl, where 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.

[0171] In some embodiments, the disclosed compound is represented by Formula III or IIIa, wherein R1 is C1-C6 alkyl, where the alkyl is optionally substituted with one halo, two halo, or three halo; R2 is isopropyl; and R6 is C1-C3 alkyl optionally substituted with one or more deuterium atoms, or C5-C6 heteroaryl optionally substituted with one or more methyl atoms, where the methyl atoms are optionally substituted with one or more fluorine atoms.

[0172] In some embodiments, each R N is independently H or C1-C6 alkyl.

[0173] In some embodiments, each R N is independently H or C1-C6 alkyl.

[0174] In some embodiments, each R N is independently H or C1-C3 alkyl.

[0175] In some embodiments, each R N is independently H or C1-C2 alkyl.

[0176] In some embodiments, each R N is independently H or C alkyl.

[0177] In some embodiments, each R N is independently H or C2 alkyl.

[0178] In some embodiments, each R N is independently H or C alkyl.

[0179] In some embodiments, each R N is H.

[0180] In some embodiments, each R N is C1-C6 alkyl.

[0181] In some embodiments, each R N is C1-C3 alkyl.

[0182] In some embodiments, each R N is C1-C2 alkyl.

[0183] In some embodiments, each R N is a C1 alkyl.

[0184] In some embodiments, each R N is a C2 alkyl.

[0185] In some embodiments, each R N is a C3 alkyl.

[0186] In some embodiments, R1 is C1-C6 alkyl substituted with one halo, two halo, or three halo, R2 is isopropyl, and R6 is CD2-CD3.

[0187] In some embodiments, R1 is C1-C3 alkyl substituted with one halo, two halo, or three halo, R2 is isopropyl, and R6 is CD2-CD3.

[0188] In some embodiments, R1 is C1-C2 alkyl substituted with one halo, two halo, or three halo, R2 is isopropyl, and R6 is CD2-CD3.

[0189] In some embodiments, R1 is C1 alkyl substituted with one halo, two halo, or three halo, R2 is isopropyl, and R6 is CD2-CD3.

[0190] In some embodiments, R1 is C2 alkyl substituted with one halo, two halo, or three halo, R2 is isopropyl, and R6 is CD2-CD3.

[0191] In some embodiments, R1 is C1-C6 alkyl substituted with two or three halo, R2 is isopropyl, and R6 is CD2-CD3.

[0192] In some embodiments, R1 is C1-C3 alkyl substituted with two or three halo, R2 is isopropyl, and R6 is CD2-CD3.

[0193] In some embodiments, R1 is C1-C2 alkyl substituted with two halo or three halo, R2 is isopropyl, and R6 is CD2-CD3.

[0194] In some embodiments, R1 is C1 alkyl substituted with two or three halo, R2 is isopropyl, and R6 is CD2-CD3.

[0195] In some embodiments, R1 is C2 alkyl substituted with two or three halo, R2 is isopropyl, and R6 is CD2-CD3.

[0196] In some embodiments, R1 is C1-C6 alkyl substituted with three halo, R2 is isopropyl, and R6 is CD2-CD3.

[0197] In some embodiments, R1 is C1-C3 alkyl substituted with three halo, R2 is isopropyl, and R6 is CD2-CD3.

[0198] In some embodiments, R1 is C1-C2 alkyl substituted with three halo, R2 is isopropyl, and R6 is CD2-CD3.

[0199] In some embodiments, R1 is C1 alkyl substituted with three halo, R2 is isopropyl, and R6 is CD2-CD3.

[0200] In some embodiments, R1 is C2 alkyl substituted with three halo, R2 is isopropyl, and R6 is CD2-CD3.

[0201] In some embodiments, R1 is C1-C6 alkyl substituted with two halo, R2 is isopropyl, and R6 is CD2-CD3.

[0202] In some embodiments, R1 is C1-C3 alkyl substituted with two halo, R2 is isopropyl, and R6 is CD2-CD3.

[0203] In some embodiments, R1 is C1-C2 alkyl substituted with two halo, R2 is isopropyl, and R6 is CD2-CD3.

[0204] In some embodiments, R1 is C1 alkyl substituted with two halo, R2 is isopropyl, and R6 is CD2-CD3.

[0205] In some embodiments, R1 is C2 alkyl substituted with two halo, R2 is isopropyl, and R6 is CD2-CD3.

[0206] In some embodiments, R1 is C1-C6 alkyl substituted with 1 halo, 2 halo, or 3 halo, R2 is isopropyl, and R6 is ethyl.

[0207] In some embodiments, R1 is C1-C3 alkyl substituted with one halo, two halo, or three halo, R2 is isopropyl, and R6 is ethyl.

[0208] In some embodiments, R1 is C1-C2 alkyl substituted with one halo, two halo, or three halo, R2 is isopropyl, and R6 is ethyl.

[0209] In some embodiments, R1 is C1 alkyl substituted with one halo, two halo, or three halo, R2 is isopropyl, and R6 is ethyl.

[0210] In some embodiments, R1 is C2 alkyl substituted with 1 halo, 2 halo, or 3 halo, R2 is isopropyl, and R6 is ethyl.

[0211] In some embodiments, R1 is C1-C6 alkyl substituted with two or three halo, R2 is isopropyl, and R6 is ethyl.

[0212] In some embodiments, R1 is C1-C3 alkyl substituted with two or three halo, R2 is isopropyl, and R6 is ethyl.

[0213] In some embodiments, R1 is C1-C2 alkyl substituted with two halo or three halo, R2 is isopropyl, and R6 is ethyl.

[0214] In some embodiments, R1 is C1 alkyl substituted with two or three halo, R2 is isopropyl, and R6 is ethyl.

[0215] In some embodiments, R1 is C2 alkyl substituted with two or three halo, R2 is isopropyl, and R6 is ethyl.

[0216] In some embodiments, R1 is C1-C6 alkyl substituted with three halo, R2 is isopropyl, and R6 is ethyl.

[0217] In some embodiments, R1 is C1-C3 alkyl substituted with three halo, R2 is isopropyl, and R6 is ethyl.

[0218] In some embodiments, R1 is C1-C2 alkyl substituted with three halo, R2 is isopropyl, and R6 is ethyl.

[0219] In some embodiments, R1 is C1 alkyl substituted with three halo, R2 is isopropyl, and R6 is ethyl.

[0220] In some embodiments, R1 is C2 alkyl substituted with three halo, R2 is isopropyl, and R6 is ethyl.

[0221] In some embodiments, R1 is C1-C6 alkyl substituted with two halo, R2 is isopropyl, and R6 is ethyl.

[0222] In some embodiments, R1 is C1-C3 alkyl substituted with two halo, R2 is isopropyl, and R6 is ethyl.

[0223] In some embodiments, R1 is C1-C2 alkyl substituted with two halo, R2 is isopropyl, and R6 is ethyl.

[0224] In some embodiments, R1 is C1 alkyl substituted with two halo, R2 is isopropyl, and R6 is ethyl.

[0225] In some embodiments, R1 is C2 alkyl substituted with two halo, R2 is isopropyl, and R6 is ethyl.

[0226] In some embodiments, R is N(R N )2, C1-C6 alkyl substituted with

[0227] In some embodiments, R1 is C1-C3 alkyl N(RN )2.

[0228] In some embodiments, R is C-C alkyl N(R N )2.

[0229] In some embodiments, R is C alkyl N(R N )2.

[0230] In some embodiments, R is C alkyl N(R N )2.

[0231] In some embodiments, R is C-C alkyl N(R N )2 and R2 is isopropyl.

[0232] In some embodiments, R1 is C1-C3 alkyl N(R N )2 and R2 is isopropyl.

[0233] In some embodiments, R is C-C alkyl N(R N )2 and R2 is isopropyl.

[0234] In some embodiments, R is C alkyl N(R N )2 and R2 is isopropyl.

[0235] In some embodiments, R is C alkyl N(R N )2 and R2 is isopropyl.

[0236] In some embodiments, R is C-C alkyl N(R N )2 and R6 is ethyl.

[0237] In some embodiments, R1 is C1-C3 alkyl N(R N )2 and R6 is ethyl.

[0238] In some embodiments, R is N(R N )2 substituted C1-C2 alkyl, and R6 is ethyl.

[0239] In some embodiments, R is N(R N )2-substituted C1 alkyl, and R6 is ethyl.

[0240] In some embodiments, R is N(R N )2-substituted C2 alkyl, and R6 is ethyl.

[0241] In some embodiments, R is C-C alkyl N(R N )2 and R2 is CD2-CD3.

[0242] In some embodiments, R1 is C1-C3 alkyl N(R N )2 and R2 is CD2-CD3.

[0243] In some embodiments, R is C-C alkyl N(R N )2 and R2 is CD2-CD3.

[0244] In some embodiments, R is C alkyl N(R N )2 and R2 is CD2-CD3.

[0245] In some embodiments, R is C alkyl N(R N )2 and R2 is CD2-CD3.

[0246] In some embodiments, R3 is N(R N )2, C1-C6 alkyl substituted with

[0247] In some embodiments, R3 is C1-C3 alkyl N(R N )2.

[0248] In some embodiments, R3 is C1-C2 alkyl N(R N )2.

[0249] In some embodiments, R3 is C1 alkyl N(R N )2.

[0250] In some embodiments, R3 is C2 alkyl N(R N )2.

[0251] In some embodiments, R3 is C1-C6 alkyl N(R N )2 and R2 is isopropyl.

[0252] In some embodiments, R3 is C1-C3 alkyl N(R N )2 and R2 is isopropyl.

[0253] In some embodiments, R3 is C1-C2 alkyl N(R N )2 and R2 is isopropyl.

[0254] In some embodiments, R3 is C1 alkyl N(R N )2 and R2 is isopropyl.

[0255] In some embodiments, R3 is C2 alkyl N(R N )2 and R2 is isopropyl.

[0256] In some embodiments, R3 is C1-C6 alkyl N(R N )2 and R6 is ethyl.

[0257] In some embodiments, R3 is C1-C3 alkyl N(R N )2 and R6 is ethyl.

[0258] In some embodiments, R3 is N(R N )2 substituted C1-C2 alkyl, and R6 is ethyl.

[0259] In some embodiments, R3 is N(R N )2-substituted C1 alkyl, and R6 is ethyl.

[0260] In some embodiments, R3 is N(R N )2-substituted C2 alkyl, and R6 is ethyl.

[0261] In some embodiments, R3 is C1-C6 alkyl N(R N )2 and R2 is CD2-CD3.

[0262] In some embodiments, R3 is C1-C3 alkyl N(R N )2 and R2 is CD2-CD3.

[0263] In some embodiments, R3 is C1-C2 alkyl N(R N )2 and R2 is CD2-CD3.

[0264] In some embodiments, R3 is C1 alkyl N(R N )2 and R2 is CD2-CD3.

[0265] In some embodiments, R3 is C2 alkyl, N(R N )2 and R2 is CD2-CD3.

[0266] In some embodiments, R is N(R N )2, wherein R2 is isopropyl and R6 is CD2-CD3.

[0267] In some embodiments, R1 is C1-C3 alkyl N(RN )2, R2 is isopropyl, and R6 is CD2-CD3.

[0268] In some embodiments, R is C-C alkyl N(R N )2, R2 is isopropyl, and R6 is CD2-CD3.

[0269] In some embodiments, R is C alkyl N(R N )2, R2 is isopropyl, and R6 is CD2-CD3.

[0270] In some embodiments, R is C alkyl N(R N )2, R2 is isopropyl, and R6 is CD2-CD3.

[0271] In some embodiments, R is C-C alkyl N(R N )2, R2 is isopropyl, and R6 is ethyl.

[0272] In some embodiments, R1 is C1-C3 alkyl N(R N )2, R2 is isopropyl, and R6 is ethyl.

[0273] In some embodiments, R is C-C alkyl N(R N )2, R2 is isopropyl, and R6 is ethyl.

[0274] In some embodiments, R is C alkyl N(R N )2, R2 is isopropyl, and R6 is ethyl.

[0275] In some embodiments, R is C alkyl N(R N )2, R2 is isopropyl, and R6 is ethyl.

[0276] In some embodiments, R is C-C alkyl N(R N )2, R2 is isopropyl, and R6 is ethyl.

[0277] In some embodiments, R1 is C1-C3 alkyl N(R N )2, R2 is isopropyl, and R6 is ethyl.

[0278] In some embodiments, R is N(R N )2, wherein R2 is isopropyl and R6 is ethyl.

[0279] In some embodiments, R is N(R N )2, C1 alkyl substituted with R2, R2 is isopropyl, and R6 is ethyl.

[0280] In some embodiments, R is N(R N )2-substituted C2 alkyl, R2 is isopropyl, and R6 is ethyl.

[0281] In some embodiments, the compound of Formula 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.

[0282] In some embodiments, the compound is represented by Formula 0, 0a, I, Ia, II, IIa, III, or IIIa in combination with any of the embodiments described herein.

[0283] Any of the groups described above for any variable can be combined, where applicable, with any of the other groups described above for any of the formulas described herein.

[0284] Representative compounds of the present disclosure are shown in the table below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16]

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

[0285] In some embodiments, a compound according to any embodiment herein (e.g., of Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) exhibits inhibitory activity against the binding of menin to MLL. In some embodiments, a compound according to any embodiment herein (e.g., of Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) exhibits inhibitory activity against the binding of menin to MLL. In some embodiments, a compound according to any embodiment herein (e.g., of Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) exhibits inhibitory activity against the binding of menin to MLL, which is useful for the treatment and / or prevention of one or more diseases involving menin and MLL. In some embodiments, a compound according to any embodiment herein (e.g., of Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) exhibits low hERG binding. In some embodiments, compounds according to any embodiment herein (e.g., Formulas 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) are useful for treating one or more diseases involving menin and MLL and minimize hERG binding. Without being bound by any theory, it is believed that one of the primary causes of QT prolongation is blockade of the hERG potassium channel in cardiomyocytes. In some embodiments, compounds of the present disclosure (e.g., Formulas 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) do not significantly block the hERG potassium channel.

[0286] In some embodiments, compounds of the present disclosure (e.g., compounds of Formulas 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) do not significantly block the hERG potassium channel (e.g., IC greater 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. 50 ).

[0287] In some embodiments, compounds of the present disclosure (e.g., compounds of Formulas 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) do not significantly block the hERG potassium channel (e.g., IC greater than 1 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 35 μM, 40 μM, or 50 μM). 50 ).

[0288] In some embodiments, without wishing to be bound by any theory, the present disclosure relates to menin-MLL interaction inhibitors comprising a pyran substitution (e.g., Formulas 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1), where the pyran substitution has been found to reduce hERG inhibition.

[0289] In some embodiments, without wishing to be bound by any theory, the present disclosure relates to menin-MLL interaction inhibitors (e.g., compounds of formulas 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) that are metabolically resistant. In some embodiments, without wishing to be bound by any theory, the present disclosure relates to menin-MLL interaction inhibitors (e.g., compounds of formulas 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) that are metabolically resistant, wherein a metabolite is an inhibitor of the hERG potassium channel. In some embodiments, without wishing to be bound by any theory, the present disclosure relates to menin-MLL interaction inhibitors (e.g., compounds of formulas 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) that are metabolically resistant, wherein metabolism reduces the bioavailability of the inhibitor. In some embodiments, without wishing to be bound by any theory, the present disclosure relates to menin-MLL interaction inhibitors (e.g., compounds of Formulas 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) that are resistant to metabolism, where metabolism reduces the bioavailability of the inhibitor and the corresponding metabolites are more effective (e.g., IC50, etc.) at binding to the hERG potassium channel.

[0290] Another embodiment is an isotopically labeled compound of any of the formulas described herein. Such compounds contain one or more isotopic atoms (e.g., methyl ... 3 H, 2 H, 14 C. 13 C. 18 F, 35 S, 32 P, 125 I, and 131 I). Such compounds are useful in drug metabolism studies and diagnostic and therapeutic applications. In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table I, or a pharmaceutically acceptable salt thereof.

[0291] A deuterium-labeled compound is understood to contain deuterium atoms having a deuterium abundance substantially greater than the natural abundance of deuterium, which is 0.015%.

[0292] 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" refers to the ratio of the abundance of deuterium to the natural abundance of deuterium.

[0293] It will be appreciated that deuterium-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein, substituting a deuterium-labeled reagent for a non-deuterium-labeled reagent.

[0294] Compounds of the present disclosure, or pharmaceutically acceptable salts or solvates thereof, containing the aforementioned deuterium atom(s) are within the scope of the present disclosure. Furthermore, substitution with deuterium (i.e., 2H) may confer certain therapeutic advantages resulting from increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0295] For the avoidance of doubt, when a group is modified herein by "as described herein," it is to be understood that the group includes each and every specific definition of that group as well as the broadest definition appearing first.

[0296] Efficacy is IC 50 It can also be determined by the value of IC 50 Compounds with lower IC values ​​have lower IC values ​​when determined under substantially similar conditions. 50 It has higher potency compared to compounds with higher values.

[0297] The compounds of the present application are defined herein by their chemical structure and / or chemical name. Where a compound is referred to by both its chemical structure and chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0298] In another aspect, the present application provides methods for synthesizing the compounds disclosed herein. Synthesis of the compounds of the present application can be found herein and in the Examples below. Another embodiment is a method for producing a compound of any of the formulas herein using any one or combination of reactions described herein. The method may include the use of one or more intermediates or chemical reagents described herein.

[0299] It should also be appreciated that certain features of the present 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 present disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0300] At various places in the present specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges. The present disclosure is specifically intended to include all individual subcombinations of the members of such groups and ranges. For example, "C 1-6 The term "alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0301] Various cycloalkyl and heterocyclyl rings are described in various places herein. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member, valence permitting. For example, the term "pyridine ring" or "pyridinyl" can refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[0302] For compounds of the present disclosure in which a variable occurs more than once, each variable may be a different moiety independently selected from the group defining the variable. For example, if a structure is depicted having two R groups co-occurring on the same compound, the two R groups may represent different moieties independently selected from the group defined for R.

[0303] As used herein, "alkyl," "C1, C2, C3, C4, C5, or C6 alkyl," or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, or C6 branched-chain saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl include moieties having 1 to 6 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-chain alkyl has 6 or fewer carbon atoms (e.g., C1-C6 for straight-chain, C3-C6 for branched-chain), and in other embodiments, a straight-chain or branched-chain alkyl has 4 or fewer carbon atoms.

[0304] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl or to an alkyl having specified substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, 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, thiocarboxylic acid, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0305] 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. Alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, 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, thiocarboxylic acid, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0306] As used herein, the term "amino," used alone or in combination with other terms, refers to a group of formula -NH. In some embodiments, an amine can be substituted with one or more groups, such as -N-(C-C alkyl). In some embodiments, when two groups are attached to an amine, they can be the same or different. Each group is selected independently of the other and can each be independently optionally substituted.

[0307] As used herein, "C" when used alone or in combination with other terms i-j "Haloalkoxy" refers to a group of the formula -O-haloalkyl having i to j carbon atoms. An example of a haloalkoxy group is OCF3. An additional example of a haloalkoxy group is OCHF2. In some embodiments, the haloalkoxy group is only fluorinated. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments, the haloalkoxy group is C 1-4 It is haloalkoxy.

[0308] As used herein, the terms "halogen" or "halo," employed alone or in combination with other terms, refer 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.

[0309] 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 only fluorinated. 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.

[0310] As used herein, the term "alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but containing 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 2 to 6 carbon atoms. The term "C3-C6" includes alkenyl groups containing 3 to 6 carbon atoms.

