Sulfur-substituted benzamide ARYL ether analogs as inhibitors of the menin-MLL interaction

Abstract

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

Description

[0001] Atorney Docket No. SYND-062 / 001WO 43707-02983

[0002] SULFUR-SUBSTITUTED BENZAMIDE ARYL ETHER ANALOGS AS INHIBITORS OF THE MENIN-MLL INTERACTION

[0003] RELATED APPLICATIONS

[0004] This application claims priority to, and the benefit of, U.S. Provisional Application No. 63 / 729,130, filed December 06, 2024, the entire contents of which is incorporated herein by reference.

[0005] BACKGROUND

[0006] The mixed-lineage leukemia (MLL), also known as KMT2A, gene encodes a protein that is a histone methyltransferase that is mutated in clinically and biologically distinctive subsets of acute leukemia. Rearranged mixed lineage leukemia (MLL-r) involves recurrent translocations of the 1 lq23 chromosome locus which lead to an aggressive form of acute leukemia with limited therapeutic options. These translocations target the MLL gene creating an oncogenic fusion protein comprising the amino-terminus of MLL fused in frame with more than 60 different fusion protein partners. Menin, a ubiquitously expressed, nuclear protein encoded by the multiple endocrine neoplasia type 1 (MEN ) tumor suppressor gene, has a high affinity binding interaction with MLL fusion proteins and is an essential co-factor of oncogenic MLL-r fusion proteins. Disruption of this interaction leads to selective growth inhibition and apoptosis of MLL-r leukemia cells both in vitro and in vivo.

[0007] The interaction between menin and MLL or MLL fusion proteins is an attractive target for therapeutic intervention, and there is a need for novel agents that inhibit the menin-MLL interaction for the treatment of various diseases and conditions, including leukemia, other cancers, and diabetes.

[0008] SUMMARY

[0009] In one aspect, the present disclosure is directed to a compound of Formula I,

[0010] Atorney Docket No. SYND-062 / 001WO 43707-02983 a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0011] W is N or CH;

[0012] Y is N or CH;

[0013] R1is 3- to 12-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 12-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a;

[0014] R2is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R2s; each R2sis independently halo, OH, oxo, CN, or N(R4a’)(R4b’);

[0015] Z is O, CH2, or NH;

[0016] Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more RAS; each RAsis independently Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy;

[0017] X3is H or Ci-Ce alkyl, wherein the Ci-Ce alkyl, is optionally substituted with one or more X3s; each X3sis independently halo, OR4a, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b);

[0018] R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or Atorney Docket No. SYND-062 / 001WO 43707-02983 more R3aor R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected; each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; each R4aand R4bis independently H, CN, or Ci-Ce alkyl; each R4a’ and R4b’ is independently H, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and n is 1, 2, or 3.

[0019] In one aspect, the present disclosure is directed to a compound of Formula II, Formula II, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0020] R1is 3- to 12-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 12-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a;

[0021] R2is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R2s; each R2Sis independently halo, OH, oxo, CN, or N(R4a’)(R4b’);

[0022] Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more RAS; each RAsis independently Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy; Atorney Docket No. SYND-062 / 001WO 43707-02983

[0023] X3is H or Ci-Ce alkyl, wherein the Ci-Ce alkyl, is optionally substituted with one or more X3s; each X3sis independently halo, OR4a, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b);

[0024] R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3aor R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected; each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; each R4aand R4bis independently H, CN, or Ci-Ce alkyl; each R4a’ and R4b’ is independently H, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and n is 1, 2, or 3.

[0025] In one aspect, the present application relates to a pharmaceutical composition comprising a compound of the application, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0026] In one aspect, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the application, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0027] In one aspect, the present application relates to a pharmaceutical composition comprising a compound of the application, and a pharmaceutically acceptable carrier.

[0028] In one aspect, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the application, and a pharmaceutically acceptable carrier.

[0029] The present disclosure further provides a use of a compound of Formula I, II, or III, or a stereoisomer, or a pharmaceutically acceptable salt thereof in a method of treating cancer in a patient in need thereof.

[0030] The present disclosure further provides a compound of Formula I, II, or III, or a stereoisomer, or a pharmaceutically acceptable salt thereof for use in a method of treating cancer in a patient in need thereof. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0031] The present disclosure further provides a compound of Formula I, II, or III, or a stereoisomer, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of cancer in a patient in need thereof.