[0311] As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, 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, thiocarboxylic acid, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0312] As used herein, the term "alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but containing 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-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkynyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkynyl groups containing 3 to 6 carbon atoms. As used herein, a "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to include a C2, C3, C4, C5, or C6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon group. For example, a C2-C6 alkenylene linker is intended to include C2, C3, C4, C5, and C6 alkenylene linker groups.

[0313] As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, 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, thiocarboxylic acid, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0314] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both unsubstituted moieties and moieties with one or more of the specified substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups such as 2,2,6,6-tetramethyl-piperidinyl and c.

[0315] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro) 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 cycloalkyls, only one of the rings of the cycloalkyl need be non-aromatic. In some embodiments, cycloalkyls may optionally contain one or more alkenylene groups as part of the ring structure. Cycloalkyl groups can include monocyclic or polycyclic ring systems. Polycyclic ring systems can include fused ring systems and spiro rings. Also included within the definition of cycloalkyl are moieties having one or more aromatic rings fused (i.e., sharing a bond) to the cycloalkyl ring, such as benzo or pyrido derivatives of cyclopentane, cyclopentene, cyclohexane, etc. Heterocyclyl groups containing fused aromatic (e.g., aryl or heteroaryl) moieties can be attached to the molecule through an atom in either the aromatic or non-aromatic portion. One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized to form a carbonyl linkage. In some embodiments, cycloalkyl is a C 3-10 Cycloalkyl, C 3-7 Cycloalkyl, or C 5-6Cycloalkyl. 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. Examples of additional cycloalkyl groups in which 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.

[0316] 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, including, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl is C 6-10 In some embodiments, aryl is C 6-14 In some embodiments, the aryl group is a naphthalene ring or a phenyl ring. In some embodiments, the aryl group is phenyl.

[0317] 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 heterocyclic moiety having one or more heteroatom ring members selected from nitrogen, sulfur, and oxygen. In some embodiments, a heteroaryl group has 1, 2, 3, or 4 heteroatom ring members. In some embodiments, a heteroaryl group has 1, 2, or 3 heteroatom ring members. In some embodiments, a heteroaryl group has 1 or 2 heteroatom ring members. In some embodiments, a heteroaryl group has 1 heteroatom ring member. In some embodiments, a heteroaryl group has 5 to 10 or 5 to 6 members. In some embodiments, a heteroaryl group has 5 members. In some embodiments, a heteroaryl group has 6 members. In some embodiments, a heteroaryl group is a 9- or 10-membered bicyclic ring. In some embodiments, a heteroaryl is a 9-membered bicyclic ring. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group may be oxidized to form an N-oxide. Examples of 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, benzothiophenyl, benzofuranyl, benzisoxazolyl, benzimidazolyl, 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.

[0318] Furthermore, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, deazapurine, indolizine.

[0319] A cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring may have at one or more ring positions (e.g., a ring carbon or a heteroatom such as N) a substituent as described above, e.g., alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, 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, thiocarboxylic acid, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Aryl and heteroaryl groups may also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic so as to form polycyclic systems (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxol-5-yl).

[0320] 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 specified atom are replaced with one selected from the specified group, provided that the normal valence of the specified atom is not exceeded and the substitution results in a stable compound. When the substituent is oxo or keto (i.e., =0), two hydrogen atoms on the atom are replaced. Keto substituents do not occur on aromatic moieties. A ring double bond, as used herein, is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). A "stable compound" and a "stable structure" are meant to refer to a compound that is sufficiently robust to be isolated to a useful degree of purity from a reaction mixture and formulated into an effective therapeutic agent.

[0321] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom to which it is bonded to the remainder of the compound of a given formula, such substituent may be bonded through any atom in such formula. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0322] 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 to 2 R moieties, that group may be optionally substituted with up to 2 R moieties, and R at each occurrence is independently selected from the definitions of R. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0323] As used herein, the term "heterocyclyl," employed alone or in combination with other terms, refers to a non-aromatic heterocyclic ring system that may optionally contain one or more unsaturations as part of the ring structure and has at least one heteroatom ring member independently selected from nitrogen, sulfur, and oxygen. In some embodiments, a heterocyclyl group has 1, 2, 3, or 4 heteroatom ring members. In some embodiments, a heterocyclyl group has 1, 2, or 3 heteroatom ring members. In some embodiments, a heterocyclyl group has 1 or 2 heteroatom ring members. In some embodiments, a heterocyclyl group has 1 heteroatom ring member. When a heterocyclyl group contains more than one heteroatom in the ring, the heteroatoms may be the same or different. Examples of ring members include CH, CH, C(O), N, NH, O, S, S(O), and S(=O). Heterocyclyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) ring systems. Polycyclic rings can include both fused and spirocyclic rings. Also included within the definition of heterocyclyl are moieties having one or more aromatic rings fused (i.e., sharing a bond) to a non-aromatic ring, such as 1,2,3,4-tetrahydroquinoline, dihydrobenzofuran, and the like. Heterocyclyl groups containing fused aromatic moieties can be attached to the molecule through an atom in either the aromatic or non-aromatic portion. Carbon atoms or heteroatoms in the ring(s) of a heterocyclyl group can be oxidized to form carbonyl, sulfinyl, or sulfonyl groups (or other oxidized linkages), or nitrogen atoms can be quaternized. In some embodiments, a heterocyclyl is 5-10, 4-10, 4-7, 5, or 6 members. 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 containing 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-dihydro-1H-benzo[d]imidazol-5-yl; 1,3-dihydrospiro[indene-2,3'-indolin]-6'-yl; 2,3-dihydro-1H-benzo[d]imidazol-5-yl; 1,3-dihydro-2 ... spiro[cyclopentane-1,3'-indoline]-6'-yl; spiro[cyclohexane-1,3'-indoline]-6'-yl; chroman-6-yl; 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl; and benzo[d][1,3]dioxol-5-yl.

[0324] As used herein, the term "isomer" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or 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."

[0325] As used herein, the term "chiral center" refers to a carbon atom bonded to four nonidentical substituents.

[0326] As used herein, the term "chiral isomer" means a compound with at least one chiral center. Compounds with two or more chiral centers can exist as either individual diastereomers or mixtures of diastereomers, termed "diastereomeric mixtures." When one chiral center is present, a stereoisomer can 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 according to 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).

[0327] As used herein, the term "geometric isomer" refers to diastereomers that exist because rotation is hindered at a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These structures are distinguished by the designation cis and trans, or Z and E, prefixes, which indicate that the groups are on the same or opposite sides of a double bond in the molecule, according to the Cahn-Ingold-Prelog rules.

[0328] It is understood that the compounds of the present disclosure may be depicted as different chiral or geometric isomers, and when a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present disclosure, and it is understood that the name of the compound does not exclude any isomeric form, and it is understood that not all isomers have the same level of activity.

[0329] It is understood that the structures and other compounds discussed in this disclosure include all atropisomers thereof. It is also understood that not all atropisomers have the same activity level.

[0330] As used herein, the term "atropisomer" refers to a type of stereoisomer in which the atoms of two isomers are arranged differently in space. The existence of atropisomers results from restricted rotation, which occurs when large groups are prevented from rotating around a central bond. Such atropisomers typically exist as mixtures, although recent advances in chromatography techniques have made it possible to separate mixtures of two atropisomers in some cases.

[0331] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This conversion involves the formal migration of a hydrogen atom accompanied by the interchange of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric populations in solution. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is achieved. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism. Of the various possible types of tautomerism, two are commonly observed: keto-enol tautomerism, in which both an electron and a hydrogen atom are transferred simultaneously. Ring-chain tautomerism occurs when an aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule to give a cyclic (ring-shaped) form, such as that exhibited by glucose.

[0332] It is understood that the compounds of the present disclosure may be depicted as different tautomeric forms. It is also understood that, where a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present disclosure, and the name of the compound does not exclude any tautomeric form. It will be understood that certain tautomers may have a higher level of activity than other tautomers.

[0333] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the spatial arrangement of their atoms are called "isomers." Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the RS ordering rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light, designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomer, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture." The compounds described herein can be asymmetric (e.g., have one or more stereocenters). Unless otherwise specified, all stereoisomers, such as enantiomers and diastereoisomers, are intended. If the name or structure of a compound does not refer to the stereochemistry of a stereocenter, all possible configurations at the stereocenter are intended. Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or stereoselective synthesis. Geometric isomers of olefins, C═N double bonds, and the like may also exist 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 can be isolated as a mixture of isomers or as separate isomeric forms.

[0334] When a compound of the present disclosure contains a chiral center, the compound may be any of the possible stereoisomers. In a compound with one chiral center, the stereochemistry of the chiral center may be (R) or (S). In a compound with two chiral centers, the stereochemistry of the chiral centers may each independently be (R) or (S), such that the configuration of the chiral centers may be (R) and (R), (R) and (S), (S) and (R), or (S) and (S). In compounds with three chiral centers, the stereochemistry of each of the three chiral centers can be independently (R) or (S), and therefore 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).

[0335] Resolution of a racemic mixture of compounds can be carried out by any of a number of methods known in the art. One example of a method is fractional recrystallization using a chiral resolving acid, which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization include, for example, optically active acids, such as D- and L-forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization include stereoisomerically pure α-methylbenzylamine (e.g., S- and R-forms, or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0336] 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 compositions can be determined by one skilled in the art.

[0337] When compounds of the present disclosure are named or depicted without indicating the stereochemistry of one or more stereocenters, each of the stereoisomers arising from the possible stereochemistry at the undefined stereocenter(s) is intended to be encompassed. For example, if a stereocenter is not designated as R or S, either one or both are intended.

[0338] The compounds of the present disclosure also include tautomeric forms. Tautomeric forms result from the interchange of a single bond with an adjacent double bond and the accompanying migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position in a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution.

[0339] The compounds of the present disclosure may contain isotopes of all atoms present in intermediates or final compounds. Isotopes include atoms with the same atomic number but different mass numbers. Isotopes of constituent atoms of the compounds of the present disclosure can exist in natural or non-natural abundance. Examples of hydrogen isotopes include deuterium and tritium. In some embodiments, the compounds of the present disclosure are deuterated, which means that at least one deuterium atom is present instead of a hydrogen atom. In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms in the compounds of the present disclosure are replaced by deuterium. Methods for replacing hydrogen with deuterium in a molecule are known in the art.

[0340] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structures. Compounds herein identified by the name or structure of one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified (e.g., in the case of a purine ring, unless otherwise specified, if the compound name or structure has a 9H tautomer, it is understood that the 7H tautomer is also encompassed).

[0341] All compounds and pharmaceutically acceptable salts thereof may exist together with other substances such as water and solvents (eg, hydrates and solvates) or may be isolated.

[0342] It will be understood that the compounds of the present disclosure, and any pharmaceutically acceptable salts thereof, include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of the compounds.

[0343] In some embodiments, a compound of the present disclosure, or a salt thereof, or any of the aforementioned crystalline forms, is purified or substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial isolation can include, for example, a composition enriched for a compound of the present disclosure. Substantial isolation can include a composition 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 a compound of the present disclosure, or a salt thereof. In some embodiments, a compound of the present disclosure, or a salt thereof, or any of the aforementioned crystalline forms, 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.

[0344] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, substances, compositions, and / or dosage forms that are suitable, within the scope of sound medical judgment, 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.

[0345] As used herein, the expressions "ambient temperature" and "room temperature" are understood in the art and generally refer to a temperature, e.g., a reaction temperature, which is a temperature that is close to the temperature of the room in which the reaction is carried out, e.g., a temperature of about 20°C to about 30°C.

[0346] The present disclosure also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present disclosure, in which the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic 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 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 containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN) are preferred.

[0347] The compounds disclosed herein include not only the compounds themselves, but also their salts, solvates, and prodrugs, if applicable. Salts can be formed, for example, between an anion and a positively charged group (e.g., protonated amino) on a compound of the present disclosure. Suitable anions include chloride, bromide, iodide, sulfate, hydrogen sulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetic acid, glutamate, glucuronic acid, glutaric acid, malate, maleate, succinate, fumarate, tartaric acid, tosylate, salicylate, lactic acid, naphthalenesulfonate, and acetate (e.g., trifluoroacetic acid). The term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation and a negatively charged group (e.g., carboxylic acid) on a compound of the present disclosure. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium. Compounds of the present disclosure also include salts containing a quaternary nitrogen atom. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing active compounds of the present disclosure.

[0348] Furthermore, physiologically acceptable, i.e., pharmaceutically compatible, salts can be salts of the compounds disclosed herein with inorganic or organic acids. Preferred are salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, or sulfuric acid, or salts with organic carboxylic or sulfonic acids, such as acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, or naphthalenedisulfonic acid.

[0349] Other pharmaceutically compatible salts which may be mentioned are the salts with common bases, for example alkali metal salts (for example sodium salts or potassium salts), alkaline earth metal salts (for example calcium salts or magnesium salts) or ammonium salts derived from ammonia or organic amines, for example diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine or methylpiperidine.

[0350] As used herein, "pharmaceutically acceptable salts" may refer to derivatives of the compounds of the present disclosure, in which the parent compound is modified by making its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include conventional non-toxic salts or 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 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolarsanilic acid, hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauric ... Examples of suitable salts include, but are not limited to, salts derived from inorganic and organic acids selected from: arylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly occurring amino acids such as glycine, alanine, phenylalanine, arginine, and the like.

[0351] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic 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 is replaced by a metal ion, for example, an alkali metal ion, or alkaline earth metal ion, such as 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.

[0352] It should be understood that all references to pharmaceutically acceptable salts include the solvent addition forms (solvates) or crystal forms (polymorphs) of the same salt, as defined herein.

[0353] Unless otherwise specified, all references to a method of treatment or prevention will be understood to include the use of a compound to provide treatment or prevention as described herein. Unless otherwise specified, all references to a method of treatment or prevention will be further understood to include the use of a compound for the preparation of a medicament for treating or preventing such a condition. Treatment or prevention includes treatment or prevention in humans or non-human animals, including rodents and other disease models.

[0354] Unless otherwise specified, all references to methods of treatment should be understood to include the use of the compounds to provide treatment as described herein. Unless otherwise specified, all references to methods of treatment should be understood to include the use of the compounds to prepare a medicament for treating such conditions. Treatment includes the treatment of humans or non-human animals, including rodents and other disease models.

[0355] 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, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The subject can also be a bird or poultry. In some embodiments, the subject is a human.

[0356] As used herein, the term "subject in need of treatment" refers to a subject who has a disease or is at high risk of developing a disease. A subject in need of treatment may be a subject who has already been diagnosed or identified as having a disease or disorder disclosed herein. A subject in need of treatment may be a subject who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need of treatment may be a subject who is at increased risk of developing such a disease or disorder compared to the population as a whole (i.e., a subject who is predisposed to developing such a disorder compared to the population as a whole). A subject in need of treatment may be refractory or resistant to 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). A subject may exhibit resistance at the start of treatment or may exhibit resistance during treatment. In some embodiments, a subject in need of treatment has undergone and failed all known effective treatments for a disease or disorder disclosed herein. In some embodiments, a subject in need of treatment has undergone at least one prior treatment.

[0357] As used herein, the term "treating" or "treat" refers to 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, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treating" may include treatment of a cell in vitro or treatment in an animal model. It is recognized that reference to "treating" or "treatment" includes the alleviation of symptoms of an established condition. Thus, "treating" or "treatment" of a disease state, disorder, or condition includes (1) preventing or delaying the onset of clinical symptoms of the disease state, disorder, or condition in a person susceptible to or predisposed to the disease state, disorder, or condition, but who has not yet experienced or displayed clinical or subclinical symptoms of the disease state, disorder, or condition; (2) inhibiting the disease state, disorder, or condition, i.e., arresting, reducing, or delaying the onset of the disease or its recurrence (in the case of maintenance treatment) or at least one clinical or subclinical symptom thereof; or (3) alleviating or attenuating the disease, i.e., causing regression of the disease state, disorder, or condition or at least one clinical or subclinical symptom thereof.

[0358] It is also understood that the compounds of the present disclosure, or pharmaceutically acceptable salts, polymorphs or solvates thereof, can also be used to prevent the associated disease, condition or disorder, or to identify suitable candidates for such purposes.

[0359] As used herein, the terms "preventing," "prevent," or "prevention against" refer to reducing or eliminating the onset of symptoms or complications of such disease, condition, or disorder.

[0360] It will be appreciated that those skilled in the art can refer to general references for detailed descriptions of known techniques or equivalent techniques discussed herein. 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 (3 rd edition),Cold Spring Harbor Press,Cold Spring Harbor,New York(2000);Coligan et al.,Current Protocols in Immunology,John Wiley & Sons,NY;Enna et al.,Current Protocols in Pharmacology,John Wiley & Sons,NY;Fingl et al.,The Pharmacological Basis of Therapeutics(1975),Remington's Pharmaceutical Sciences,Mack Publishing Co.,Easton,PA,18 th These texts may, of course, be referenced when making or using aspects of the present disclosure.

[0361] It should be understood that the present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0362] The compounds of the present disclosure may be administered in the form of prodrugs that are broken down in the human or animal body to release the compounds of the present disclosure. Prodrugs can be used to modify the physical and / or pharmacokinetic properties of the compounds of the present disclosure. Prodrugs can be formed when the compounds of the present disclosure contain 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 on the sulfonylurea group of any one of the compounds of the formulas disclosed herein.

[0363] Thus, the present disclosure includes compounds of the present disclosure, as defined above, that are made available by organic synthesis and that are made available in the human or animal body by cleavage of a prodrug thereof. Thus, the present disclosure also includes compounds of the present disclosure produced by organic synthetic means, as well as those compounds produced in the human or animal body by metabolism of a precursor compound, i.e., compounds of the present disclosure can be synthetically produced compounds or metabolically produced compounds.

[0364] Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure are those that, based on sound medical judgment, are suitable for administration to the human or animal body without undesirable pharmacological activity or undue toxicity. Various forms of prodrugs are described, for example, in the following literature: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Prodrugs, 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 Prodrugs", by H. Bundgaard, pp. 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. al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACS Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0365] Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure that possess a hydroxy group include, for example, their in vivo cleavable esters or ethers. The in vivo cleavable esters or ethers of the compounds of the present disclosure that contain a hydroxy group are, for example, pharmaceutically acceptable esters or ethers that are 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, substituted benzoyl and substituted phenylacetyl groups, C1-C10 alkoxycarbonyl groups, such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2 carbamoyl, 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 α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl.

[0366] Suitable pharmaceutically acceptable prodrugs of compounds of the present disclosure possessing a carboxy group are, for example, in vivo cleavable amides thereof, for example, amides formed with amines such as ammonia, C1-C4 alkylamines such as methylamine, (C1-C4 alkyl)2 amines such as dimethylamine, N-ethyl N-methylamine or diethylamine, C1-C4 alkoxy C2-C4 alkylamines such as 2 methoxyethylamine, phenyl C1-C4 alkylamines such as benzylamine and amino acids such as glycine, or esters thereof.

[0367] Suitable pharmaceutically acceptable prodrugs of the disclosed compounds that possess an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, C1-C2 acetyl, benzoyl, phenylacetyl, substituted benzoyl, and substituted phenylacetyl groups. 10 Included are amides formed with alkanoyl 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.

[0368] The in vivo effects of the compounds of the present disclosure may be exerted in part by one or more metabolic products formed in the human or animal body after administration of the compounds of the present disclosure. As mentioned above, the in vivo effects of the compounds of the present disclosure may also be exerted by metabolism of precursor compounds (prodrugs).

[0369] All percentages and ratios used herein are by weight unless otherwise specified. Other features and advantages of the present disclosure will be apparent from the different examples. The examples provided are illustrative of various components and methodologies useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure, one skilled in the art will be able to identify and employ other components and methodologies useful in practicing the present disclosure.

[0370] In the synthetic schemes described herein, compounds may be depicted in one specific configuration for simplicity. Such specific configurations are not to be construed as limiting the present disclosure to one or other isomers, tautomers, positional isomers or stereoisomers, nor do they exclude mixtures of isomers, tautomers, positional isomers or stereoisomers. However, it will be understood that a given isomer, tautomer, positional isomer or stereoisomer may have a higher activity level than another isomer, tautomer, positional isomer or stereoisomer.

[0371] All publications and patent documents cited herein are herein incorporated by reference to the same extent as if each such publication or document was specifically and individually indicated to be incorporated by reference. The citation of publications and patent documents is not intended as an admission that any is directly relevant prior art, nor does it constitute any admission as to the contents or date thereof. Having thus described the invention in writing, those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the foregoing description and the following examples are intended to be illustrative and not limiting on the scope of the claims which follow.

[0372] As used herein, the phrase "compounds of the present disclosure" refers generally and specifically to compounds disclosed herein.

[0373] synthesis In some aspects, the present disclosure provides methods of preparing the compounds disclosed herein.

[0374] In some embodiments, the present disclosure provides a method of preparing a compound, comprising one or more steps described herein.

[0375] In some aspects, the present disclosure provides compounds obtainable by, obtained by, or obtained directly by the methods of preparing compounds described herein.

[0376] In some aspects, the present disclosure provides intermediates suitable for use in the methods for preparing the compounds described herein.

[0377] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Specific processes for the preparation of these compounds are further described in the accompanying Examples.

[0378] In the descriptions of synthetic methods described herein and in any reference synthetic methods used to prepare starting materials, it is understood that all suggested reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, experimental time, and work-up procedures, can be selected by one of ordinary skill in the art.

[0379] 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 used.

[0380] It will be recognized that during the synthesis of the compounds of the present disclosure or during the synthesis of certain starting materials in the processes defined herein, it may be desirable to protect certain substituents to prevent undesired reactions. A skilled chemist will recognize when such protection is necessary and how such protecting groups can be placed and subsequently removed. For examples of protecting groups, see one of the many general texts on this subject, such as 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to a skilled chemist as being suitable for removing such protecting groups, and such methods will be selected so as to achieve removal of the protecting group with minimal disruption to groups elsewhere in the molecule. Thus, when a reactant contains a group such as amino, carboxy, or hydroxy, it may be desirable to protect that group in some of the reactants mentioned herein.

[0381] For example, suitable protecting groups for amino or alkylamino groups include, for example, acyl groups, such as alkanoyl groups (e.g., acetyl), alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl), arylmethoxycarbonyl groups (e.g., benzyloxycarbonyl), or aroyl groups (e.g., benzoyl (Bn)). The deprotection conditions for the above-mentioned protecting groups necessarily vary depending on the selection of the protecting group. Thus, for example, acyl groups, such as alkanoyl groups or alkoxycarbonyl groups or aroyl groups, can be removed by hydrolysis with a suitable base, such as, for example, alkali metal hydroxides (e.g., lithium hydroxide or sodium hydroxide). Alternatively, acyl groups such as tertbutoxycarbonyl groups may be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid, for example borontris(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.

[0382] Suitable protecting groups for hydroxyl groups include, for example, acyl groups, such as alkanoyl groups (e.g., acetyl), aroyl groups (e.g., benzoyl), or arylmethyl groups (e.g., benzyl). The deprotection conditions for the above-mentioned protecting groups necessarily vary depending on the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or aroyl groups, can be removed by hydrolysis with a suitable base, such as an alkali metal hydroxide (e.g., lithium hydroxide, sodium hydroxide, or ammonia). Alternatively, arylmethyl groups, such as benzyl groups, can be removed by hydrogenation over a catalyst, such as palladium on carbon.

[0383] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or ethyl group which may be removed by hydrolysis with a base such as sodium hydroxide, or for example a tertbutyl group which may be removed by treatment with an acid, for example an organic acid, such as trifluoroacetic acid, or for example a benzyl group which may be removed by hydrogenation over a catalyst such as palladium on carbon.

[0384] Once a compound of the present disclosure has been synthesized by any one of the processes defined herein, the process may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound of the present disclosure to another compound of the present disclosure; (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0385] The resulting compounds of the present disclosure are isolated and purified using techniques well known in the art.

[0386] Conveniently, the reaction of compounds is carried out in the presence of a suitable solvent, which is preferably inert under each reaction condition.Examples of suitable solvents include hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 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, For example, ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones such as acetone, methyl isobutyl ketone (MIBK) or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidone (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 aforementioned solvents or with water.

[0387] The reaction temperature is preferably between about -100°C and 300°C, depending on the reaction step and reaction conditions used.

[0388] The reaction time generally ranges from several minutes to several days, depending on the reactivity of each compound and the reaction conditions. Suitable reaction times can be easily determined by methods known in the art, such as reaction monitoring. Based on the reaction temperature described above, suitable reaction times are generally within the range of 10 minutes to 48 hours.

[0389] Moreover, by utilizing the procedures described herein, in conjunction with routine methods of one of ordinary skill 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.

[0390] As will be appreciated by those skilled in the art of organic synthesis, the compounds of the present disclosure are readily accessible by a variety of synthetic routes, some of which are illustrated in the accompanying examples. Those skilled in the art will readily recognize what types of reagents and reaction conditions should be used to obtain the compounds of the present disclosure, and how to apply and adapt them in any particular case (whenever necessary or useful). Furthermore, some of the compounds of the present disclosure can be readily synthesized by reacting other compounds of the present disclosure under suitable conditions, for example, by applying standard synthetic methods such as reduction, oxidation, addition, or substitution reactions, to convert one specific functional group present in the compounds of the present disclosure or suitable precursor molecules to another functional group, which methods are well known to those skilled in the art. Similarly, those skilled in the art will recognize that synthetic protecting (or protective) groups will be applied whenever necessary or useful; suitable protecting groups and methods for introducing and removing protecting groups are well known to those skilled in the art of chemical synthesis and are described in more detail, for example, in P.G.W.Wuts, T.W. Greene, "Greene's Protective Groups in Organic Synthesis," 4th edition (2006) (John Wiley & Sons). The compounds of the present 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 intermediates shown are also available as commercially available reagents from a number of commercial sources.

[0391] The compounds of the present disclosure can be prepared according to the general methods illustrated in the following schemes. [ka] Scheme 1 illustrates a general method for preparing key intermediates such as compound 1-K. A suitably substituted 2-halophenol, e.g., 4-fluoro-2-bromophenol (1-A), reacts with a 5-halopyrimidine (1-B), e.g., 5-bromopyrimidine or 5-iodopyrimidine, to give the corresponding diaryl ether (1-C). This reaction is typically carried out in a suitable aprotic solvent, such as DMA (dimethylacetamide) or NMP (N-methylpyrrolidinone), in the presence of an acid scavenger, such as Na2CO3, K2CO3, Cs2CO3, K3PO4, Et3N (triethylamine), or (iPr)2NEt (diisopropylethylamine, also known as Huning's base). In some cases, this transformation is facilitated by the addition of a suitable ligand, e.g., rel-(1R,2R)-N 1 ,N 2The conversion of compound 1-C to compound 1-D can be facilitated by the addition of an appropriate catalyst, typically CuO or CuI, in the presence of 1-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 easily achieved by Pd-catalyzed carbonylation in the presence of an acid scavenger and a suitable alcohol (typically used as the reaction solvent). The palladium catalyst used is often Pd(dppf)Cl2 (dppf = 1,1-bis(diphenylphosphino)ferrocene), but other catalyst systems, such as Pd(Ph3P)2Cl2 (Ph3P = triphenylphosphine) or Pd(OAc)2 / Ph3P, can also be used. Typically, Et3N or (i-Pr)2NEt is used as the acid scavenger, and methanol is used as the solvent. These reactions are most typically carried out under a CO atmosphere, although other CO sources, such as oxalic acid, can be used in some cases. The ester group of compound 1-D is then saponified to the corresponding carboxylic acid 1-E. Typically, this conversion 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 for achieving this type of conversion and are generally well known to those skilled in the art. For example, the carboxylic acid can be reacted with thionyl chloride or oxalyl chloride to form the corresponding acid chloride. This reaction can be carried out in a suitable aprotic solvent such as CHCl, using thionyl chloride as both the reactant and the solvent when thionyl chloride is used. The acid chloride is then reacted with a suitable amine R, R, NH in the presence of a suitable acid scavenger, such as EtN, (i-Pr)NEt, or pyridine, in an aprotic solvent such as CHCl or THF. In some cases, pyridine can be used as an acid scavenger and reaction solvent.Alternatively, the carboxylic acid and amine R,R,NH can be combined in an aprotic solvent, often DMF, CHCl, or THF, and coupled using reagents such as DCC (dicyclohexylcarbodiimide), 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 some cases, when DCC or EDC is used as the coupling agent, HOBt (hydroxybenzotriazole) may be added to the reaction to facilitate the desired coupling reaction. Reaction of 1-F with a suitable oxidizing agent, such as urea hydrogen peroxide, in the presence of trifluoroacetic anhydride or meta-chloroperoxybenzoic acid (mCPBA) in a suitable solvent, typically CHCl or THF, provides the pyrimidine N-oxide 1-G. This can then be chlorinated using an appropriate chlorinating agent, typically POCl or oxalyl chloride, in the presence of an acid scavenger, typically EtN or (i-Pr)NEt, in an aprotic solvent such as CHCl or isopropyl acetate to give compound 1-H. The chloride in compound 1-H can be readily displaced with an amine or a suitably protected diamine, such as tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (1-I), to give compounds such as 1-J. This reaction is carried out in an aprotic solvent such as CHCl, THF, DMF, or isopropyl acetate in the presence of an acid scavenger, typically EtN or (i-Pr)NEt. When a protected diamine is used, the protecting group can be subsequently removed depending on the nature of the protecting group. The use of protecting groups in organic synthesis is well known to those skilled in the art, and conditions for adding and removing protecting groups can be found in well-established references, such as Greene's Protective Groups in Organic Synthesis, 4. thEdition (ISBN: 9780470053485). For example, the Boc (tert-butyloxycarbonyl) protecting group in compound 1-J can be removed under acidic conditions using an acid such as HCl, TFA (trifluoroacetic acid), or p-TsOH (para-toluenesulfonic acid) in a suitable solvent, often CHCl or THF. The Boc group can also be removed using TMSCl in 2,2,2-trifluoroethanol. The desired deprotected amine can be isolated as a salt, such as salt 1-K (where HX indicates a salt form), or as a free base after workup under standard basic conditions. After removing the protecting group, the amine can be alkylated with various alkylating agents, as shown in Scheme 3.

[0392] [ka] Scheme 2 shows another method for preparing key intermediate 1-K. Benzoic acid derivative 2-A is converted to the corresponding amide 2-B according to the general conditions for preparing amides from carboxylic acids described in Scheme 1 (see 1-E to 1-F). The methyl ether protecting group of 2-B is then removed using Greene's Protective Groups in Organic Synthesis, 4 th The diaryl ether 1-F can be removed by various methods described in the "Immuno- and Diaryl Ethers" (ISBN: 9780470053485) edition. For example, reaction of 2-B with boron tribromide (BBr) in an aprotic solvent, typically CHCl, affords the 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 converted to the key intermediate 1-K as described in Scheme 1.

[0393] [ka] Scheme 3 illustrates a method for preparing selected pyran alkylating agents that can be used to alkylate key intermediates such as 1-K. Commercially available 1,5-anhydro-2,3,4-trideoxy-2-[[(1,1-dimethylethoxy)carbonyl]amino]-D-erythro-hexitol (3-A) can be reacted with a suitable sulfonyl chloride, preferably p-toluenesulfonyl chloride (TsCl) or methanesulfonyl chloride (MsCl), to afford the sulfonate derivative 3-B (R = p-MePh or Me). Alternatively, 3-A can be converted to the corresponding bromide or iodide under standard conditions known to those skilled in the art. For example, reaction of 3-A with CBr in the presence of PPh in an aprotic solvent, typically CHCl, affords the halide 3-C (X = Br). Compound 2-C (X = Br or I) can also be obtained by reacting 3-B with an anionic halide source such as LiBr or LiI in an aprotic solvent such as THF or diethyl ether. Compounds 3-B and 3-C can be used to alkylate key intermediates such as 1-K, as shown in Scheme 4.

[0394] [ka] Scheme 4 illustrates a method for converting key intermediate 1-K to compound (4-D) of the present disclosure. 1-K, which can be prepared according to the general procedures described in Schemes 1 and 2, is reacted with an appropriate alkylating agent, e.g., compound 3-B or 3-C, in the presence of an acid scavenger, such as EtN or (iPr)NEt, in an aprotic solvent such as CHCl, THF, DMF, or NMP to afford compound 4-A. KI or tetrabutylammonium iodide (TBAI) may be added to facilitate the reaction. The Boc protecting group in 4-A can be removed according to the general method for removing the Boc group described in Scheme 1 to afford 4-B (see 1-J–1-K), 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 such as EtN or (iPr)NEt in an aprotic solvent such as CHCl, THF, DMF, or NMP provides compound (4-D) of the present disclosure. For illustrative purposes, reaction of 4-B with an alkylsulfonyl chloride (4-C, R = alkyl group) provides the sulfonyl derivative 4-D. Other compounds of the present disclosure can be similarly formed via reaction with an appropriate acylating agent, such as an acid chloride (to provide an amide), an alkyl chloroformate (to provide a carbamate), or an alkyl carbamoyl chloride or alkyl isocyanate (to provide a urea).

[0395] [ka] Scheme 5 shows a general method for preparing key intermediate 5-C. Compound 1-D, which can be prepared according to the general procedure described in Scheme 1, can be oxidized to form pyrimidine N-oxide 5-A according to the general methods described in Scheme 1 (see 1-F to 1-G). N-oxide 5-A can then be chlorinated to 4-chloropyrimidine derivative 5-B according to the general methods described in Scheme 1 (see 1-G to 1-H). The chloro group of 5-B can then be displaced with a suitable amine, such as tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (1-I), according to the general methods described in Scheme 1 (see 1-H to 1-J), to give compound 5-C. Those skilled in the art will recognize that compound 5-C is a flexible intermediate that can be converted to compound 4-D of the present disclosure by a variety of methods. Some of these methods are described below (see Schemes 6 to 8).

[0396] [ka] Scheme 6 shows one general method for converting compound 5-C to a compound of the present disclosure. The ester of compound 5-C (prepared according to the general procedure 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 method for preparing amides from carboxylic acids described in Scheme 1 (see 1-E to 1-F). Compound 1-J can then be converted to compound 4-D of the present disclosure as described above (see Schemes 1 and 4).

[0397] [ka] Scheme 7 shows another general method for converting compound 5-C to a compound of the present disclosure. Removal of the Boc group of 5-C can be achieved using the general procedure for removing the Boc group 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 discussed in Scheme 1. Alkylation of the amine of compound 7-A can provide compound 7-B, as described in Scheme 4 (see 1-K to 4-A). Saponification of the ester of 7-B, as described in Scheme 1 (see 1-D to 1-E), gives the carboxylic acid derivative 7-C, which can be converted to the corresponding amide 4-A according to the general method for amide formation described in Scheme 1 (see 1-E to 1-F). Compound 4-A can then be converted to compound 4-D of the present disclosure according to Scheme 4.

[0398] [ka] Scheme 8 shows another general method for converting compound 7-B to a compound of the present disclosure. The Boc group of compound 7-B (prepared according to the general procedure described in Scheme 7) can be removed using the general procedure for removing a Boc group 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 discussed in Scheme 1. Acylation of the amine of compound 8-A can be performed according to the general method discussed in Scheme 4 (see 4-B to 4-D) to give compound 8-B. Saponification of the ester of compound 8-B can be achieved via the general procedure for ester saponification described in Scheme 1 (see 1-D to 1-E). The resulting carboxylic acid 8-C can then be converted to the corresponding amide using the general method for amide formation described in Scheme 1 (see 1-E to 1-F) to give compound (4-D) of the present disclosure.

[0399] General Biological Methods Homogeneous Time-Resolved Fluorescence (HTRF) HTRF is the leading commercially available TR-FRET (time-resolved fluorescence resonance energy transfer) technology. TR-FRET technologies, such as HTRF, combine the sensitivity of fluorescence with the homogeneous nature and low time-resolved background of FRET (fluorescence resonance energy transfer). HTRF uses two fluorophores, a donor dye and an acceptor dye, that transfer energy upon their proximity. This creates a homogeneous assay format, eliminating the need to separate bound and unbound partners, as fluorescence emission from the acceptor occurs only upon binding. HTRF can be used in competitive and non-competitive formats and can be performed as a cellular or biochemical assay in 96-, 384-, and 1536-well plate formats. HTRF has been applied to a variety of applications, including quantification of GPCRs, kinases, epigenetics, biological therapeutics, and various biomarkers, and can be used to evaluate the compounds of the present disclosure, according to the knowledge of one of ordinary skill in the art.

[0400] 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 a PatchPlate. Amphotericin is used as a perforating agent to gain electrical access to the cells. Before adding the test compound, the hERG tail current is measured by the perforated patch clamp method. After adding a defined concentration or range of concentrations of the test compound, a second recording of the hERG current is performed. The percent inhibition is obtained by measuring the amplitude of the tail current induced by a 2-second pulse to +20 mV followed by a 1-second test pulse to -40 mV before and after drug incubation (the difference current is normalized to the control and multiplied by 100 to obtain percent inhibition). Patch clamp assays can be used according to the knowledge of those skilled in the art to evaluate the compounds of the present disclosure.

[0401] In any one of the embodiments described herein, the compound has an IC of greater than 10, 15, 20, 25, or 30 μM in a standard human ether-a-go-go related gene (hERG) patch clamp assay. 50 It has.

[0402] Because many drugs have been withdrawn from late-stage clinical trials due to cardiotoxic effects, it is important to identify and avoid potentially cardiotoxic compounds early in drug development. 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 cardiac inwardly rectifying voltage-gated potassium channel (IKr), which is involved in cardiac repolarization. Inhibition of hERG current can cause QT interval prolongation and potentially lead to a fatal ventricular tachyarrhythmia called Torsade de Pointes. Compounds with an IC50 greater than about 10 μM or greater than about 15 μM in the hERG assay can be considered free of any cardiovascular toxicity. In some embodiments, compounds of Formulae 0, 0a, I, Ia, II, IIa, III, IIIa, and / or Table 1 exhibit reduced hERG binding compared to structural analogs. In some embodiments, compounds of Formula 0, 0a, I, Ia, II, IIa, III, IIIa, and / or Table 1 have an IC50 of greater than 10 μM, 15 μM, 20 μM, 25 μM, or 30 μM in a standard patch clamp hERG assay.

[0403] In some embodiments, compounds of the present disclosure (e.g., compounds of Formulas 0, 0a, I, Ia, II, IIa, III, IIIa, and Table 1) do not significantly block the hERG potassium channel in a standard patch clamp hERG assay (e.g., IC greater than 1 μM, μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 35 μM, 40 μM, or 50 μM). 50 ).

[0404] How to use The compounds of the present disclosure are inhibitors of the interaction between menin and MLL or MLL fusion proteins. In some embodiments, the present disclosure relates to methods for inhibiting the interaction between menin and MLL or MLL fusion proteins by contacting the menin and MLL or MLL fusion proteins with a compound of the present disclosure. The contacting can be carried out in vitro or in vivo. In some embodiments, the compounds of the present disclosure can bind to menin, thereby preventing MLL from binding to menin. In some embodiments, the present disclosure provides methods for inhibiting the activity of menin by contacting menin with a compound of the present disclosure in the presence of an MLL or MLL fusion protein. In further embodiments, the present disclosure provides a method for inhibiting the binding of MLL or MLL fusion proteins to menin, comprising contacting menin with a compound of the present disclosure in the presence of an MLL or MLL fusion protein.