[0032] The present disclosure further provides a method of inhibiting the interaction between menin and MLL comprising contacting the menin and MLL with an effective amount of a compound of Formula I, II, or III, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0033] 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 I, II, or III, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0034] The present disclosure further provides a method of inhibiting the interaction between menin and MLL comprising contacting the menin and MLL with a compound of Formula I, II, or III, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0035] The present disclosure further provides a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula I, II, or III, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0036] The present disclosure further provides a use of a compound of Formula I or II, or a stereoisomer, or a pharmaceutically acceptable salt thereof in a method of treating cancer in a patient in need thereof.

[0037] The present disclosure further provides a compound of Formula I or II, or a stereoisomer, or a pharmaceutically acceptable salt thereof for use in a method of treating cancer in a patient in need thereof.

[0038] The present disclosure further provides a compound of Formula I or II, or a stereoisomer, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of cancer in a patient in need thereof.

[0039] The present disclosure further provides a method of inhibiting the interaction between menin and MLL comprising contacting the menin and MLL with an effective amount of a compound of Formula I or II, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0040] 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 I or II, a stereoisomer, or a pharmaceutically acceptable salt thereof. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0041] The present disclosure further provides a method of inhibiting the interaction between menin and MLL comprising contacting the menin and MLL with a compound of Formula I or II, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0042] The present disclosure further provides a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula I or II, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0043] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, illustrative methods and materials are now described. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0044] DETAILED DESCRIPTION

[0045] In one aspect, the present disclosure is directed to a compound of Formula I, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0046] W is N or CH;

[0047] Y is N or CH;

[0048] R1is 3- to 12-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 12-membered heterocyclyl is optionally substituted with one or two Rls; Atorney Docket No. SYND-062 / 001WO 43707-02983 each Rlsis independently oxo or =NR4a;

[0049] R2is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R2s; each R2Sis independently halo, OH, oxo, CN, or N(R4a’)(R4b’);

[0050] Z is O, CH2, or NH;

[0051] Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more RAS; each RAsis independently Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy;

[0052] X3is H or Ci-Ce alkyl, wherein the Ci-Ce alkyl, is optionally substituted with one or more X3s; each X3sis independently halo, OR4a, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b);

[0053] R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3aor R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected; each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; each R4aand R4bis independently H, CN, or Ci-Ce alkyl; each R4a’ and R4b’ is independently H, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and n is 1, 2, or 3.

[0054] In one aspect, the present disclosure is directed to a compound of Formula II, Atorney Docket No. SYND-062 / 001WO 43707-02983 a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0055] R1is 3- to 12-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 12-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a;

[0056] R2is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R2s; each R2Sis independently halo, OH, oxo, CN, or N(R4a’)(R4b’);

[0057] Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more RAS; each RAsis independently Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy;

[0058] X3is H or Ci-Ce alkyl, wherein the Ci-Ce alkyl, is optionally substituted with one or more X3s; each X3sis independently halo, OR4a, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b);

[0059] R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3aor R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected; Atorney Docket No. SYND-062 / 001WO 43707-02983 each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; each R4aand R4bis independently H, CN, or Ci-Ce alkyl; each R4a’ and R4b’ is independently H, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and n is 1, 2, or 3.

[0060] Embodiments

[0061] For any of Formulae I, II, or III where applicable, the following embodiments are considered both alone and in conjunction with another where a stable compound is formed.

[0062] For any of Formulae I and II where applicable, the following embodiments are considered both alone and in conjunction with another where a stable compound is formed.

[0063] In some embodiments, W is N or CH.

[0064] In some embodiments, W is N.

[0065] In some embodiments, W is CH.

[0066] In some embodiments, Y is N or CH.

[0067] In some embodiments, Y is N.

[0068] In some embodiments, Y is CH.

[0069] In some embodiments, R1is 3- to 12-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 12-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

[0070] In some embodiments, R1is 3- to 11-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 11-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

[0071] In some embodiments, R1is 3- to 10-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 10-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

[0072] In some embodiments, R1is 3- to 9-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 9-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0073] In some embodiments, R1is 3- to 8-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 8-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

[0074] In some embodiments, R1is 3- to 7-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 7-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

[0075] In some embodiments, R1is 3- to 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 6-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

[0076] In some embodiments, R1is 3- to 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 5-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

[0077] In some embodiments, R1is 3- to 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 4-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

[0078] In some embodiments, R1is 3- to 12-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 12-membered heterocyclyl is substituted with one or two oxo.