[0405] In some embodiments, compounds of the present disclosure minimize hERG interaction. In some embodiments, the present disclosure relates to methods of inhibiting the interaction between menin and an MLL or MLL fusion protein by contacting the menin and an MLL or MLL fusion protein with a compound of the present disclosure, wherein the compound minimizes hERG activity. In some embodiments, the present disclosure relates to methods of inhibiting the interaction between menin and an MLL or MLL fusion protein by contacting the menin and an MLL or MLL fusion protein with a compound of the present disclosure, wherein the compound of the present disclosure avoids drug-induced blockade of hERG.

[0406] The evaluation of hERG activity can be achieved by many methods known in the art. Such methods for evaluating hERG properties include patch clamp electrophysiological assays in hERG transfected cells. Various other strategies, including radiolabeled binding assays, functional assays, and rubidium release assays, also quantify hERG potency.

[0407] The compounds of the present disclosure are also useful for treating diseases associated with menin-MLL interaction or menin-MLL fusion protein interaction. For example, diseases and conditions treatable according to the methods of the present disclosure include cancer, such as leukemia, and other diseases or disorders mediated by menin-MLL interaction or menin-MLL fusion protein interaction, such as diabetes.

[0408] Thus, the compounds of the present disclosure are believed to be effective against a wide range of cancers, including, but not limited to, hematological cancers (e.g., leukemia and lymphoma), bladder cancer, brain cancers (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)), colon cancer, cervical cancer, gastrointestinal cancers (e.g., colon cancer, gastric cancer), genitourinary system cancer, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer (e.g., castration-resistant prostate cancer), kidney 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 a gain-of-function p53 mutation.

[0409] In some embodiments, specific cancers that may be treated by the compounds, compositions, and methods described herein include cardiac cancers, such as sarcomas (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung cancers, such as bronchogenic carcinoma (e.g., squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, and adenocarcinoma), alveolar and bronchial carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell lung carcinoma, small cell lung carcinoma, bronchial adenoma / carcinoid, and pulmonary pleuroblastoma; gastrointestinal cancers, such as cancer of the esophagus (e.g., , squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma), cancer of the stomach (e.g., carcinoma, lymphoma, and leiomyosarcoma), cancer of the pancreas (e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, and vipoma), cancer of the small intestine (e.g., adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma), cancer of the large intestine 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, anal canal cancer, tongue cancer, 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 cancer, such as cancer of the kidney (e.g., adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, and leukemia), cancer of the bladder and urethra (e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma), cancer of the prostate (e.g., adenocarcinoma and sarcoma), cancer of the testis (e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, and lipoma), and transitional cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter and other urinary tract, urethral cancer, and and bladder cancer; liver cancer, e.g., hepatoma (e.g., hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; bone cancer, e.g., osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroid exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; nervous system cancer, e.g., cancer of the skull (e.g., osteoma, hemangioma, granuloma, xanthomatosis, and osteitis deformans); cancer of the meninges (e.g., meningioma, meningeal sarcoma, 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 tumors, central nervous system cancers, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, pediatric cerebellar astrocytoma, pediatric cerebral astrocytoma, primary central nervous system lymphoma, visual pathway and hypothalamic glioma, nervous system lymphoma, tentorial supratentorial primitive neuroectodermal tumor, pineoblastoma, and supratentorial primitive neuroectodermal tumor; gynecological cancers, such as cancer of the uterus (e.g., endometrial carcinoma), cancer of the cervix (e.g., cervical carcinoma and preneoplastic cervical dysplasia), cancer of the ovary (including, e.g., ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosathecocytoma, Sertoli-Leydig cell tumor, dysgerminoma, and malignant teratoma), cancer of the vulva (e.g., squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, and melanoma), cancer of the vagina (e.g., clear cell carcinoma, squamous cell carcinoma, cancer of the fallopian tubes (e.g., carcinoma); other reproductive system cancers, e.g., endometrial cancer, endometrial carcinoma, 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, endometrial cancer, uterine sarcoma; lymphatic and hematologic cancers, e.g., blood cancers (e.g., acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLM), blastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, and myelodysplastic syndromes, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma) and Waldenström's macroglobulinemia), and other lymphatic or hematologic cancers, such as childhood leukemia, myeloproliferative disorders (e.g., primary myelofibrosis), plasma cell neoplasm / multiple myeloma, myelodysplasia, myelodysplastic syndromes, cutaneous T-cell lymphoma, lymphoid neoplasms, AIDS-related lymphoma, thymoma, thymoma and thymic carcinoma, mycosis fungoides, and Sézary syndrome;Skin cancers, such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, atypical nevus syndrome, lipoma, hemangioma, dermal fibrosis, keloid, psoriasis, Merkel cell carcinoma, Merkel cell skin cancer, melanoma, and carcinoid tumors; adrenal gland cancers, such as neuroblastoma; other cancers related to the endocrine system, such as adrenocortical carcinoma, multiple endocrine neoplasia (e.g., multiple endocrine neoplasia type I), multiple endocrine neoplasia syndrome, parathyroid carcinoma, pituitary tumor, brown tumor connective tissue cancers (e.g., bone cancer, osteoarticular cancer, osteosarcoma, and malignant fibrous histiocytoma); cancers associated with the head, neck, and mouth (e.g., head and neck cancer, paranasal sinus and nasal cancer, metastatic cervical squamous cell carcinoma, oral 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 cancers associated with the eye (e.g., eye cancer, intraocular melanoma). In some embodiments, the cancer is Ewing's sarcoma;

[0410] In some embodiments, the cancer is a blood cancer such as leukemia or lymphoma. Examples of leukemias and lymphomas treatable by the compounds of the present disclosure include mixed lineage leukemia (MLL), MLL-related leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage leukemia (MLL-r), MLL rearrangements or leukemias associated with rearrangements of the MLL gene, acute leukemia, chronic leukemia, asymptomatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, myeloid leukemia, childhood leukemia, acute lymphocytic leukemia (ALL) (also called acute lymphoblastic leukemia or acute lymphocytic leukemia), acute myeloid leukemia (AML) (also called acute myeloid leukemia or acute myeloblastic leukemia), acute granulocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia (CLL) (chronic lymphoblastic leukemia), leukemia), chronic myeloid leukemia (CML) (also called chronic myeloid leukemia), therapy-related leukemia, myelodysplastic syndromes (MDS), myeloproliferative disorders (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, mycosis fungoides, Sézary syndrome, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, meningeal leukemia, leukemic leptomeningeal inflammation, leukemic meningitis, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma), or Waldenstrom's macroglobulinemia. In some embodiments, the acute myeloid leukemia (AML) is nucleophosmin (NPM1)-mutated acute myeloid leukemia (i.e., NPM1 mut acute myeloid leukemia).

[0411] In certain embodiments, compounds of the present disclosure are used to treat leukemia associated with MLL rearrangements, acute lymphocytic leukemia associated with MLL rearrangements, acute lymphoblastic leukemia associated with MLL rearrangements, acute lymphocytic leukemia associated with MLL rearrangements, acute myeloid leukemia associated with MLL rearrangements, acute myelogenous leukemia associated with MLL rearrangements, or acute myeloblastic leukemia associated with MLL rearrangements. As used herein, "MLL rearrangements" refers to rearrangements of the MLL gene.

[0412] In some embodiments, diseases and conditions treatable with compounds of the present disclosure include insulin resistance, prediabetes, 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 present disclosure include hyperglycemia. In some embodiments, hyperglycemia is associated with diabetes, such as type 2 diabetes. In some embodiments, compounds of the present disclosure are used to treat loss of response to other antidiabetic agents and / or reduced beta cell function in a patient or subject. In some embodiments, compounds of the present disclosure are used to restore response to other antidiabetic agents and / or restore beta cell function and / or reduce the need for insulin in a patient or subject. In some embodiments, compounds of the present disclosure are used to reduce insulin resistance, reduce the risk of diabetes, or reduce statin-induced blood glucose elevation in patients taking statins. In some embodiments, compounds of the present disclosure are used to treat diabetes in patients taking statins or to prevent diabetes in patients taking statins. Methods of the present disclosure include lowering, reducing, inhibiting, suppressing, limiting, or controlling blood glucose elevation in a patient. In a further aspect, the methods of the present disclosure include increasing, stimulating, enhancing, promoting, inducing, or activating insulin sensitivity in a subject using statins, including, but not limited to, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0413] In some embodiments, patients are treated (e.g., administered) with a compound of the present disclosure in an amount sufficient (e.g., a therapeutically effective amount) to treat or ameliorate one or more of the above diseases and conditions. The compounds of the present disclosure may also be useful in the prevention of one or more of the above diseases.

[0414] Combination therapy The present disclosure further relates to combination therapies for treating the diseases or disorders described herein. In some embodiments, the combination therapy involves administering at least one compound of the present disclosure in combination with one or more other pharmaceutically active agents to treat cancer or other disorders mediated by menin / MLL. In some embodiments, the combination therapy involves 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 the compounds of the present disclosure in a single dosage form, or the therapeutic agents can be administered simultaneously or sequentially as separate dosage forms.

[0415] In some embodiments, the present invention provides combination therapies 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 present invention provides pharmaceutical compositions 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 present invention relates to methods 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.

[0416] Some embodiments of the present invention relate to combination therapies designed to treat or manage cancer in a subject, wherein the combination therapy comprises 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 the present invention relate 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.

[0417] In some embodiments, the CYP3A inhibitor is an antiarrhythmic agent; an antihistamine; an azole antifungal agent; a benzodiazepine; a calcium channel blocker; an HIV antiviral; an HMG CoA reductase inhibitor; a macrolide antibiotic; a prokinetic agent; a protease inhibitor; or any combination thereof. In some embodiments, the CYP3A inhibitor is selected from the group consisting of posaconazole, alprazolam; amiodarone; amlodipine; aprepitant; aripiprazole; astemizole; atorvastatin; boceprevir; buspirone; chloramphenicol; chlorpheniramine; cimetidine; ciprofloxacin; cisapride; clarithromycin; cobicistat (GS-9350); an analog or derivative of cobicistat (GS-9350); cyclosporine; delaviridine; diazepam→3-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; quinidine → 3-OH; ritonavir; saquinavir; sildenafil; simvastatin; starfruit; tacrolimus (FK506); tamoxifen; telaprevir; telithromycin; trazodone; triazolam; verapamil; telaprevir; vincristine; voriconazole; or any combination thereof.

[0418] In some embodiments, the CYP3A4 inhibitor is posaconazole, cobicistat (GS-9350), or an analog or derivative 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 a combined dosage form. In some embodiments, the CYP3A4 inhibitor is posaconazole.

[0419] In some embodiments, the pharmaceutical composition comprises an amount of a CYP3A4 inhibitor effective to increase the oral bioavailability of the menin inhibitor. Compounds according to the present 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 the diseases or disorders disclosed herein.

[0420] In certain embodiments, the compounds according to the present disclosure are used in combination with one or more passive immunotherapies, such as, 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, the antibody rituximab (Rituxan®) directed against the CD20 antigen; the antibody trastuzumab (Herceptin®) directed against the HER2 protein; the antibody alemtuzumab (Lemtrada®, Campath®) directed against the CD52 antigen; the antibody cetuximab (Erbitux®) directed against the EGFR protein; and the anti-angiogenic inhibitor bevacizumab (Avastin®) directed against the VEGF protein.

[0421] Examples of conjugated monoclonal antibodies that can be used include, but are not limited to, the radiolabeled antibody ibritumomab tiuxetan (Zevalin®); the radiolabeled antibody tositumomab (Bexxar®); and the calicheamicin-containing gemtuzumab ozogamicin (Mylotarg®) immunotoxin; BL22, an anti-CD22 monoclonal antibody-immunotoxin conjugate; radiolabeled antibodies such as OncoScint® and ProstaScint®; brentuximab vedotin (Adcetris®); and ado-trastuzumab emtansine (Kadcyla®, also known as TDM-1).

[0422] Further examples of therapeutic antibodies that can be used include the antibody REOPRO® (abciximab) against the platelet glycoprotein IIb / IIIa receptor; the humanized anti-CD25 monoclonal antibody immunosuppressant ZENAPAX® (daclizumab); the murine anti-17-IA cell surface antigen IgG2a antibody PANOREX™; the murine anti-idiotypic (GD3 epitope) IgG antibody BEC2; the chimeric anti-EGFR IgG antibody IMC-C225; the humanized anti-αVβ3 integrin antibody VITAXIN™; the humanized anti-CD52 IgG1 antibody Campath 1H / LDP-03; the humanized anti-CD33 IgG antibody Smart M195; and the humanized anti-CD22 IgG antibody LYMPHOCIDE™; LYMPHOCIDE™ Y-90; Lymphoscan; Nuvion® against CD3; humanized anti-ICAM3 antibody CM3; primatized anti-CD80 antibody IDEC-114; humanized anti-CD40L antibody IDEC-131; primatized anti-CD4 antibody IDEC-151; primatized anti-CD23 antibody IDEC-152; SMART anti-CD3, humanized anti-CD3 IgG; humanized anti-complement factor 5 (C5) antibody 5G1.1; humanized anti-TNF-α antibody D2E7; humanized anti-TNF-α Fab fragment CDP870; primatized anti-CD4 IgG1 antibody IDEC-151; human anti-CD4 IgG antibody MDX-CD4; CD20-streptavidin (+biotin-yttrium 90); humanized anti-TNF-α These include, but are not limited to, the IgG4 antibody CDP571; the humanized anti-α4β7 antibody LDP-02; the humanized anti-CD4 IgG antibody OrthoClone OKT4A; the humanized anti-CD40L IgG antibody ANTOVA™; the humanized anti-VLA-4 IgG antibody ANTEGREN™; and the human anti-TGF-β2 antibody CAT-152.

[0423] In certain embodiments, compounds according to the present disclosure are used in combination with one or more targeted immunotherapies that include a toxin rather than an antibody, such as, but not limited to, denileukin diftitox (Ontak®), which is a combination of IL-2 and diphtheria toxin.

[0424] Compounds according to the present disclosure may also be used in combination with adjuvant immunotherapy for the treatment of the diseases or disorders disclosed herein. Such 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-Guerin (BCG); keyhole limpet hemocyanin (KLH); incomplete Freund's adjuvant (IFA); QS-21; DETOX; levamisole; and dinitrophenyl (DNP), and combinations thereof, such as a combination of an interleukin, e.g., IL-2, with another cytokine such as IFN-alpha.

[0425] In certain embodiments, compounds according to the present disclosure are used in combination with vaccine therapies, including, but not limited to, autologous and allogeneic tumor cell vaccines, antigen vaccines (including multivalent antigen vaccines), dendritic cell vaccines, and viral vaccines.

[0426] In another embodiment, the present disclosure includes administering to a subject having cancer an effective amount of a compound of the present disclosure and one or more additional anti-cancer therapies selected from surgery, anti-cancer agents / drugs, biological therapy, radiation therapy, anti-angiogenic therapy, immunotherapy, adoptive transfer of effector cells, gene therapy, or hormone therapy. Examples of anti-cancer agents / drugs are described below.

[0427] In some embodiments, the anti-cancer agent / drug is, for example, adriamycin, actinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adzelesin; aldesleukin; altretamine; ambomycin; amethanthrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; visna dimesylate Fido; Bizelesin; Bleomycin sulfate; Brequinar sodium; Bropirimine; Busulfan; Cactinomycin; Calsterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cilolemycin; Cladribine; Crisnatol mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Daunorubicin hydrochloride; Decitabine; Dexorumaplatin; Dezaguanine; Dezaguanine mesylate; Diazicon; Doxorubicin; Doxorubicin hydrochloride; Droloxifene droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; elbrozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etopurine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; foskidone; fostri Escin 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; Mitocalcin; Mitochromin; Mitogillin; Mitomarcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Pegaspargase; Periomycin; Pentamustine; Peplomycin sulfate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone hydrochloride; Plicamycin; Promestane; Porfimer sodium; Porfiromycin; Prednimustine; Procal Bazan hydrochloride; Puromycin; Puromycin hydrochloride; Pirazofurin; Ribopurin; Rogletimide; Safingol; Safingol hydrochloride; Semustine; Simtrazene; Sparphosate sodium; Sparsomycin; Spirogermanium hydrochloride; Spiromustine; Spiroplatin; Streptonigrin; Streptozocin; Surofenur; Tallysomycin; Tecogalan sodium; Tegafur; Teloxantrone hydrochloride; Temoporfin; Teniposide; Teloxylon; Testolactone; Thiamin Phosphorus; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; Toremifene citrate; Trestron acetate; Triciribine phosphate; Trimetrexate; Trimetrexate glucuronate; Triptorelin; Tubrozole hydrochloride; Uracil mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine sulfate; Vincristine sulfate; Vindesine; Vindesine sulfate; Vinepidine sulfate; Vincristine sulfate; Vinorelbine tartrate; Vinlocidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride; palbociclib; Yervoy® (ipilimumab); Mekinist™ (trametinib); pegylated interferon alfa-2b, recombinant interferon alfa-2b; Sylatron™ (pegylated interferon alfa-2b); Tafinlar® (dabrafenib); Zelboraf® (vemurafenib); or nivolumab.

[0428] The compounds of the present disclosure can be administered in combination with existing methods for treating cancer, such as chemotherapy, radiation, or surgery. Accordingly, a method for treating cancer is further provided, comprising administering an effective amount of a compound of the present 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 abarelix, ado-trastuzumab emtansine, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, bleomycin, bortezomib, iv busulfan, oral busulfan, calsterone, capecitabine, carboplatin, carmustine, and cetuximab. Mab, 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 cyclophosphamide, 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, lafluvial Patinib ditosilate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, 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, pertuzumab, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, sorafenib, streptozocin, sulfatinib, sunitinib, sunitinib malate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, voritinib, vorinostat, and zoledronate.

[0429] In certain embodiments, compounds according to the present disclosure are used in combination with one or more anti-cancer agents for the treatment of breast cancer selected from methotrexate, paclitaxel albumin-stabilized nanoparticle formulations, 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.

[0430] Other anticancer agents / drugs include 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecipenol; adzelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsal morphogenetic protein-1; antiandrogen; antiestrogen; antineoplaston; antisense oligonucleotide; aphidicolin glycinate; apoptotic gene regulators; apoptosis control agents; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; aslak Phosphate; Atamestane; Atlimustine; Axinastatin 1; Axinastatin 2; Axinastatin 3; Azasetron; Azatoxin; Azatyrosine; Baccatin III derivatives; Balanol; Batimastat; BCR / ABL antagonists; Benzochlorins; Benzoylstaurosporine; Beta-lactam derivatives; Beta-arretin; Betaclamycin B; Betulinic acid; bFGF inhibitors; Bicalutamide; Bisantrene; Bisaziridinylspermine; Bisnafide; Bistraten A; Bizelesin; Breflate; Bropirimine; Budotitanium; Buthionine sulfoximine; Calcipotriol; Calphostin C; Camptothecin derivatives; Canarypox IL-2; Capecitabine; Carboxamido-amino-triazoles; Carboxamidotriazoles; CaRest M3; CARN 700; cartilage-derived inhibitor; carzelesin; casein kinase inhibitor; castanospermine; cecropin B; cetrorelix; chlorin; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analog; clotrimazole; colismycin A; colismycin B; combretastatin A4; combretastatin analog; conagenin; crambecidin 816; crisnatol; cryptophycin 8; cryptophycin A derivative; curacin A; cyclin-dependent kinase inhibitor; cyclopentaanthraquinone; cycloplatam; sipemycin; cytarabine ocfosfate; cytolytic factor; cytostatin;Dacliximab; Decitabine; Dehydrodidemnin B; Deslorelin; Dexamethasone; Dexphosphamide; Dexrazoxane; Dexverapamil; Diazicon; Didemnin B; Didox; Diethylnorspermine; Dihydro-5-azacytidine; 9-dioxamycin; Diphenylspiromustine; Docosanol; Dolasetron; Doxifluridine; Droloxifene; Dronabinol; Duocarmycin SA; Ebselen; Ecomustine; Edelfosine; Edrecolomab; Eflornithine; Elemene; Emiteflu; Epirubicin; Epriste Lid;Estramustine analogues;Estrogen agonists;Estrogen antagonists;Etanidazole;Etoposide phosphate;Fadrozole;Fazarabine;Fenretinide;Filgrastim;Finasteride;Flavopiridol;Flezelastine;Fludarabine;Fludarabine;Fluorodaunornithine hydrochloride;Forfenimex;Formestane;Fostriecin;Fotemustine;Gadolinium texaphyrin;Gallium nitrate;Galocitabine;Ganirelix;Gelatinase inhibitors;Gemcitabine;Glutathione inhibitors;Hepsulfam;Hele Glyn;Hexamethylenebisacetamide;Hypericin;Ibandronic acid;Idarubicin;Idoxifene;Idramanton;Ilmofosine;Ilomastat;Imidazoacridone;Imiquimod;Immunostimulating peptides;Insulin-like growth factor-1 receptor inhibitors;Iobenguane;Iododoxorubicin;Ipomeanol, 4-;Ilopract;Irsogladine;Isobengazole;Isohomohalichondrin B;Itasetron;Jasplakinolide;Kahalide F;Lamellarin-N triacetate;Lanreotide;Leinamycin;Lenograstim;Len Thiamin sulfate; leptolstatin; letrozole; leukemia inhibitory factor; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogs; lipid-soluble disaccharide peptides; lipid-soluble platinum compounds; lisoclinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lisofylline; lytic peptides; maytansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors;Matrix metalloproteinase inhibitors; menogaril; melbarone; meterelin; methioninase; metoclopramide; MIF inhibitors; mifepristone; miltefosine; millimostim; mismatched double-stranded RNA; mitoguazone; mitolactol; mitomycin analogs; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofalotene; molgramostim; monoclonal antibodies, human chorionic gonadotropin; monophosphoryl lipid A + Myobacterium cell wall sk; mopidamol; multidrug resistance gene inhibitors; multitumor suppressors Factor 1-based therapy; mustard anticancer drugs; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagressip; naloxone + pentazocine; napavine; naphterpine; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitric oxide antioxidants; nitrulline; O6-benzylguanine; octreotide; oxenone; oligonucleotides; onapristone; ondansetron; onda Lansetron; Oracin; Oral cytokine inducer; Ormaplatin; Osateron; Oxaliplatin; Oxaunomycin; Palauamine; Palmitoylrhizoxin; Pamidronate; Panaxytriol; Panomyphen; Parabactin; Pazeliptin; Pegasuspargase; Perdecin; Pentosan polysulfate sodium; Pentostatin; Pentrazole; Perflubron; Perfosfamide; Perillyl alcohol; Phenazinomycin; Phenyl acetate; Phosphatase inhibitors; Picibanil; Pilocarpine hydrochloride; Pirarubicin; Piritre Oximes; Prasetin A; Prasetin B; Plasminogen activator inhibitors; Platinum complexes; Platinum compounds; Platinum-triamine complexes; Porfimer sodium; Porfiromycin; Prednisone; Propylbis-acridone; Prostaglandin J2; Proteasome inhibitors; Protein A system immunomodulators; Protein kinase C inhibitors; Microalgae; Protein tyrosine phosphatase inhibitors; Purine nucleoside phosphorylase inhibitors; Purpurins; Pyrazoloacridines; Pyridoxylated hemoglobin polyoxyethylene conjugates; RAF antagonists;Raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; demethylated leteriptin; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukin; romurtide; roquinimex; rubiginone B1; ruboxil; safingol; saintpin; SarCNU; sarcophytol A; sargramostim; Sdi1 mimetic; semustine; senescence-derived inhibitory factor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single Chain antigen-binding protein; Sizofiran; Sobuzoxane; Borocaptate sodium; Sodium phenylacetate; Sorberolol; Somatomedin-binding protein; Sonermin; Sparfosic acid; Spicamycin D; Spiromustine; Splenopentin; Spongistatin 1; Squalamine; Stem cell inhibitors; Stem cell division inhibitors; Stipiamide; Stromlysin inhibitors; Sulfinosine; Super-acting vasoactive intestinal peptide antagonists; Sladista; Suramin; Swainsonine; Synthetic glycosaminoglycans; Talimustine; Tamoxifen methiodide; Ta Uromustine; Tazarotene; Tecogalan sodium; Tegafur; Terlapyrylium; Telomerase inhibitors; Temoporfin; Temozolomide; Teniposide; Tetrachlorodecaoxide; Tetrazomine; Saliblastine; Thiocoraline; Thrombopoietin; Thrombopoietin mimetics; Thymalfasin; Thymopoietin receptor agonists; Thymotrin; Thyroid-stimulating hormone; Ethyl etiopurinse; Tirapazamine; Titanocene dichloride; Topsentin; Toremifene; Pluripotent 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 systems, erythrocyte gene therapy; veraresol; veramine; verudin; verteporfin; vinorelbine; vinxartin; vitaxin; zanoteron; zilascorub; zinostatin stimalamer; 5-fluorouracil; and leucovorin.

[0431] In some embodiments, the anti-cancer agent / drug is an agent that stabilizes microtubules. As used herein, "microtubulin stabilizer" refers to an anti-cancer agent / drug that acts by stabilizing microtubules, thereby arresting cells in the G2-M phase. Examples of microtubulin stabilizers include ACLITAXEL® and Taxol® analogs. Further examples of microtubulin stabilizers include, but are not limited to, the following marketed and investigational drugs: discodermolide (also known as NVP-XX-A-296); epothilones (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 AN-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 B (also known as 26-fluoroepothilone B ... Chiron, etc.); 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); physianolide B; laulimalide; caribeoside; caribeolin; taccalonolide; eleutherobin; sarcodictyin; laulimalide; dictyostatin-1; jatrophane esters; and analogs and derivatives thereof.

[0432] In another embodiment, the anti-cancer agent / drug is an agent that inhibits microtubules. As used herein, "microtubulin inhibitor" refers to an anti-cancer agent that acts by inhibiting tubulin polymerization or microtubule formation. Examples of microtubulin inhibitors include, but are not limited to, the following marketed and investigational drugs: elbrozole (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); altriltins (such as altriltin A and altriltin C); spongistatins (spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, and spongistatin 9). Gistatin 9, etc.; Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356); Auristatin PE (also known as NSC-654663); Sobridotin (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); bitilebamide; tubulysin A; canadensol; centaureidin (also known as NSC-106969);T-138067 (also known as Tularik, 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 AA1 (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); nacrocin (also known as NSC-5366); nascapine, D-24851 (Asta Medica), A-105972 (Abbott); hemiasterin; 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-191); TMPN (Arizona State University); vanadocene acetylacetonate; T-138026 (Tularik); Monsatrol; inanosin (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); eleutherobin (such as desmethyleleutherobin, desaethyleleutherobin, 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; (-)-phenylahistine (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 (SPA-110, also known as trifluoroacetate) (Wyeth); D-82317 (Zentaris); D-82318 (Zentaris); SC-12983 (NCI); resberastatin sodium phosphate; BPR-0Y-007 (National Health Research Institutes); SSR-250411 (Sanofi); combretastatin A4; eribulin (Halaven®); and analogs and derivatives thereof.

[0433] In further embodiments, compounds according to the present disclosure are used in combination with one or more alkylating agents, antimetabolites, natural products, or hormones.

[0434] Examples of alkylating agents useful in the methods of the present disclosure include, but are not limited to, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethyleneimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin, etc.), or triazenes (e.g., decarbazine, etc.).

[0435] Examples of antimetabolites useful in the methods of the present disclosure include, but are not limited to, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, cytarabine), and purine analogs (e.g., mercaptopurine, thioguanine, pentostatin). Examples of natural products useful in the methods of the present disclosure include, but are not limited to, vinca alkaloids (e.g., vinblastine, vincristine), epipodophyllotoxins (e.g., etoposide, teniposide), antibiotics (e.g., actinomycin D, daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin), or enzymes (e.g., L-asparaginase).

[0436] Examples of hormones and antagonists useful in the treatment of cancer include, but are not limited to, corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), and gonadotropin-releasing hormone analogs (e.g., leuprolide).

[0437] Other agents that can be used in combination with the compounds of the present disclosure for the treatment of cancer include platinum coordination complexes (e.g., cisplatin, carboplatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), and adrenocortical suppressants (e.g., mitotane, aminoglutethimide). Other anti-cancer agents / drugs that can be used in combination with the compounds of the present disclosure include liver X receptor (LXR) modulators, such as LXR agonists and LXR beta-selective agonists; aryl hydrocarbon receptor (AhR) inhibitors; poly ADP-ribose polymerase (PARP) enzyme inhibitors, such as olaparib, iniparib, rucaparib, and veliparib; vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors, such as cediranib; and programmed cell death protein 1 (PD-1) inhibitors, such as nivolumab (Bristol-Myers Squibb). Co.) and pembrolizumab (Merck & Co., Inc.; MK-3475); MEK inhibitors, such as cobimetinib; B-Raf enzyme inhibitors, such as vemurafenib; cytotoxic T-lymphocyte antigen (CTLA-4) inhibitors, such as tremelimumab; programmed death-ligand 1 (PD-L1) inhibitors, such as MEDI4736 (AstraZeneca); Wnt pathway inhibitors; epidermal growth factor receptor (EGFR) inhibitors, such as AZD9291 (AstraZeneca), erlotinib, gefitinib, panitumumab, and cetuximab; adenosine A2A receptor inhibitors; adenosine A2B receptor inhibitors; colony-stimulating factor-1 receptor (CSF1R) inhibitors, such as PLX3397 (Plexxikon), and CD73 inhibitors.

[0438] The compounds of the present disclosure can be used in combination with one or more treatment strategies, including immune checkpoint inhibitors, including inhibitors of PD-1, PD-L1, and CTLA-4.

[0439] The compounds of the present disclosure may be used in combination with one or more anticancer agents selected from MCL-1 inhibitors, such as homoharringtonine (HHT) and omacetaxine; BCL-2 inhibitors, such as venetoclax (ABT-199), navitoclax (ABT-263), ABT-737, gossypol (AT-101), apogossypolone (ApoG2), and obatoclax; and selective inhibitors of nuclear export (SINE), such as selinexor (KPT-330).

[0440] In certain embodiments, the compound of the disclosure is selected from methotrexate (Abitrexate®; Folex®; FolexPFS®; Mexate®; Mexate-AQ®); nelarabine (Arranon®); blinatumomab (Blincyto®); rubidomycin hydrochloride or daunorubicin hydrochloride (Cerubidine®); cyclophosphamide (Clafen®; Cytoxan®; Neosar®); clofarabine (Clofarex®; Clolar®); cytarabine (Cytosar-U®; TarabinePFS®); 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 liposomal (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 (Lem Trada®, Campath®); chlorambucil (Ambochlorin®, Amboclorin®, Leukeran®, Linfolizin®); ofatumumab (Arzerra®); bendamustine hydrochloride (Treanda®); fludarabine phosphate (Fludara®); obinutuzumab (Gazyva®); ibrutinib (Imbruvica®);used in combination with one or more anti-cancer agents for the treatment of leukemia selected from idelalisib (Zydelig®); mechlorethamine hydrochloride (Mustargen®); rituximab (Rituxan®); chlorambucil-prednisone; CVP (cyclophosphamide, vincristine, and prednisone); bosutinib (Bosulif®); busulfan (Busulfex®; Myleran®); omacetaxine mepesuxinate (Synribo®); nilotinib (Tasigna®); Intron® A (recombinant interferon alpha-2b); DOT1L inhibitors, e.g., EPZ-5676 (Epizyme, Inc.); and bromodomain and extraterminal motif (BET) protein inhibitors (BET inhibitors), e.g., MS417, JQ1, I-BET 762, and I-BET 151;

[0441] The compounds of the present disclosure may be used in combination with one or more other agents or therapies for the treatment of insulin resistance, prediabetes, diabetes (e.g., type 2 diabetes or type 1 diabetes), and risk of diabetes, including, but not limited to, insulin and insulin analogs, such as Humulin® (Eli Lilly), Lantus® (Sanofi Aventis), Novolin® (Novo Nordisk), and Exubera® (Pfizer); Avandamet® (metformin HCl and rosiglitazone maleate, GSK); Avandaryl® (glimepiride and rosiglitazone maleate, GSK); Metaglip® (glipizide and metformin HCl, Bristol Myers Squibb); Glucovance® (glyburide and metformin HCl, Bristol Myers Squibb); Squibb; PPAR gamma agonists such as Avandia® (rosiglitazone 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 HCl, Bristol Myers Squibb) and Glumetza® (metformin HCl, Depomed); thiazolidinediones; amylin analogs; GLP-1 analogs;DPP-IV inhibitors, such as Januvia® (sitagliptin, Merck) and Galvus® (vildagliptin, Novartis); PTB-1B inhibitors; protein kinase inhibitors (including AMP-activated protein kinase inhibitors); glucagon antagonists, glycogen synthase kinase-3 beta inhibitors; glucose-6-phosphatase inhibitors; glycogen phosphorylase inhibitors; sodium glucose cotransporter 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 agents. 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); SGLT2 inhibitors (e.g., dapagliflozin, remogliflozin etabonate, sergliflozin, canagliflozin, and 1-chloro-4-(β-D-glucoplanos-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., KRP297); 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 analogs (e.g., exendin-4); amylin;Protein tyrosine phosphatase 1 inhibitors; substances that affect the dysregulation of glucose production in the liver, such as inhibitors of glucose-6-phosphatase, fructose-1,6-bisphosphatase, and glycogen phosphorylase; glucagon receptor antagonists; phosphoenolpyruvate carboxykinase inhibitors; glycogen synthase kinase and glucokinase activators; lipid-lowering agents, such as HMG-CoA-reductase inhibitors (e.g., simvastatin, atorvastatin); fibrates (e.g., bezafibrate, fenofibrate), nicotinic acid and its derivatives, PPAR-alpha agonists, PPAR-delta agonists; ACAT inhibitors (e.g., avasimibe); cholesterol absorption inhibitors such as ezetimibe. It can be used in combination with bile acid binding substances such as cholestyramine, ileal bile acid transporter inhibitors, HDL-raising compounds such as CETP inhibitors and ABC1 regulators, active substances for the treatment of obesity such as sibutramine and tetrahydrolipostatin, SDRIs, axokines, leptin, leptin mimetics, cannabinoid I receptor antagonists, and MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 and NPY2 antagonists, beta-3 adrenergic agonists such as SB-418790 and AD-9677, 5HT2c receptor agonists, GABA receptor antagonists, Na channel blockers, topiramate, protein kinase C inhibitors, advanced glycation end product inhibitors, and aldose reductase inhibitors.

[0442] Pharmaceutical Formulations, Administration, and Dosage Forms When used as pharmaceuticals, the compounds of the present disclosure can be administered in the form of a pharmaceutical composition, which refers to a combination of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, with at least one pharmaceutically acceptable carrier. These compositions can be prepared by methods well known in the pharmaceutical arts and can be administered by various routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (ophthalmic administration and administration to mucous membranes, including intranasal, intravaginal, and rectal delivery), pulmonary (e.g., inhalation or insufflation of powders or aerosols, including those via nebulizers; intratracheal, intranasal, epidermal, and transdermal administration), ocular, oral, or parenteral. Ocular delivery methods can include topical administration (eye drops), subconjunctival, periocular, or intravitreal injection, or introduction via a balloon catheter or ophthalmic insert surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial administration, for example, intrathecal or intraventricular administration.Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous perfusion pump.Pharmaceutical compositions and formulations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders.Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, etc. may be required or desirable.

[0443] The present disclosure also includes pharmaceutical compositions containing one or more of the compounds of the present disclosure as an active ingredient, in combination with one or more pharmaceutically acceptable carriers.In preparing the crude product of the present disclosure, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper, or other container.When the excipient functions as a diluent, it can be a solid, semi-solid, or liquid substance, and acts as a vehicle, carrier, or medium for the active ingredient.Therefore, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid medium), ointments, for example, containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders.

[0444] The compounds and compositions described herein can be administered to a patient in any amount and using any route of administration effective for treating or reducing 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 subject's race, age, and general condition, the severity of the infection, disease, or disorder, the specific agent, its mode of administration, and the like. The provided compounds are preferably formulated into specific unit dosage forms for ease of administration and uniformity of dosage. As used herein, "unit dosage form" refers to a physically discrete unit of agent appropriate for the patient to be treated.

[0445] Therapeutic dosages of the compounds of the present disclosure can vary according to, for example, the particular application for which the treatment is being administered, the mode 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 present disclosure in a pharmaceutical composition can vary depending on many factors, including dosage, chemical properties (e.g., hydrophobicity), and the route of administration. For example, a compound of the present disclosure, for parenteral administration, can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound. The dosage can depend on variables such as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological effectiveness of the selected compound, the excipient formulation, and its route of administration. [Example]

[0446] As shown in the examples below, compounds of the present disclosure are prepared and isolated according to the following general procedures. While the general methods may be directed to the synthesis of specific compounds of the present disclosure, it is understood that the following general methods, and other methods known to those skilled in the art, can be applied to all compounds described herein and each subclass and species of these compounds. [Table 2-1] [Table 2-2]

[0447] LCMS Instrument name: Shimadzu LC2020 Nexera Series; Shimadzu MS2020 N-Series; Agilent 1290 Method A: Mobile phase A: 10 mM ammonium bicarbonate aqueous solution; Mobile phase B: ACN; Flow rate: 0.8 mL / min; Column: X Bridge C8 (50 x 4.6 mm), 3.5 μm Method B: Mobile phase: 0.1% HCOOH aqueous solution / 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: 10 mM NH4OAc aqueous solution / ACN (95:5); Flow rate: 0.6 mL / min; Column: Acquity UPLC BEH C18 (2.1×50 mm), 1.7 um Method D: Mobile phase: A: 0.1% TFA aqueous solution, B: ACN; Column: Acquity UPLC BEH C18 (2.1×50) mm, 1.7 μm. Method E: Mobile phase: A: 10 mM NH4HCO3 aqueous solution, B: ACN; Column: Phenomenex Kinetex EVO C18 (3.0×50 mm), 2.6 μm. Method F: Mobile phase: A: 0.1% TFA aqueous solution, B: ACN; Column: ZORBAX ECLIPSE PLUS C18 (50×2.1 mm), 1.8 μm.