[0079] In some embodiments, R1is 3- to 11-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 11-membered heterocyclyl is substituted with one or two oxo.

[0080] In some embodiments, R1is 3- to 10-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 10-membered heterocyclyl is substituted with one or two oxo.

[0081] In some embodiments, R1is 3- to 9-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 9-membered heterocyclyl is substituted with one or two oxo. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0082] In some embodiments, R1is 3- to 8-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 8-membered heterocyclyl is substituted with one or two oxo.

[0083] In some embodiments, R1is 3- to 7-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 7-membered heterocyclyl is substituted with one or two oxo.

[0084] In some embodiments, R1is 3- to 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 6-membered heterocyclyl is substituted with one or two oxo.

[0085] In some embodiments, R1is 3- to 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 5-membered heterocyclyl is substituted with one or two oxo.

[0086] In some embodiments, R1is 3- to 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 4-membered heterocyclyl is substituted with one or two oxo.

[0087] In some embodiments, R1is 3-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

[0088] In some embodiments, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

[0089] In some embodiments, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

[0090] In some embodiments, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls; Atorney Docket No. SYND-062 / 001WO 43707-02983 each Rlsis independently oxo or =NR4a. In some embodiments, some

[0091] H3C-N p

[0092] 9 embodiments, R1is

[0093] In some embodiments, R1is 7-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 7-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

[0094] In some embodiments, R1is 8-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 8-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

[0095] In some embodiments, R1is 9-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 9-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

[0096] In some embodiments, R1is 10-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 10-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

[0097] In some embodiments, R1is 11-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 11 -membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

[0098] In some embodiments, R1is 12-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 12-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a. Attorney Docket No. SYND-062 / 001WO 43707-02983

[0099] In some embodiments, R1is 3-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3-membered heterocyclyl is substituted with one or two oxo.

[0100] In some embodiments, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is substituted with one or two oxo. In some embodiments, some embodiments,

[0101] In some embodiments, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is substituted with one or two oxo. In some embodiments, specific embodiment, specific embodiment,

[0102] In some embodiments, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is substituted with one or two oxo. In o o s some embodiments, R1is .

[0103] In some embodiments, R1is 7-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 7-membered heterocyclyl is substituted with one or two oxo.

[0104] In some embodiments, R1is 8-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 8-membered heterocyclyl is substituted with one or two oxo.

[0105] In some embodiments, R1is 9-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 9-membered heterocyclyl is substituted with one or two oxo.

[0106] In some embodiments, R1is 10-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 10-membered heterocyclyl is substituted with one or two oxo.

[0107] In some embodiments, R1is 11-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 11 -membered heterocyclyl is substituted with one or two oxo. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0108] In some embodiments, R1is 12-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 12-membered heterocyclyl is substituted with one or two oxo.

[0109] In some embodiments, R1is 3-membered heterocyclyl comprising a sulfur atom.

[0110] In some embodiments, R1is 4-membered heterocyclyl comprising a sulfur atom. In some embodiments,

[0111] In some embodiments, R1is 5-membered heterocyclyl comprising a sulfur atom.

[0112] In some embodiments, R1is 6-membered heterocyclyl comprising a sulfur atom.

[0113] In some embodiments, R1is 7-membered heterocyclyl comprising a sulfur atom.

[0114] In some embodiments, R1is 8-membered heterocyclyl comprising a sulfur atom.

[0115] In some embodiments, R1is 9-membered heterocyclyl comprising a sulfur atom.

[0116] In some embodiments, R1is 10-membered heterocyclyl comprising a sulfur atom.

[0117] In some embodiments, R1is 11 -membered heterocyclyl comprising a sulfur atom.

[0118] In some embodiments, R1is 12-membered heterocyclyl comprising a sulfur atom.

[0119] In some embodiments, R1is 3- to 12-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 12-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo, =NH, or =N-CH3.

[0120] In some embodiments, R1is 3- to 11-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 11-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo, =NH, or =N-CH3.