[0448] HPLC Instrument name: Shimadzu LC; Prominence-I series instrument (using % in UV detection (Maxplot)) Method A: Mobile phase: A - 10 mM NH4HCO3 aqueous solution, B: ACN; Flow rate: 2.0 mL / min; Column: X-Bridge C8 (150×4.6 mm, 5 μm). Method B: Mobile phase: A; 0.1% TFA aqueous solution, B: ACN; Flow rate: 2.0 mL / min; Column: X-Bridge C8 (50×4.6 mm, 3.5 μm). Method C: Mobile phase: A - 0.1% TFA aqueous solution, B: ACN; Flow rate: 1.0 mL / min; Column: Atlantis column C18 (4.6×250 mm, 5 μm). Method D: Mobile phase: A - 10 mm NH4OAc aqueous solution, B: ACN; Flow rate: 1.5 mL / min; Column: Gemini NX C18 (4.6×150 mm, 3 μm). Method E: Mobile phase A: 0.1% HCOOH aqueous solution, B: ACN; Flow rate: 2.0 mL / min; Column: X-Select C18 (4.6×150 mm, 5 μm). Method F: Mobile phase A: 0.1% HCOOH aqueous solution, B: ACN; Flow rate: 2.0 mL / min; Column: X-Select C18 (4.6×150 mm, 5 μm). Method G: Mobile phase A: 0.1% TFA aqueous solution, B: ACN; Flow rate: 2.0 mL / min; Column: X-Select C18 (4.6×150 mm, 5 μm).

[0449] Preparative HPLC Instrument name: Agilent Technologies 1260 Infinity II Series LC / 6125 Quadrupole MSD Shimadzu Nexera Prep HPLC equipped with LCMS2020 Method A: Mobile phase A: 10 mM NH4HCO3 aqueous solution; Mobile phase B: ACN; Flow rate: 15 mL / min; Column: XBridge C18 (150×19 mm), 5um

[0450] Preparative HPLC Instrument name: Agilent Technologies 1260 Infinity II Series LC / 6125 MSD; Shimadzu Prep HPLC-MS2020 Method A: Mobile phase A: 10 mm NH4HCO3 aqueous solution; Mobile phase B: ACN; Flow rate: 15.0 mL / min; Column: ZORBAX C18 (50×21.2 mm), 5 μm. Method B: Mobile phase A: 10 mm NH4HCO3 aqueous solution; Mobile phase B: ACN; Flow rate: 15.0 mL / min; Column: X-Bridge C18 (150×19.0 mm), 5 μm. Method C: Mobile phase A: 10 mm NH4HCO3 aqueous solution; Mobile phase B: ACN; Flow rate: 15.0 mL / min; Column: SHIMPACK GIST C18 (150×20.0 mm) 5μm. Method D: Mobile phase A: 10 mm NH4HCO3 aqueous solution; Mobile phase B: ACN; Flow rate: 15.0 mL / min; Column: SHIMPACK GIST C18 (250×20.0 mm) 5μm. Method E: Mobile phase A: 10 mm NH4HCO3 aqueous solution; Mobile phase B: ACN; Flow rate: 15.0 mL / min; Column: SHIMPACK SCEPTER C8 (150×20.0 mm) 5μm. Method F: Mobile phase A: 10 mm aqueous NH4HCO3; 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 aqueous NH4HCO3; Mobile phase B: ACN; Flow rate: 15.0 mL / min; Column: Gemini-NX-C18 ((250 × 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 NH4HCO3 aqueous solution; 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 aqueous NH4HCO3; 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 C18 (250 x 21.2 mm), 5 μm. Method L: Mobile phase A: 10 mm aqueous NH4HCO3; Mobile phase B: ACN; flow rate: 15.0 mL / min; column: YMC C18 (250 x 20.0 mm), 5 μm.

[0451] Chiral SFC Instrument name: SFC Analytical-PIC 10-20 and Shimadzu Analytical (equipped with MS and ELSD detectors). Method A: Mobile phase A: CO2; Co-solvent - 0.5% isopropylamine / IPA:MeOH (50:50); Flow rate: 4.0 mL / min; Co-solvent %: 35%, Column: Lux-A1 (250 × 4.6), 5 μm. Method B: Mobile phase A: CO2; Co-solvent-0.5% isopropylamine / IPA; Flow rate: 5.0 mL / min; Co-solvent %: 40%, Column: Lux-A1 (250 × 4.6), 5 μm. Method C: Mobile phase A: CO2; Co-solvent-0.5% isopropylamine / MeOH; Flow rate: 5.0 mL / min; Co-solvent %: 40%, Column: Lux-A1 (250 × 4.6), 5 μm. Method D: Mobile phase A: CO2; Co-solvent - 0.5% isopropylamine / MeOH; Flow rate: 5.0 mL / min; Co-solvent %: 40%, Analysis time: 12 min; Column: LUX-C4, (250 × 4.6), 5 μm. Method E: Mobile phase A: CO2; Co-solvent - 0.5% isopropylamine / MeOH; Flow rate: 4.0 mL / min; Co-solvent %: 40%, Analysis time: 12 min; Column: LUX-C4, (250 × 4.6), 5 μm. Method F: Mobile phase A: CO2; Co-solvent - 0.5% isopropylamine / MeOH; Flow rate: 5.0 mL / min; Co-solvent %: 50%, Analysis time: 12 min; Column: LUX-C4, (250 × 4.6), 5 μm. Method G: Mobile phase A: CO2; Co-solvent - 0.5% isopropylamine / IPA; Flow rate: 4.0 mL / min; Co-solvent %: 40%; Column: I-Cellulose B (250 x 4.6), 5 μm. Method H: Mobile phase A: CO2; Co-solvent - 0.5% isopropylamine / IPA; Flow rate: 5.0 mL / min; Co-solvent %: 50%; Column: I-Cellulose B (250 × 4.6), 5 μm. Method I: Mobile phase A: CO2; Co-solvent - 0.5% isopropylamine / MeOH; Flow rate: 4.0 mL / min; Co-solvent %: 40%; Column: I-Cellulose B (250 × 4.6), 5 μm. Method J: Mobile phase A: CO2; Co-solvent - 0.5% isopropylamine / MeOH; Flow rate: 4.0 mL / min; Co-solvent %: 40%, Column: Whelk-01_(R,R) (250 × 4.6), 5 μm. Method K: Mobile phase A: CO2; Co-solvent - 0.1% NH3 / IPA:MeOH (50:50); Flow rate: 4.0 mL / min; Co-solvent %: 20%, Column: Reflect I-Amylose A (250 x 4.6), 5 μm. Method L: Mobile phase A: CO2; Co-solvent-0.5% isopropylamine / IPA; Flow rate: 4.0 mL / min; Co-solvent %: 40%, Column: YMC Amylose-SA (250 × 4.6), 5 μm. Method M: Mobile phase A: CO2; Co-solvent-0.5% isopropylamine / MeOH; Flow rate: 5.0 mL / min; Co-solvent %: 50%, Column: Chiralpak AS-H, (250 x 4.6), 5 μm. Method K: Mobile phase A: CO2; Co-solvent-0.5% isopropylamine / IPA; Flow rate: 5.0 mL / min; Co-solvent %: 35%, Column: Lux-A3, (250 x 4.6), 5 μm. Method L: Mobile phase A: CO2; Co-solvent - 0.5% isopropylamine / MeOH; Flow rate: 5.0 mL / min; Co-solvent %: 30%; Column: I-Cellulose B (250 × 4.6), 5 μm.

[0452] Preparative SFC Equipment name SFC preparative-PIC-175 Method A: Mobile phase: CO2:0.5% isopropylamine / IPA:ACN (70:30); Flow rate: 100 mL / min; Column: Lux Amylose-1 (250*30) mm, 5 μm. Method B: Mobile phase: CO2:0.5% isopropylamine / IPA (65:35); Flow rate: 100 mL / min; Column: YMC Amylose-SA (250*30) mm, 5 μm. Method C: Mobile phase: CO2:0.5% isopropylamine / IPA:ACN (1:1) [65:35]; Flow rate: 100 mL / min; Column: Lux Amylose-3 (250*30) mm, 5 μm.

[0453] 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 [ka] Step 1. 5-(2-Bromo-4-fluorophenoxy)pyrimidine [ka] In a 1000 mL three-necked round-bottom flask under a dry 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 25°C under a nitrogen atmosphere. The reaction mixture was stirred at 120°C for 64 hours under a nitrogen atmosphere. The reaction progress was monitored by LCMS (Method B; 58% product, 20.7% bromopyridine, 14.5% phenolic compounds). After this time, the reaction was cooled to 25°C and back-quenched with water (1000 mL). The aqueous layer was then extracted with MTBE (3 x 300 mL). The combined organic layers were washed with 2N 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 under reduced pressure on a rotary evaporator (bath temperature 45 °C) to give the crude compound as a yellow oil (51.4 g). The crude compound was purified by Isolera column chromatography using 100-200 silica and eluting with ethyl acetate / hexane (the desired product eluted with 20% ethyl acetate / hexane) to give 5-(2-bromo-4-fluorophenoxy)pyrimidine (38 g, 117 mmol, 44.8% yield) as a pale yellow oil: Rf = 0.52 (20% EtOAc / petroleum ether; 1 H NMR (400 MHz, DMSO-d6): δ 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) + .

[0454] Step 2. Methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate [ka] To a nitrogen-purged 250 mL small chamber containing 5-(2-bromo-4-fluorophenoxy)pyrimidine (9 g, 33.4 mmol) and methanol (125 mL) was added triethylamine (23.34 mL, 167 mmol), followed by 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) dichloromethane complex (2.447 g, 3.34 mmol). The reaction was stirred at 80 °C under 100 psi of carbon monoxide gas (WARNING: toxic gas) for 48 h. The reaction was monitored by TLC (30% EtOAc / hexanes; 36 h, LCMS Method B showed 34% product, 30% SM). Upon completion of the reaction, the reaction mixture was cooled to 25 °C and filtered through a Celite® pad to remove the palladium catalyst. The Celite® pad was washed with methanol (2 × 50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure on a rotary evaporator (bath temperature 45°C) to give the crude product (12 g, brown liquid). The crude product was purified by column chromatography (Isolera) using ethyl acetate and hexane as the elution solvent system (product eluted with 20% ethyl acetate / hexane) to give pure methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate (3.6 g, 41.5% yield) as a colorless liquid: 1 H NMR (400 MHz, CDCl3):δ 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) + .

[0455] Step 3. 5-Fluoro-2-(pyrimidin-5-yloxy)benzoic acid [ka] In a 500 mL three-neck 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 °C for 20 h. Reaction progress was monitored by TLC (100% EtOAc). Upon complete consumption of the ester, the reaction mixture was concentrated under reduced pressure on a rotary evaporator (bath temperature 45 °C) and diluted with water (200 mL). The reaction mixture was extracted with ethyl acetate (3 × 100 mL). These organic extracts were discarded. The remaining aqueous layer was acidified by dropwise addition of 6 N HCl (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure on a rotary evaporator (bath temperature 45° C.) to give 5-fluoro-2-(pyrimidin-5-yloxy)benzoic acid (14.1 g, 91%) as an off-white solid: 1 -NMR (400 MHz, DMSO-d6):δ 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) + .

[0456] Step 4. N-Ethyl-5-fluoro-N-isopropyl-2-(pyrimidin-5-yloxy)benzamide [ka] In a 500 mL two-necked round-bottom flask under a dry 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 under a nitrogen atmosphere at 25°C. The reaction mixture was stirred at 25°C for 11 hours. 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, filtered, and the filtrate was concentrated on a rotary evaporator (bath temperature 40°C) to give the crude compound. The crude compound was purified by column chromatography (Isolera) using 100-200 silica gel and eluting with ethyl acetate / hexanes (the desired product eluted with 55-60% EtOAc / hexanes). Fractions containing the desired product were concentrated under reduced pressure to give N-ethyl-5-fluoro-N-isopropyl-2-(pyrimidin-5-yloxy)benzamide (16.1 g, 86.0% yield) as an oil: 1 H NMR (400 MHz, DMSO-d6):δ 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) + .

[0457] Step 5. 5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine 1-oxide [ka] In a dry 250 mL three-neck round-bottom flask, N-ethyl-5-fluoro-N-isopropyl-2-(pyrimidin-5-yloxy)benzamide (16 g, 52.7 mmol) in tetrahydrofuran (160 mL) was added. The resulting mixture was cooled to 0 °C, and hydrogen peroxide urea (1 / 1; 9.92 g, 105 mmol) was added, followed by the dropwise addition of TFAA (15.17 mL, 108 mmol) while maintaining the reaction temperature below 10 °C. The reaction mixture was then stirred at 0-10 °C 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) while maintaining the temperature below 10 °C. The product was extracted with DCM (2 × 150 mL), and the organic layer was washed with 5% NaHCO3 (2 × 60 mL). To the organic layer was added 1M NaSO solution (70 mL), and the mixture was stirred for 15 minutes. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure on a rotary evaporator (bath temperature 30 °C) until approximately 1 volume remained in the flask. Ethyl acetate (2 × 60 mL) was added to the 1 volume of solution remaining in the flask, and the solution was concentrated again on a rotary evaporator until 1 volume remained in the flask (Note: Do not allow the material to dry completely). Hexane (250 mL) was added to the flask containing the concentrate. The resulting precipitate was stirred at 25 °C for 30 minutes. The solid was collected by filtration and dried under suction to give 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). + .

[0458] Step 6. 2-((4-chloropyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide [ka] In a 500 mL three-necked round-bottom flask under a dry 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 0° C. The reaction mixture was stirred at 0° C. for 10 minutes, and then phosphoryl trichloride (5.62 mL, 60.1 mmol) was added dropwise at 0° C. After the addition was complete, the reaction mixture was stirred at 0° C. for 30 minutes, slowly warmed to 25° C., and stirred for 2 hours. 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 (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure on a rotary evaporator (bath temperature 45 °C) to give the crude compound. The crude compound was purified by column chromatography (Isolera) using 100-200 mesh silica gel and eluting with ethyl acetate / hexanes (the desired product eluted with 25% ethyl acetate / hexanes). Fractions containing the required product were concentrated under reduced pressure to give 2-((4-chloropyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (5.82 g, 30.0% yield) as a brown, viscous liquid: LCMS (Method B): Rt = 1.96 min, 338.0 (M+H). + .

[0459] Step 7. tert-Butyl 2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate [ka] In a dry 250 mL three-neck 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 under a nitrogen atmosphere at 25 °C, and the resulting reaction was heated at 80 °C for 18 h. The reaction progress was monitored by TLC (100% EtOAc). Upon complete consumption of the amine, the solvent was evaporated, and the residue was quenched with ice-water (20 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over Na SO , and filtered. The filtrate was concentrated under reduced pressure on a rotary evaporator (bath temperature 45 °C) to give the crude product. The crude product was purified by column chromatography (Isolera) using 100-200 mesh silica gel and eluting with ethyl acetate / hexanes (the desired product eluted with 30-70% ethyl acetate / hexanes). Fractions containing the desired product were concentrated under reduced pressure to give tert-butyl 2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (6.1 g, 61.5% yield) as a semi-solid: 1 H NMR (400 MHz, CDCl3):δ 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) + .

[0460] Step 8. 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide hydrochloride [ka] In a 250 mL three-necked round-bottom flask under a dry nitrogen atmosphere, 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) was placed in 2,2,2-trifluoroethanol (40 mL). To this solution, TMS-Cl (6.59 mL, 51.6 mmol) was added dropwise at 0° C., and the reaction mixture was then stirred at 25° C. for 2 h. The reaction progress was monitored by TLC (10% MeOH / DCM). After 2 h, the solvent was removed under reduced pressure on a rotary evaporator, and the residue was co-distilled with ethyl acetate (2×20 mL). The residue was triturated with hexane to give 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) + .

[0461] 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 bistosylate salt [ka] Step 1. 5-(2-Bromo-4-fluorophenoxy)pyrimidine [ka] Step 1 was carried out in three batches: an 8.00 kg batch (4.00 kg and 4.00 kg in one reactor, split into two reactors for workup) and a 3.00 kg batch.

[0462] A 100 L cylindrical reactor was charged with 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.). The batch was heated to 119°C over 9 hours and maintained at that temperature for 82 hours. The batch was then cooled to 34°C, and an IPC sample was taken, which indicated 82.2% conversion from phenol by NMR. The internal temperature of the batch was adjusted to 25°C, and the batch was split into two 100 L reactors. MTBE (10.6 L, 2.66 vol.) and deionized water (48 L, 12 vol.) were added to each batch and stirred for 15 minutes. The resulting aqueous phase was extracted five times with MTBE (5 × 10.6 L, 5 × 2.66 volumes each). The MTBE extracts were combined and washed sequentially with 2 N sodium hydroxide (8 L, 2 volumes, 50% NaOH), 0.5 M citric acid (4 L, 1 volume, solids), and finally with 5 wt % sodium bicarbonate (4 L, 1 volume). The MTBE solutions were combined and concentrated by rotary evaporation (bath temperature 55 °C). The residue from the combined batches was then stored in a carboy until thin-film distillation 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).

[0463] A 4-inch Pope thin-film distillation apparatus (WFE) was used to purify 8.17 kg of crude 5-(2-bromo-4-fluorophenoxy)pyrimidine in multiple passes. The conditions for the first pass of the WFE distillation were as follows: vacuum 10-12 Torr (empty), wiper speed 328-333 rpm, jacket temperature 160°C, condenser temperature 85°C, and addition rate approximately 4 mL / min. The conditions for the second pass of the WFE distillation were as follows: vacuum 0.8 Torr (empty), wiper speed 320-330 rpm, jacket temperature 150°C, condenser temperature 50°C, and addition rate approximately 10 mL / min. The third pass was completed by repassing the pot fraction containing the majority of the product. The conditions for the third pass of the WFE distillation were as follows: vacuum 0.8 Torr (empty), wiper speed 320-330 rpm, jacket temperature 130 °C, condenser temperature 50 °C, and addition rate approximately 15 mL / min. After the third pass, the product spontaneously crystallized upon cooling. All material was collected and placed in several jars along with pure material (6.58 kg, 43% total yield, 95.9% AUC, 91.2% wt % 1H qNMR).

[0464] Steps 2 and 3. 5-Fluoro-2-(pyrimidin-5-yloxy)benzoic acid [ka] A 22-gal jacketed stainless steel pressure vessel was charged with [1,1'-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) dichloromethane adduct (Pd(dppf)Cl DCM complex, 0.989 kg, 1.21 mol, 0.05 equiv.), 5-(2-bromo-4-fluorophenoxy)pyrimidine (6.52 kg, 24.2 mol, 1.00 equiv.), triethylamine (4.93 kg, 48.4 mol, 2.00 equiv.), and methanol (32.6 L, 5 vol.). The reactor was purged with nitrogen (up to 60 psig nitrogen pressure three times) and then with carbon monoxide gas (up to 50 psig carbon monoxide three times). The internal temperature of the reactor was adjusted to 70 ± 5 °C over 1 hour, and the internal pressure was adjusted to 40 ± 5 psig with carbon monoxide gas. The batch was stirred at 70±5°C for 13 hours, cooled to 25°C, and purged three times with nitrogen at 50 psig pressure. The batch was filtered through a Celite® pad to remove the palladium catalyst and rinsed with MeOH (6.5 L, 1 volume). The solution containing methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate was transferred to a 100 L jacketed glass reactor and diluted with water (13 L, 2 volumes). 50 wt% aqueous sodium hydroxide (7.8 kg, 96.9 moles, 4 equivalents) was added while maintaining the internal batch temperature below 45°C (maximum temperature 42.4°C). The batch was stirred for 14 hours and then concentrated under reduced pressure (28.5 Hg, 42°C) to 4 volumes (24 L). The batch was diluted with water (34 L, 7 volumes), cooled to 25°C, 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 twice with MTBE (13 L, 2 vol), for 30 minutes each time. The batch was acidified to a pH of approximately 2 using 6 M hydrochloric acid (approximately 13 L, 2.3 vol; concentrated HCl), maintaining an internal batch temperature of 20°C. Once acid addition was complete, the batch was stirred for 20 hours and then filtered through polypropylene cloth using a filter / dryer. The filter cake was washed three times with water (3 x 13 L, 3 x 2 vol) and dried under a nitrogen stream at 40-45°C for 5 days until the moisture content was 0.3 wt% by KF analysis. The product was isolated in 98% yield (5.58 kg, 98.8% AUC).

[0465] Step 4. N-Ethyl-5-fluoro-N-isopropyl-2-(pyrimidin-5-yloxy)benzamide [ka] Step 4 was carried out following the same procedure on two batches: a 2.80 kg batch and a 5.00 kg batch.

[0466] A 100 L cylindrical, glass-jacketed reactor was inerted with N2 flow-through and connected to a 2N 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 was initiated, forming a light beige suspension, and the batch was cooled to below 10°C. 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 being added at a rate slightly faster than the triethylamine. The temperature was adjusted to 15 °C and held for 80 minutes. Sampling of the batch for IPC indicated 94.6% conversion to the acid chloride (an aliquot of the reaction mixture was quenched with benzylamine prior to analysis). After holding at 15 °C for 1 hour, the batch was cooled to <5 °C, 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 hours, maintaining the batch temperature below 10 °C. After warming to 15 °C over 1 hour, the reaction was held at 15–20 °C for 12 hours, 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 volumes, concentrated HCl) and 2 N NaOH (20.0 L, 4 volumes, 50% NaOH), stirring for 20 minutes each and allowing the layers to separate for 10 minutes. The batch was then concentrated to near dryness by rotary evaporation to 1.6 volumes (8 L), and MTBE (6 L, 1.2 volumes) was added in portions. The batch was then again rotary evaporated to near dryness (6.25 L), at which point it began to crystallize, indicating a low concentration of DCM. Using 3 L of MTBE as a rinse, the batch was returned to the reactor and cooled to 0°C.Once at 0°C, heptane (9.3 L, 1.9 vol, containing 0.005% Statsafe 6000) was slowly charged over 1 hour to achieve an approximately 1:1 MTBE / heptane ratio. The batch was initially oily but after 1 hour at 20°C became a thick slurry with a thin shell along the reactor walls. While cooling to 0-5°C, the remaining heptane (60 L) was slowly added over 70 minutes, and the shell was physically scraped off the reactor walls. The batch was stirred at 0°C for 13 hours and then filtered through a Nutsche filter equipped with polypropylene cloth. The reactor was rinsed once with heptane (5 L, 1 vol), and the rinse was applied to the filter cake. The isolated solid was dried in a vacuum oven at 30-40 °C for 5 days to give N-ethyl-5-fluoro-N-isopropyl-2-(pyrimidin-5-yloxy)benzamide as a brown solid (5.60 kg, 87% yield, 96.4% AUC, 89.0 wt%).

[0467] Step 5. 5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine 1-oxide [ka] Step 5 was carried out following the same procedure for 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 5 °C over 15 minutes. 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 hours, maintaining the batch temperature below 10 °C. The reactor was then purged with N for 30 minutes to ensure the atmosphere was free of any O that may have been generated. This was followed by the 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 17 h of stirring, conversion was 92.0% by HPLC. To further increase the conversion, 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 1 h of stirring, conversion reached 96.7% by HPLC. The reaction was quenched with 1 M sodium sulfite solution (12.4 L, 2.6 vol, 0.8 equiv) and stirred for 30 min, followed by the addition of 5% NaHCO3 (23.2 L, 5.0 vol, solid NaHCO3) over 30 min, maintaining the temperature below 20 °C. The mixture was stirred for 2 h, as bubbles remained, indicating ongoing neutralization. The layers were separated, and the organic phase tested negative for peroxides using KI-starch test paper. The batch was washed twice for 15 minutes with 5% NaHCO3 (32.9 L, 5 vol). The organic phase was split into two glass carboys, and 4 Å 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 hours, the moisture 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 washes were charged to the reactor.The batch (88.5% AUC, 7.6 wt % by qNMR, equivalent to 3.58 kg, 73% yield) was held at 0° C. for 18 hours before carrying out step 6.

[0468] Step 6. 2-((4-chloropyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide [ka] Step 6 was carried out following the same procedure on two batches: a 2.86 kg batch and a 3.58 kg batch.

[0469] A 100 L cylindrical jacketed reactor was charged with a solution of 5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine 1-oxide in DCM (total volume approximately 36 L). The amount of 5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine 1-oxide in DCM solution was determined to be 3.58 kg (11.2 mol, 1 equiv.) by 1H qNMR gravimetric assay. The batch temperature was adjusted to 4 °C to 11 °C, and triethylamine (2.34 L, 16.8 mol, 1.5 equiv.) was added while maintaining the batch temperature below 15 °C. Oxalyl chloride (1.23 L, 14.6 mol, 1.3 equiv.) was charged in portions over 3 h to control the vigorous gas evolution. The batch was warmed to 30°C over 1 hour and held at 30-35°C for 1 hour. 2.6% 5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine 1-oxide remained, so additional triethylamine (90 mL, 0.65 mol, 0.06 equiv.) and oxalyl chloride (71 g, 0.56 mol, 0.05) were charged, and the batch was stirred for an additional 15 hours. 1N HCl (17.9 L, 5 vol, concentrated HCl) was charged over 30 minutes while maintaining the batch temperature below 20°C, followed by stirring for 2 hours while sparging with N2 gas at 10 psi through the bottom outlet valve (BOV). The opaque, dark brown phase was separated, and the organic phase was held overnight before being washed with 5% NaHCO3 solution (17.9 L, 5 vol.). The batch was again sparged with N2 gas through the BOV for 30 minutes. Both phases again became dark brown and opaque. The phases were separated, and the organic phase was stripped to dryness by rotary evaporation (bath temperature 35° C.) to give 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 purity, 78% adjusted yield, 81.8% AUC, 60.1% titer by H NMR), which was stored in IPAc (19.6 L, 6.6 volumes relative to 2-((4-chloropyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide) at 0° C. until use.

[0470] Step 7. tert-Butyl 2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate [ka] Step 7 was performed following the same procedure on two batches: a 2.06 kg batch and a 2.96 kg batch.

[0471] Crude 2-((4-chloropyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (adjusted charge based on gravimetric titer, 2.96 kg, 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 75-80 °C over 3 h and stirred at that temperature for 8 h. HPLC analysis of the reaction indicated 95.0% conversion, so an additional 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. After 3 hours of heating, 96.5% conversion was achieved and the batch was cooled to 50°C. A 0.5 M citric acid solution (14.8 L, 5 vol) was charged over 10 minutes, maintaining the temperature below 40°C, and stirred at 40°C for 20 minutes. An opaque, dark brown phase separated, and 0.5 M citric acid solution (14.8 L, 5 vol) was charged, stirred for 20 minutes, and the phases were separated. The batch was cooled and held at 20°C overnight, after which 5 wt% NaHCO3 (29.6 L, 5 vol) was charged over 45 minutes, maintaining the batch temperature between 35 and 40°C. After stirring for 20 minutes, the phases were separated. The organic phase was rotary evaporated to 4 volumes (approximately 20 L) over 1 hour. The batch spontaneously solidified in the rotary evaporator valve and was transferred to the reactor. The brown suspension was then cooled to 20°C and n-heptane (35.5 L, 12 volumes) was charged over 1 hour. The light brown suspension was stirred at approximately 20°C for 13 hours, cooled to 5°C over 1 hour, held at 5°C for 2 hours, and then filtered. The filtrate was analyzed by HPLC to confirm that no further precipitation had occurred after an additional hour, and the batch was then filtered through a Nutsche funnel equipped with polypropylene cloth over 2 hours. n-heptane (5.9 L, 2 volumes) was then used to wash the reactor, and the wash was passed through the wet cake over 20 minutes.The wet cake was conditioned for 42 hours and then dried under high vacuum at 40-45 °C to give 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 brown solid (3.99 kg, 92.2% AUC, 88.2 wt% by H qNMR, 76% yield adjusted for product titer).

[0472] 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±5°C and held for 1 hour. After cooling to 5°C (target 0°C) for 4.5 hours, the batch was held for 16 hours and then filtered using a Nutche filter with polypropylene cloth. Two portions of MTBE (2 × 14 L, 2 × 2 vol) were used to rinse the reactor, cool to 5 °C, and wash through the wet cake. The light brown solid was dried under high vacuum at 40 °C to give 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).

[0473] Step 8. 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide bistosylate salt [ka] 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, and p-toluenesulfonic acid monohydrate (pTSA, 3.90 kg, 19.9 mol, 3.0 equiv.) was then dissolved in THF (18 L, 5 vol.) and purified water (540 mL, 0.15 vol.), and the solution was heated to 55±5° C. 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 hours, maintaining the batch at 55±5°C. After 16 hours, the batch was cooled to 20±5°C over 1.5 hours and held for 2 hours before filtering. The wet cake was washed three times with THF (3×18 L, 3×5 vol). Filtration and washing were completed in 1.75 hours, and the wet cake was then conditioned under vacuum for 17.5 hours before drying at 45±5°C under reduced pressure. 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide bistosylate salt was isolated in 94% yield (4.80 kg).

[0474] Intermediate 2. ((2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate [ka] In a dry 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 CHCl (20 mL), and the solution was cooled to 0 °C 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 0 °C. The reaction mixture was then warmed to 25 °C over 30 min and stirred at 25 °C 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 × 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, filtered, and the filtrate was concentrated on a rotary evaporator (bath temperature 40 °C) to give the crude product (810 mg). The crude product was purified by column chromatography (SepaBean) using 100-200 silica gel and eluting with ethyl acetate / hexanes (the desired product eluted with 40% ethyl acetate / hexanes). Fractions containing the required product were concentrated under reduced pressure to give ((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):δ 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, 2H). LCMS (Method B): Rt = 2.92 min, 330.2 (M-56).

[0475] Intermediate 3: 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride [ka] Step 1. 5-Fluoro-N,N-diisopropyl-2-(pyrimidin-5-yloxy)benzamide [ka] In a 500 mL two-necked, dry round-bottom flask under a 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 under a nitrogen atmosphere at 25°C, and the reaction was stirred at 25°C for 20 hours. The reaction progress was monitored by TLC (50% EtOAc / 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 layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated on a rotary evaporator (bath temperature 40°C) to give the crude product. The crude product was purified by column chromatography (Isolera) using 100-200 mesh silica gel and eluting with ethyl acetate / hexanes (the desired product was eluted with 25% EtOAc / hexanes). Fractions containing the desired product were concentrated under reduced pressure to give 5-fluoro-N,N-diisopropyl-2-(pyrimidin-5-yloxy)benzamide (7.2 g, 48.9% yield) as an off-white solid: 1 H NMR (400 MHz, DMSO-d6):δ 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) + .

[0476] Step 2. 5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine 1-oxide [ka] In a 250 mL three-necked round-bottom flask under a dry 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 0 °C, and hydrogen peroxide urea (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 10 °C. The reaction was stirred at 0 °C–10 °C for 1 h, and reaction progress was monitored by TLC (100% EtOAc). Upon complete consumption of the starting material, the reaction was quenched by the addition of 5% NaHCO (50 mL) while maintaining the temperature below 10 °C. The reaction mixture was extracted with DCM (2 × 100 mL), and the combined organic layers were washed sequentially with 5% NaHCO (2 × 50 mL) and 1 M NaSO solution (60 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced to 1 volume in the RBF using a rotary evaporator (bath temperature 30 °C). This was co-evaporated with ethyl acetate (2 × 60 mL), and the organic layer was again reduced to 1 volume in the RBF (Note: Do not evaporate to dryness). Hexane (250 mL) was slowly added to the remaining reaction volume in the evaporation flask. The resulting precipitate was stirred at 25 °C for 30 minutes, filtered, and dried by suction to give 5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine 1-oxide (6 g, 77.64% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6):δ 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) + .

[0477] Step 3. 2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide [ka] In a 250 mL three-necked round-bottom flask under a 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 −5° C. and then stirred for 10 minutes. POCl (1.678 mL, 18.00 mmol) was then added dropwise at −5° C. The reaction mixture was stirred at 0° C. for 30 minutes, then slowly warmed to 25° C. and stirred for 1 hour. The reaction progress was monitored by TLC (30% EtOAc / hexane). After completion of the reaction, the reaction mixture was quenched with cold water (20 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure on a rotary evaporator (bath temperature 45° C.) to give the crude product. The crude product was purified by column chromatography (Isolera) using 100-200 mesh silica gel and eluting with ethyl acetate / hexanes (the desired product eluted with 22% ethyl acetate / hexanes). Fractions containing the required product were concentrated under reduced pressure to give 2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (2.4 g, 39.0% yield) as a yellow solid: 1 H NMR (400 MHz, DMSO-d6):δ 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) + .

[0478] Step 4. tert-Butyl 2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate [ka] In a 100 mL three-necked, dry round-bottom flask under a 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 25 °C under a nitrogen atmosphere. The resulting reaction was heated at 80 °C for 13 h, and the reaction progress was monitored by TLC (100% EtOAc). After 13 h, the solvent was evaporated, and the residue was dissolved in ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure on a rotary evaporator (bath temperature 45 °C) to give the crude product. The crude product was purified by column chromatography (Isolera) using 100-200 silica gel and eluting with ethyl acetate / hexanes (the desired product eluted with 67-70% ethyl acetate / hexanes). Fractions containing the required product were concentrated under reduced pressure to give 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):δ 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) + .

[0479] Step 5. 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide hydrochloride [ka] In a 100 mL three-necked, dry round-bottom flask under nitrogen, 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-trifluoroethanol (27 mL). To this solution, TMS-Cl (2.230 mL, 17.45 mmol) was added dropwise at 10 °C, and the reaction mixture was stirred at 25 °C for 1 h. The reaction progress was monitored by TLC (10% MeOH / DCM). After 1 h, the solvent was removed under reduced pressure on a rotary evaporator, and the residue was co-evaporated with ethyl acetate (2 × 20 mL). The resulting residue was triturated with hexane and dried under vacuum to give 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):δ 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) + .

[0480] 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 [ka] 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 [ka] In a 250 mL two-necked round-bottom flask under a dry nitrogen atmosphere, 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide bistosylate salt (1.3 g, 1.68 mmol) was dissolved in N-methyl-2-pyrrolidinone (5 mL). To this solution, KCO (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 under a nitrogen atmosphere at 25 °C. The resulting reaction was heated at 70°C for 17 hours, and the reaction progress was monitored by TLC (5% MeOH / DCM). After completion of the reaction, the reaction mixture was cooled to 25°C and quenched with water (100 mL). The aqueous layer was extracted with ethyl acetate (2 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated on a rotary evaporator (bath temperature 40°C) to give 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 / DCM (the desired product eluted with 4-5% methanol / DCM). The fractions containing the desired product were concentrated under reduced pressure to give 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):δ 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) + .

[0481] 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 [ka] In a 100 mL three-necked round-bottom flask under a dry nitrogen atmosphere, 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) was added. The resulting mixture was cooled to 10 °C, and chlorotrimethylsilane (153 mg, 1.40 mmol) was added. The reaction mixture was then stirred at 26 °C for 2.5 h, and the reaction progress was monitored by TLC (10% methanol / DCM). Upon complete consumption of the starting material, the reaction was concentrated on a rotary evaporator (bath temperature 40 °C) to give 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 resulting solid was dried under vacuum to give 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). + .

[0482] 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 [ka] 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 [ka] In a 100 mL two-necked round-bottom flask under a dry 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, KCO (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 under a nitrogen atmosphere at 25 °C. The resulting reaction was heated at 70°C for 12 hours, and the reaction progress was monitored by TLC (10% MeOH / DCM). After completion of the 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 layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated on a rotary evaporator (bath temperature 40°C) to give the crude product. The crude compound was purified by column chromatography (Isolera) using 100-200 silica and eluting with methanol / DCM (the desired product eluted with 8-9% methanol / DCM). Fractions containing the required product were concentrated under reduced pressure to give 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, 73.6% yield) as a light brown syrup: LCMS (Method A): Rt = 2.08 min, 655.8 (M+H) + .

[0483] 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 [ka] In a 100 mL three-necked round-bottom flask under a dry 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 10 °C, and TMS-Cl (2.391 mL, 18.71 mmol) was added to it. The reaction was stirred at 25 °C for 1 h, and the reaction progress was monitored by TLC (10% methanol / DCM). After 1 h, the reaction mixture was concentrated on a rotary evaporator (bath temperature 40 °C) to give the crude compound. The crude compound was stirred with ethyl acetate (50 mL). The resulting solid was filtered, washed with ethyl acetate (5 mL) and dried under vacuum to give 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 pale pink solid: LCMS (Method A): Rt = 1.76 min, 555.2 (M+H) + .

[0484] Intermediate 6. tert-Butyl 2-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate [ka] Step 1. 5-(2-Bromo-4-fluorophenoxy)pyrimidine [ka] To a mixture of 2-bromo-4-fluorophenol (350 g, 1.83 mol, 1.00 equiv.) in DMA (2.10 L) was added CsCO (776 g, 2.38 mol, 1.30 equiv.) and 5-bromopyrimidine (335 g, 2.11 mol, 1.15 equiv.) under a nitrogen atmosphere at 25 °C. The mixture was stirred at 140 °C under nitrogen for 64 h. LCMS-IPC analysis indicated that most of the starting material had been consumed. The reaction mixture was cooled to 20–25 °C. The reactions (1 × 300 g and 8 × 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 × 3). The combined organic layers were washed with sodium hydroxide solution (15.4 L, 2N), citric acid solution (15.4 L, 0.50 M), and sodium bicarbonate solution (15.4 L, 5%), dried over anhydrous Na2SO4, and concentrated under reduced pressure. 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, yield 29.5%, purity 64.5%) as a yellow oil, and crude 5-(2-bromo-4-fluorophenoxy)pyrimidine (1.10 kg): 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (d, 1H, J = 2.4 Hz), 8.55 (s, 2H), 7.80-7.77 (m, 1H), 7.44-7.36(m, 2H).

[0485] Step 2. Methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate [ka] To a solution of 5-(2-bromo-4-fluorophenoxy)pyrimidine (100, 372 mmol, 1.00 equiv.) in MeOH (700 mL) was added TEA (188 g, 1.86 mol, 259 mL, 5.00 equiv.) and Pd(dppf)Cl.CHCl (9.11 g, 11.2 mmol, 0.03 equiv.) under N. The suspension was degassed under vacuum and purged with CO three times. The mixture was stirred at 80 °C under CO (40 psi) for 48 h. LCMS-IPC analysis indicated complete consumption of the starting material. The reaction mixture was cooled to 20–25 °C. The 15 reactions (15 × 100 g) were combined and filtered through 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 / 1-8 / 1, TLC (petroleum ether / ethyl acetate=3 / 1, Rf (product)=0.3)) to give a pale yellow solid of methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate (427 g, 1.54 mol, 43.0% yield, 89.7% purity) and crude methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate (500 g, 37.3% yield, 66.5% purity): 1 H NMR (400 MHz CDCl3) δ 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).

[0486] Step 3. 5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidine 1-oxide [ka] To a solution of methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate (190 g, 765 mmol, 1.00 equiv.) in THF (1.90 L) was added UHP (144 g, 1.53 mol, 2.00 equiv.) and TFAA (322 g, 1.53 mol, 213 mL, 2.00 equiv.) under N at 0–10 °C. The mixture was stirred at 0–10 °C for 1 h. LCMS-IPC analysis indicated complete consumption of the starting material. The reaction was quenched by adding 5% NaHCO (950 mL) while maintaining the temperature below 10 °C. The two reactions (2 × 190 g) were combined. The product was extracted with DCM (2 × 1.90 L). The organic layer was washed with 5% NaHCO (2 × 1.90 L). The organic layer was treated with 5% NaHCO (2.30 L) and 1 M NaSO solution (1.90 L) and stirred at 20 °C for 15 min. The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure at 45 °C to give a residue. The three reactions (1 × 200 g and 2 × 190 g) were combined. The crude product was triturated with n-heptane (8.0 L) and stirred at 25 °C for 30 min. The mixture was filtered, and 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: 1 H NMR (400 MHz DMSO-d6) δ 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).