[0121] In some embodiments, R1is 3- to 10-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 10-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo, =NH, or =N-CH3.

[0122] In some embodiments, R1is 3- to 9-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 9-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo, =NH, or =N-CH3.

[0123] In some embodiments, R1is 3- to 8-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 8-membered heterocyclyl is optionally substituted with one or two Rls; Atorney Docket No. SYND-062 / 001WO 43707-02983 each Rlsis independently oxo, =NH, or =N-CH3.

[0124] In some embodiments, R1is 3- to 7-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 7-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo, =NH, or =N-CH3.

[0125] In some embodiments, R1is 3- to 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 6-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo, =NH, or =N-CH3.

[0126] In some embodiments, R1is 3- to 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 5-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo, =NH, or =N-CH3.

[0127] In some embodiments, R1is 3- to 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 4-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo, =NH, or =N-CH3.

[0128] In some embodiments, R1is 3-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo, =NH, or =N-CH3.

[0129] In some embodiments, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo, =NH, or =N-CH3.

[0130] In some embodiments, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo, =NH, or =N-CH3.

[0131] In some embodiments, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo, =NH, or =N-CH3. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0132] In some embodiments, R1is 7-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 7-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo, =NH, or =N-CH3.

[0133] In some embodiments, R1is 8-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 8-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo, =NH, or =N-CH3.

[0134] In some embodiments, R1is 9-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 9-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo, =NH, or =N-CH3.

[0135] In some embodiments, R1is 10-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 10-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo, =NH, or =N-CH3.

[0136] In some embodiments, R1is 11-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 11 -membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo, =NH, or =N-CH3.

[0137] In some embodiments, R1is 12-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 12-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo, =NH, or =N-CH3.

[0138] In some embodiments,

[0139] In some embodiments, Attorney Docket No. SYND-062 / 001WO 43707-02983

[0140] In some embodiments,

[0141] In some embodiments,

[0142] In some embodiments,

[0143] In some embodiments,

[0144] In some embodiments,

[0145] In some embodiments,

[0146] In some embodiments,

[0147] In some embodiments,

[0148] In some embodiments, Atorney Docket No. SYND-062 / 001WO 43707-02983

[0149] In some embodiments, o o s

[0150] In some embodiments, R1is

[0151] In some embodiments,

[0152] In some embodiments,

[0153] In some embodiments, R2is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy,

[0154] C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R2s; each R2sis independently halo, OH, oxo, CN, or N(R4a’)(R4b’), wherein each R4a’ and R4b’ is independently H, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0155] In some embodiments, R2is H.

[0156] In some embodiments, R2is Ci-Ce alkyl.

[0157] In some embodiments, R2is C1-C5 alkyl.

[0158] In some embodiments, R2is C1-C4 alkyl.

[0159] In some embodiments, R2is C1-C3 alkyl.

[0160] In some embodiments, R2is C1-C2 alkyl.

[0161] In some embodiments, R2is methyl.

[0162] In some embodiments, R2is ethyl.

[0163] In some embodiments, R2is propyl.

[0164] In some embodiments, R2is isopropyl. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0165] In some embodiments, R2is butyl.

[0166] In some embodiments, R2is tert-butyl.

[0167] In some embodiments, Z is O, CH2, or NH .

[0168] In some embodiments, Z is O.

[0169] In some embodiments, Z is CH2.

[0170] In some embodiments, Z is NH.

[0171] In some embodiments, Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more RAs; each RAsis independently Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy.

[0172] In some embodiments, Ring A is 6- to 10-membered aryl optionally substituted with one or more RAs; each RAsis independently Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy.

[0173] In some embodiments, Ring A is 6- to 9-membered aryl optionally substituted with one or more RAs; each RAsis independently Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy.

[0174] In some embodiments, Ring A is 6- to 8-membered aryl optionally substituted with one or more RAs; each RAsis independently Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy.

[0175] In some embodiments, Ring A is 6- to 7-membered aryl optionally substituted with one or more RAs; each RAsis independently Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy.

[0176] In some embodiments, Ring A is a phenyl ring.

[0177] In some embodiments, Ring A is a phenyl ring optionally substituted with one or more RAS; each RAsis independently Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy.

[0178] In some embodiments, Ring A is 6- to 10-membered heteroaryl optionally substituted with one or more RAs; each RAsis independently Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy.

[0179] In some embodiments, Ring A is 6- to 9-membered heteroaryl optionally substituted with one or more RAs; each RAsis independently Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0180] In some embodiments, Ring A is 6- to 8-membered heteroaryl optionally substituted with one or more RAs; each RAsis independently Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy.

[0181] In some embodiments, Ring A is 6- to 7-membered heteroaryl optionally substituted with one or more RAs; each RAsis independently Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy.

[0182] In some embodiments, Ring A is a pyridine ring.

[0183] In some embodiments, Ring A is a pyrimidine ring.

[0184] In some embodiments, Ring A is represents a bond to Z.

[0185] In some embodiments, X3is H or Ci-Ce alkyl, wherein the Ci-Ce alkyl, is optionally substituted with one or more X3s; each X3sis independently halo, OR4a, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b); and wherein: each R4aand R4bis independently H, CN, or Ci-Ce alkyl.

[0186] In some embodiments, X3is H.

[0187] In some embodiments, X3is Ci-Ce alkyl.

[0188] In some embodiments, X3is C1-C5 alkyl.

[0189] In some embodiments, X3is C1-C4 alkyl.

[0190] In some embodiments, X3is C1-C3 alkyl.

[0191] In some embodiments, X3is C1-C2 alkyl.

[0192] In some embodiments, X3is methyl. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0193] In some embodiments, X3is ethyl.

[0194] In some embodiments, X3is propyl.

[0195] In some embodiments, X3is isopropyl.

[0196] In some embodiments, X3is butyl.

[0197] In some embodiments, X3is tert-butyl.

[0198] In some embodiments, R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0199] In some embodiments, R3is H.

[0200] In some embodiments, R3is Ci-Ce alkyl, wherein the Ci-Ce alkyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0201] In some embodiments, R3is C1-C5 alkyl, wherein the C1-C5 alkyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0202] In some embodiments, R3is C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0203] In some embodiments, R3is C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and Atorney Docket No. SYND-062 / 001WO 43707-02983 each R4ais independently H, CN, or Ci-Ce alkyl.

[0204] In some embodiments, R3is C1-C2 alkyl, wherein the C1-C2 alkyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0205] In some embodiments, R3is Ci-Ce alkyl.

[0206] In some embodiments, R3is C1-C5 alkyl.

[0207] In some embodiments, R3is C1-C4 alkyl.

[0208] In some embodiments, R3is C1-C3 alkyl.

[0209] In some embodiments, R3is C1-C2 alkyl.

[0210] In some embodiments, R3is methyl.

[0211] In some embodiments, R3is ethyl.

[0212] In some embodiments, R3is propyl.

[0213] In some embodiments, R3is isopropyl.

[0214] In some embodiments, R3is butyl.

[0215] In some embodiments, R3is tert-butyl.

[0216] In some embodiments, R3is pentyl.

[0217] In some embodiments, R3is hexyl.

[0218] In some embodiments, R3is Ci-Ce alkyl that is optionally substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0219] In some embodiments, R3is C1-C5 alkyl that is optionally substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0220] In some embodiments, R3is C1-C4 alkyl that is optionally substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0221] In some embodiments, R3is C1-C3 alkyl that is optionally substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0222] In some embodiments, R3is C1-C2 alkyl that is optionally substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0223] In some embodiments, R3is methyl that is optionally substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0224] In some embodiments, R3is ethyl that is optionally substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0225] In some embodiments, R3is propyl that is optionally substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0226] In some embodiments, R3is isopropyl that is optionally substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0227] In some embodiments, R3is butyl that is optionally substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl .

[0228] In some embodiments, R3is tert-butyl that is optionally substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0229] In some embodiments, R3is pentyl that is optionally substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0230] In some embodiments, R3is hexyl that is optionally substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0231] In some embodiments, R3is Ci-Ce alkyl that is substituted with one or more R3a, wherein R3ais 3- to 12-membered heterocyclyl.

[0232] In some embodiments, R3is C1-C5 alkyl that is substituted with one or more R3a, wherein R3ais 3- to 12-membered heterocyclyl.

[0233] In some embodiments, R3is C1-C4 alkyl that is substituted with one or more R3a, wherein R3ais 3- to 12-membered heterocyclyl.