[0487] Step 4. Methyl 2-((4-chloropyrimidin-5-yl)oxy)-5-fluorobenzoate [ka] To a solution of 5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidine 1-oxide (268 g, 1.01 mol, 1.00 equiv) in EtOAc (2.70 L) was added DIPEA (655 g, 5.07 mol, 883 mL, 5.00 equiv) under N at −5°C. POCl (187 g, 1.22 mol, 113 mL, 1.2 equiv) was added to the reaction mixture at 0°C under N. The reaction mixture was stirred at 20–25°C under N for 1.5 h. LCMS-IPC analysis showed complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure at 45°C to give the crude product (834 g). The reactions (54.0 g crude product from 2 × 9.5 g; 300 g crude product from 1 × 100 g; 12.0 g crude product from 1 × 4.00 g; 1.30 kg crude product from 2 × 224 g; 834 g crude product from 1 × 268 g) were combined and purified together. The crude product (2.5 kg) was purified by passing through a silica pad, and the silica pad was eluted with a premixed solution (petroleum ether / ethyl acetate = 2 / 1) to give the product as a yellow solid (575 g). The crude product (575 g) was triturated with n-heptane / ethyl acetate (2 / 1, 3V) and stirred at 25 °C for 12 hours to give a yellow suspension. The mixture was filtered, and 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: 1 H NMR (400 MHz CDCl3) δ 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).

[0488] Step 5. tert-Butyl 2-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate [ka] To a mixture of methyl 2-((4-chloropyrimidin-5-yl)oxy)-5-fluorobenzoate (80.0 g, 283 mmol, 1.00 equiv.) in IPA (800 mL) was added TEA (85.9 g, 849 mmol, 118 mL, 3.00 equiv.) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (89.2 g, 340 mmol, 1.20 equiv., HCl) at 25° C. under a nitrogen atmosphere. The mixture was stirred at 80° C. under nitrogen for 3 h. HPLC-IPC and LCMS-IPC showed complete consumption of the starting material. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure at 50° C. The reactions were combined (10.0 g crude product from 1 × 5.00 g; 80.0 g crude product from 2 × 20.0 g; 2 × 80.0 g crude product). The crude product (410 g) was triturated with n-heptane (600 mL) and stirred at 25 °C for 12 hours. The mixture was filtered, the filter cake was washed with n-heptane (60.0 mL), and dried under vacuum to give crude product (330 g). The crude product (330 g) was triturated with water (3.30 L) and stirred at 25 °C for 12 hours to remove residual TEA.HCl. The mixture was filtered, the filter cake was washed with water (300 mL), and dried under vacuum to give crude product (300 g). The crude product (300 g) was dissolved in dichloromethane (300 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure 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: 1 H NMR (400 MHz DMSO-d6) δ 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).

[0489] 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 [ka] Step 1. Lithium 2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate [ka] In a 250 mL three-neck reaction flask, 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) was added 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 25 °C, and the reaction mixture was stirred at 25 °C for 18 h. The reaction progress was monitored by TLC (20% MeOH / DCM). Upon complete consumption of the ester, the reaction was concentrated to dryness on a rotary evaporator. The residue was azeotroped with toluene (3×25 mL) to remove traces of water and dried under vacuum to give 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):δ 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) + .

[0490] 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 [ka] In a 50 mL three-neck reaction flask under a nitrogen atmosphere, 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) was added. To the resulting solution, HATU (3.07 g, 8.07 mmol) and DIPEA (3.13 g, 24.22 mmol) were added. Then, (3S,5R)-3,5-dimethylmorpholine hydrochloride (1.224 g, 8.07 mmol) was added under a nitrogen atmosphere at 25 °C, and the reaction mixture was stirred at 25 °C for 18 h. The reaction progress was monitored by TLC (5% MeOH / DCM). After 18 h, the reaction was quenched with water (200 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with water (3 × 100 mL), brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure on a rotary evaporator to give 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 sticky solid: LCMS (Method B): Rt = 1.48 min, 556.2 (M+H). + .

[0491] 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 [ka] In a 50 mL three-necked round-bottom flask under a 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 was added 4 M HCl in dioxane (7.83 mL, 31.3 mmol) at 25° C. The reaction mixture was then stirred at 25° C. for 2 hours, and the reaction progress was monitored by TLC (10% MeOH / DCM). After 2 hours, the reaction was concentrated to dryness on a rotary evaporator to give a crude residue. The crude residue was triturated with ethyl acetate. The supernatant layer was decanted and the remaining solid was dried under vacuum to give (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) + .

[0492] 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 [ka] In a 50 mL three-necked round-bottom flask under a dry 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), KCO (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 25 °C. The reaction mixture was then stirred at 75°C for 18 hours, and the reaction progress was monitored by TLC (10% MeOH / DCM). After 18 hours, the reaction was quenched with water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with water (3 x 100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure on a rotary evaporator to give the crude product. The crude product was purified by flash column chromatography (Isolera) eluting with methanol / DCM (the desired product eluted at 0-6%). Fractions containing the desired product were concentrated under reduced pressure to give 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 sticky solid: LCMS (Method B): Rt = 1.14 min, 669.4 (M+H) + .

[0493] 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 [ka] In a 50 mL three-necked round-bottom flask under a 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 10° C. The reaction was stirred at 25° C. for 2 hours, and the reaction progress was monitored by TLC (10% MeOH / DCM). After 2 hours, the reaction was concentrated to dryness under reduced pressure on a rotary evaporator to give the crude product. The crude residue was triturated with ethyl acetate. The supernatant layer was decanted and the remaining solid was dried under vacuum to give (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). + .

[0494] 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 [ka] 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 [ka] In a 100 mL three-necked round-bottom flask under a dry 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 was added (3R,5R)-3,5-dimethylmorpholine hydrochloride (1.959 g, 12.92 mmol) at 25 °C, and the reaction mixture was stirred at 25 °C for 18 h. The reaction progress was monitored by TLC (10% MeOH / DCM). After 18 h, the reaction was quenched with water (200 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with water (3 x 100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure on a rotary evaporator to give 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, 74.5% yield) as a yellow sticky solid: 1 H NMR (400 MHz, CDCl3) δ 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) + .

[0495] 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 [ka] In a 100 mL three-necked round-bottom flask under a dry 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 was slowly added hydrochloric acid (4 M in dioxane, 19.80 mL, 79 mmol) at 25 °C. The reaction mixture was then stirred at 25 °C for 1 h, and the reaction progress was monitored by TLC (10% MeOH / DCM). After 1 h, the reaction was concentrated to dryness on a rotary evaporator. The resulting sticky solid was triturated twice with ethyl acetate. The supernatant layer was decanted and the resulting solid was dried under reduced pressure to give (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 a yellow solid: LCMS (Method A): Rt = 1.17 min, 456.2 (M+H) +

[0496] 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 [ka] In a 50 mL three-necked round-bottom flask under nitrogen, (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), KCO (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 25 °C. The reaction mixture was then stirred at 75°C for 18 hours, and reaction progress was monitored by TLC (10% MeOH / DCM). After 18 hours, the reaction was quenched with water (250 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with water (3 x 150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure on a rotary evaporator to give the crude product. The crude product was purified by flash column chromatography (Isolera) using methanol / DCM (the desired product eluted with 0-6% MeOH / DCM). Fractions containing the required product were concentrated under reduced pressure to give 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 sticky solid: LCMS (Method B): Rt = 1.15 min, 669.4 (M+1) + .

[0497] 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 [ka] In a 25 mL three-neck 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 slowly added at 25° C., and the reaction mixture was stirred at 25° C. for 1 hour. The reaction progress was monitored by TLC (10% MeOH / DCM). After 1 hour, the reaction was concentrated to dryness under reduced pressure on a rotary evaporator to give a crude residue. The crude residue was triturated with ethyl acetate. The supernatant layer was decanted and the remaining solid was dried under vacuum to give (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) + .

[0498] 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 [ka] Step 1. Methyl 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate Hydrochloride [ka] In a 500 mL three-necked round-bottom flask under a dry nitrogen atmosphere, 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) was placed in 2,2,2-trifluoroethanol (200 mL). To this solution was added TMS-Cl (20.29 mL, 159 mmol) dropwise at 10° C. The reaction mixture was then stirred at 25° C. for 1 h, and the progress was monitored by TLC (10% MeOH / DCM). After 1 h, the solvent was removed under reduced pressure on a rotary evaporator, and the residue was co-distilled with ethyl acetate (2×100 mL). The resulting residue was triturated with hexane to give 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: 1 H NMR (400 MHz, DMSO-d6):δ 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) + .

[0499] 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 [ka] In a 250 mL two-necked round-bottom flask under a dry 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, KCO (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 under a nitrogen atmosphere at 25 °C. The resulting reaction was heated at 70 °C for 12 h, and the reaction progress was monitored by TLC (10% MeOH / DCM). After 12 hours, the reaction mixture was cooled to room temperature, quenched with water (200 mL), and extracted with ethyl acetate (2 × 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated on a rotary evaporator (bath temperature 40 °C) to give the crude product. The crude product was purified by column chromatography (Isolera) using 100-200 silica gel and eluting with methanol / DCM (the desired product eluted with 4% methanol / DCM). Fractions containing the desired product were concentrated under reduced pressure to give 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):δ 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) + .

[0500] 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 [ka] In a 500 mL three-necked round-bottom flask under a dry 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 (5 g, 8.54 mmol) was placed in 2,2,2-trifluoroethanol (50 mL). To this solution was added TMS-Cl (3.27 mL, 25.6 mmol) dropwise at 10° C. The reaction was then stirred at 25° C. for 1 h, and the progress was monitored by TLC (10% MeOH / DCM). After 1 h, the solvent was removed under reduced pressure on a rotary evaporator, and the residue was co-distilled with ethyl acetate (2×50 mL). The resulting residue was triturated with hexane and dried to give 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). + .

[0501] 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 [ka] In a 25 mL three-necked round-bottom flask under a dry 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 CHCl (50 mL) and cooled to 0 °C. To this solution was added TEA (12.16 mL, 86 mmol), and the reaction was stirred at 0 °C for 30 min. Ethanesulfonyl chloride (4.12 mL, 43.2 mmol) was then added slowly, and the reaction was stirred at 25 °C for 16 h, and the reaction progress was monitored by TLC (10% methanol / DCM). After 16 h, the reaction was quenched with water (10 mL) and extracted with DCM (2 × 15 mL). The organic layer was washed with aqueous NaHCO3 (2 x 10 mL) and brine (2 x 10 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated on a rotary evaporator (bath temperature 40 °C) to give the crude product. The crude product was purified by column chromatography (Isolera) using 100-200 silica and eluting with methanol / DCM (the desired product eluted with 5% methanol / DCM). Fractions containing the pure product were concentrated under reduced pressure to give methyl 2-((4-(7-(((2S,5R)-5-(ethylsulfonamido)t...

Claims

1. A compound of formula 0, 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, W is N or CH; X is C=O, S(=O)(=NR ５ ), or S(=O) ２ and Y is NH, O, or a bond; R １ is C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C ３ -C １２ Cycloalkyl, C ６ -C １０ aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from one or more of halo, OH, OBn, oxo, CN, N(R Ｎ ) ２ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ optionally substituted with alkoxy; R ２ is C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C ３ -C １２ Cycloalkyl, C ６ -C １０ aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from one or more of halo, OH, OBn, oxo, CN, N(R Ｎ ) ２ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ optionally substituted with alkoxy; R １ and R ２ optionally forms a 3- to 12-membered heterocyclyl, wherein said heterocyclyl is selected from one or more C １ -C ６ Alkyl, halo, OH, CN, or C １ -C ６ optionally substituted with alkoxy; R ３ is H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C ３ -C １２ Cycloalkyl, NH ２ , N.H.-C. １ -C ６ Alkyl, N-(C １ -C ６ Alkyl) ２ , C ６ -C １０ aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from one or more of halo, OH, OBn, oxo, CN, N(R Ｎ ) ２ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ optionally substituted with alkoxy or aryl; R ４ H, halo, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, or N(R Ｎ ) ２ and Each R Ｎ are independently H, C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, Each R ５ are independently H, C １ -C ６ Alkyl, or C １ -C ６ haloalkyl).

2. The compound of the formula: 【Chemistry 2】 or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof; The compound of claim 1. (a) W is N; or (b) W is CH; 3. A compound according to claim 1 or 2.

4. X is C=O or S(=O) ２ and 3. The compound of claim 1 or 2, optionally wherein X is S(=O)2.

5. Y is NH, O, or a bond; Optionally, Y is NH or a bond; 3. The compound of claim 1 or 2, further optionally, wherein Y is NH.

6. The compound of claim 1 or 2, wherein: (a) R １ But, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, or C １ -C ６ Alkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy is selected from one or more of halo, OH, OBn, oxo, CN, or C ３ -C ６ optionally substituted by cycloalkyl; (b) R １ But, C １ -C ６ Alkyl, or C １ -C ６ Alkoxy, wherein the alkyl, alkoxy is one or more of halo, OH, oxo, CN, or C ３ -C ６ optionally substituted with cycloalkyl; (c) R １ is one or more of halo, OH, oxo, CN, or C ３ -C ６ C optionally substituted with cycloalkyl １ -C ６ is alkyl; (d) R １ is one or more of halo, OH, oxo, CN, or C ３ -C ６ C optionally substituted with cycloalkyl １ -C ４ is alkyl; (e) R １ is optionally substituted by one or more halo; １ -C ４ is alkyl; (f) R １ But, C １ -C ４ is alkyl; (g) R １ is ethyl substituted by one or more halo, and optionally R １ But -CH ２ -CHF ２ , or -CH ２ -CF ３ or (h) R １ is isopropyl; The compound.

7. The compound of claim 1 or 2, wherein: (a) R １ But, C ３ -C １２ Cycloalkyl, C ６ -C １０ aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein said cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from one or more of halo, OH, oxo, CN, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ optionally substituted with alkoxy; (b) R １ But, C ３ -C １２ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein said cycloalkyl, heteroaryl, or heterocyclyl is selected from one or more of halo, OH, oxo, CN, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ optionally substituted with alkoxy; (c) R １ But, C ３ -C １２ cycloalkyl, wherein the cycloalkyl is one or more of halo, OH, oxo, CN, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ optionally substituted with alkoxy; (d) R １ but the following: (i) one or more of halo, OH, oxo, CN, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ Alkoxy; (ii) one or more halo, C １ -C ６ Alkyl, or C １ -C ６ haloalkyl; or (iii) one or more C １ -C ６ alkyl or OH, is a 3- to 6-membered heterocyclyl optionally substituted by (e) R １ But one or more C １ -C ６ 3-5 membered heterocyclyl optionally substituted by alkyl or OH; or (f) R １ But one or more C １ -C ６ 3-5 membered heterocyclyl substituted by alkyl or OH; The compound.

8. The compound of claim 1 or 2, wherein: (a) R ２ But, C １ -C ６ Alkyl, or C １ -C ６ Alkoxy, wherein said alkyl or alkoxy is one or more of halo, OH, oxo, CN, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ optionally substituted with alkoxy; (b) R ２ is optionally substituted by one or more halo; １ -C ４ is alkyl; (c) R ２ is optionally substituted by one or more halo; １ -C ３ is alkyl; (d) R ２ is ethyl; or (e) R ２ is propyl, optionally isopropyl; The compound.

9. The compound of claim 1 or 2, wherein: (a) R ３ But, H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, NH ２ , N.H.-C. １ -C ６ Alkyl, or N-(C １ -C ６ Alkyl) ２ wherein the alkyl, alkenyl, alkynyl, or alkoxy is selected from one or more of halo, OH, oxo, CN, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ optionally substituted with alkoxy; (b) R ３ But, C １ -C ６ Alkyl, NH-C １ -C ６ Alkyl or N-(C １ -C ６ Alkyl) ２ wherein the alkyl is one or more of halo, OH, oxo, CN, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ optionally substituted with alkoxy, said alkyl optionally substituted with one or more halo; (c) R ３ But, C １ -C ６ Alkyl, NH-C １ -C ６ Alkyl, N-(C １ -C ６ Alkyl) ２ or 5-10 membered heteroaryl, wherein said alkyl or heteroaryl is selected from the group consisting of one or more halo, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ optionally substituted with alkoxy; (d) R ３ But, C ３ -C １２ Cycloalkyl, C ６ -C １０ aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein said cycloalkyl, aryl, heteroaryl, or heterocyclyl is selected from one or more of halo, OH, oxo, CN, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ optionally substituted with alkoxy; (e) R ３ is a 5-10 membered heteroaryl, wherein said heteroaryl is selected from one or more of halo, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ Optionally, said heteroaryl is substituted with one or more halo or C １ -C ６ optionally substituted with alkyl; (f) R ３ is a 5-6 membered heteroaryl, wherein said heteroaryl has one or more C １ -C ６ optionally substituted with alkyl; (g) R ３ is a 5-membered heteroaryl, wherein said heteroaryl has one or more C １ optionally substituted with alkyl; (h) R ３ But, C １ -C ３ Alkyl, NH-C １ -C ３ Alkyl, N-(C １ -C ３ Alkyl) ２ or 5-6 membered heteroaryl, wherein said alkyl or heteroaryl is selected from the group consisting of one or more halo, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ optionally substituted with alkoxy; or (i) R ３ But, C １ -C ３ Alkyl, NH-C １ -C ３ Alkyl, N-(C １ -C ３ Alkyl) ２ or 5-6 membered heteroaryl, wherein said alkyl or heteroaryl is selected from the group consisting of one or more halo, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C １ -C ６ substituted with alkoxy; The compound.

10. R ４ is H or halo, and optionally R ４ The compound according to claim 1 or 2, wherein is H.

11. Each R ５ is independently H, or C １ -C ６ alkyl, and optionally each R ５ The compound according to claim 1 or 2, wherein is H.

12. A compound shown in Table 1 or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof; optionally, a compound shown in Table 1 or a pharma- ceutically acceptable salt thereof; further optionally, a compound shown in Table 1.

13. 3. A pharmaceutical composition comprising a compound according to claim 1 or 2, or a pharma- ceutically acceptable salt or crystalline form thereof, and at least one pharma- ceutically acceptable carrier.

14. 14. The pharmaceutical composition of claim 13, for use in a method of inhibiting the interaction between menin and MLL, said method comprising contacting menin and MLL with said pharmaceutical composition.

15. 14. The pharmaceutical composition of claim 13 for use in a method for treating or preventing cancer in a patient.

16. 16. The pharmaceutical composition for use according to claim 15, wherein the cancer is a blood cancer.

17. The cancer is below: (a) Leukemia; (b) lymphoma; (c) 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 MLL rearrangement or MLL gene rearrangement, acute leukemia, chronic leukemia, asymptomatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, myeloid leukemia, childhood leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute granulocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), therapy-related leukemia, myelodysplastic syndromes ... myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), 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, mycosis fungoides, Sezary 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, or Waldenstrom's macroglobulinemia; (d) Abstract Nucleophosmin (NPM1)-mutated acute myeloid leukemia (i.e., NPM1 ｍｕｔ acute myeloid leukemia); (e) rearranged mixed lineage leukemia (MLL-r), 16. The pharmaceutical composition of claim 15.

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