[0234] In some embodiments, R3is C1-C3 alkyl that is substituted with one or more R3a, wherein R3ais 3- to 12-membered heterocyclyl.

[0235] In some embodiments, R3is C1-C2 alkyl that is substituted with one or more R3a, wherein R3ais 3- to 12-membered heterocyclyl.

[0236] In some embodiments, R3is methyl that is substituted with one or more R3a, wherein R3ais 3- to 12-membered heterocyclyl.

[0237] In some embodiments, R3is ethyl that is substituted with one or more R3a, wherein R3ais 3- to 12-membered heterocyclyl.

[0238] In some embodiments, R3is propyl that is substituted with one or more R3a, wherein R3ais 3- to 12-membered heterocyclyl.

[0239] In some embodiments, R3is isopropyl that is substituted with one or more R3a, wherein R3ais 3- to 12-membered heterocyclyl.

[0240] In some embodiments, R3is butyl that is substituted with one or more R3a, wherein R3ais 3- to 12-membered heterocyclyl. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0241] In some embodiments, R3is tert-butyl that is substituted with one or more R3a, wherein R3ais 3- to 12-membered heterocyclyl.

[0242] In some embodiments, R3is pentyl that is substituted with one or more R3a, wherein R3ais 3- to 12-membered heterocyclyl.

[0243] In some embodiments, R3is hexyl that is substituted with one or more R3a, wherein R3ais 3- to 12-membered heterocyclyl.

[0244] In some embodiments, R3is Ci-alkyl substituted with an 8- to 11 -membered spirocycle with 0-3 heteroatoms selected from N, O, and S(O)2.

[0245] In some embodiments, R3is C2-alkyl substituted with an 8- to 11 -membered spirocycle with 0-3 heteroatoms selected from N, O, and S(O)2.

[0246] In some embodiments, R3is Cs-alkyl substituted with an 8- to 11 -membered spirocycle with 0-3 heteroatoms selected from N, O, and S(O)2.

[0247] In some embodiments, R3is C4-alkyl substituted with an 8- to 11 -membered spirocycle with 0-3 heteroatoms selected from N, O, and S(O)2.

[0248] In some embodiments, R3is Cs-alkyl substituted with an 8- to 11 -membered spirocycle with 0-3 heteroatoms selected from N, O, and S(O)2.

[0249] In some embodiments, R3is Ce-alkyl substituted with an 8- to 11 -membered spirocycle with 0-3 heteroatoms selected from N, O, and S(O)2.

[0250] In some embodiments, R3is Ci-alkyl substituted with an 8- to 9-membered spirocycle with 0-2 heteroatoms selected from N, O, and S(O)2.

[0251] In some embodiments, R3is C2-alkyl substituted with an 8- to 9-membered spirocycle with 0-2 heteroatoms selected from N, O, and S(O)2.

[0252] In some embodiments, R3is Cs-alkyl substituted with an 8- to 9-membered spirocycle with 0-2 heteroatoms selected from N, O, and S(O)2.

[0253] In some embodiments, R3is C4-alkyl substituted with an 8- to 9-membered spirocycle with 0-2 heteroatoms selected from N, O, and S(O)2.

[0254] In some embodiments, R3is Cs-alkyl substituted with an 8- to 9-membered spirocycle with 0-2 heteroatoms selected from N, O, and S(O)2.

[0255] In some embodiments, R3is Ce-alkyl substituted with an 8- to 9-membered spirocycle with 0-2 heteroatoms selected from N, O, and S(O)2.

[0256] In some embodiments, R3is Ci-alkyl substituted with an 8- to 9-membered spirocycle with 1-2 heteroatoms selected from N, O, and S(O)2. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0257] In some embodiments, R3is C2-alkyl substituted with an 8- to 9-membered spirocycle with 1-2 heteroatoms selected from N, O, and S(O)2.

[0258] In some embodiments, R3is C3-alkyl substituted with an 8- to 9-membered spirocycle with 1-2 heteroatoms selected from N, O, and S(O)2.

[0259] In some embodiments, R3is C4-alkyl substituted with an 8- to 9-membered spirocycle with 1-2 heteroatoms selected from N, O, and S(O)2.

[0260] In some embodiments, R3is Cs-alkyl substituted with an 8- to 9-membered spirocycle with 1-2 heteroatoms selected from N, O, and S(O)2.

[0261] In some embodiments, R3is Ce-alkyl substituted with an 8- to 9-membered spirocycle with 1-2 heteroatoms selected from N, O, and S(O)2.

[0262] In some embodiments,

[0263] In some embodiments,

[0264] In some embodiments, R3is Ci-Ce alkyl, wherein the C1-C6 alkyl IS optionally substituted by one or more R3aand wherein R3ais a halo.

[0265] In some embodiments, R3is C1-C5 alkyl, wherein the C1-C5 alkyl is optionally substituted by one or more R3aand wherein R3ais a halo.

[0266] In some embodiments, R3is C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted by one or more R3aand wherein R3ais a halo.

[0267] In some embodiments, R3is C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted by one or more R3aand wherein R3ais a halo.

[0268] In some embodiments, R3is C1-C2 alkyl, wherein the C1-C2 alkyl is optionally substituted by one or more R3aand wherein R3ais a halo.

[0269] In some embodiments, R3is a C2-C6 alkenyl, wherein the C2-C6 alkenyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0270] In some embodiments, R3is a C2-C5 alkenyl, wherein the C2-C5 alkenyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and Atorney Docket No. SYND-062 / 001WO 43707-02983 each R4ais independently H, CN, or Ci-Ce alkyl.

[0271] In some embodiments, R3is a C2-C4 alkenyl, wherein the C2-C4 alkenyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0272] In some embodiments, R3is a C2-C3 alkenyl, wherein the C2-C3 alkenyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0273] In some embodiments, R3is a C2-C6 alkynyl, wherein the C2-C6 alkynyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0274] In some embodiments, R3is a C2-C5 alkynyl, wherein the C2-C5 alkynyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0275] In some embodiments, R3is a C2-C4 alkynyl, wherein the C2-C4 alkynyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0276] In some embodiments, R3is a C2-C3 alkynyl, wherein the C2-C3 alkynyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0277] In some embodiments, R3is a Ci-Ce alkoxy, wherein the Ci-Ce alkoxy is optionally substituted by one or more R3a; wherein: Atorney Docket No. SYND-062 / 001WO 43707-02983 each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0278] In some embodiments, R3is a C1-C5 alkoxy, wherein the C1-C5 alkoxy is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0279] In some embodiments, R3is a C1-C4 alkoxy, wherein the C1-C4 alkoxy is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0280] In some embodiments, R3is a C1-C3 alkoxy, wherein the C1-C3 alkoxy is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0281] In some embodiments, R3is a C1-C2 alkoxy, wherein the C1-C2 alkoxy is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0282] In some embodiments, R3is a C3-C12 cycloalkyl, wherein the C3-C12 cycloalkyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0283] In some embodiments, R3is a C3-C11 cycloalkyl, wherein the C3-C11 cycloalkyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0284] In some embodiments, R3is a C3-C10 cycloalkyl, wherein the C3-C10 cycloalkyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0285] In some embodiments, R3is a C3-C9 cycloalkyl, wherein the C3-C9 cycloalkyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0286] In some embodiments, R3is a C3-C8 cycloalkyl, wherein the C3-C8 cycloalkyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0287] In some embodiments, R3is a C3-C7 cycloalkyl, wherein the C3-C7 cycloalkyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0288] In some embodiments, R3is a C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0289] In some embodiments, R3is a C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0290] In some embodiments, R3is a C3-C4 cycloalkyl, wherein the C3-C4 cycloalkyl is optionally substituted by one or more R3a; wherein: Atorney Docket No. SYND-062 / 001WO 43707-02983 each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0291] In some embodiments, R3is a Ce-Cio aryl, wherein the Ce-Cio aryl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0292] In some embodiments, R3is a C6-C9 aryl, wherein the C6-C9 aryl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0293] In some embodiments, R3is a Ce-Cs aryl, wherein the Ce-Cs aryl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0294] In some embodiments, R3is a C6-C7 aryl, wherein the C6-C7 aryl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0295] In some embodiments, R3is a 5- to 10-membered heteroaryl, wherein the 5- to 10- membered heteroaryl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0296] In some embodiments, R3is a 5- to 9-membered heteroaryl, wherein the 5- to 9- membered heteroaryl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0297] In some embodiments, R3is a 5- to 8-membered heteroaryl, wherein the 5- to 8- membered heteroaryl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0298] In some embodiments, R3is a 5- to 7-membered heteroaryl, wherein the 5- to 7- membered heteroaryl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0299] In some embodiments, R3is a 5- to 6-membered heteroaryl, wherein the 5- to 6- membered heteroaryl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0300] In some embodiments, R3is a 3- to 12-membered heterocyclyl, wherein the 3- to 12- membered heterocyclyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0301] In some embodiments, R3is a 3- to 11-membered heterocyclyl, wherein the 3- to 11- membered heterocyclyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0302] In some embodiments, R3is a 3- to 10-membered heterocyclyl, wherein the 3- to 10- membered heterocyclyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0303] In some embodiments, R3is a 3- to 9-membered heterocyclyl, wherein the 3- to 9- membered heterocyclyl is optionally substituted by one or more R3a; wherein: Atorney Docket No. SYND-062 / 001WO 43707-02983 each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0304] In some embodiments, R3is a 3- to 8-membered heterocyclyl, wherein the 3- to 8- membered heterocyclyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0305] In some embodiments, R3is a 3- to 7-membered heterocyclyl, wherein the 3- to 7- membered heterocyclyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0306] In some embodiments, R3is a 3- to 6-membered heterocyclyl, wherein the 3- to 6- membered heterocyclyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0307] In some embodiments, R3is a 3- to 5-membered heterocyclyl, wherein the - to 5- membered heterocyclyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0308] In some embodiments, R3is a 3- to 4-membered heterocyclyl, wherein the - to 4- membered heterocyclyl is optionally substituted by one or more R3a; wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.

[0309] In some embodiments, R3ais Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0310] In some embodiments, R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected. In some embodiments,

[0311] In some embodiments, n is 1.

[0312] In some embodiments, n is 2.

[0313] In some embodiments, n is 3.

[0314] In some embodiments, W is CH, Y is N, Z is O, and Ring A is

[0315] In some embodiments, W is CH, Y is N, Z is O, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, and

[0316] In some embodiments, W is CH, Y is N, Z is O, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring isopropyl.

[0317] In some embodiments, W is CH, Y is N, Z is O, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, and Atorney Docket No. SYND-062 / 001WO 43707-02983

[0318] In some embodiments, W is CH, Y is N, Z is O, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is or A ON, and X3, is H, methyl, ethyl, or isopropyl.

[0319] In some embodiments, W is CH, Y is N, Z is O, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, and

[0320] Ring

[0321] In some embodiments, W is CH, Y is N, Z is O, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is or QN, and X 3 is H, methyl, ethyl, or isopropyl. odiments, W is CH, Y is N, Z is O, Ring A is

[0322] In some embodiments, W is CH, Y is N, Z is O, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring

[0323] In some embodiments, W is CH, Y is N, Z is O, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally Atorney Docket No. SYND-062 / 001WO 43707-02983 substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring

[0324] In some embodiments, W is CH, Y is N, Z is O, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring

[0325] In some embodiments, W is CH, Y is N, Z is O, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is

[0326] In any one of the preceding embodiments, R3is selected from one or more of the following: a. H; b. methyl, ethyl, or isopropyl;

[0327] In any one of the previous embodiments, wherein n is 1.

[0328] In any one of the previous embodiments, wherein n is 2.

[0329] In any one of the previous embodiments, wherein n is 3. Attorney Docket No. SYND-062 / 001WO 43707-02983

[0330] In some embodiments, W is CH, Y is N, Z is O, Ring A is , and R3is H, methyl, ethyl, isopropyl, or

[0331] In some embodiments, W is CH, Y is N, Z is O, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring , and R3is H, methyl, ethyl, isopropyl, or

[0332] In some embodiments, W is CH, Y is N, Z is O, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is

[0333] In some embodiments, W is CH, Y is N, Z is O, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring , and R3is H, methyl, ethyl, isopropyl, or

[0334] In some embodiments, W is CH, Y is N, Z is O, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is

[0335] In some embodiments, W is CH, Y is N, Z is O, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally Atorney Docket No. SYND-062 / 001WO 43707-02983 substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring , and R3is H, methyl, ethyl, isopropyl, or

[0336] In some embodiments, W is CH, Y is N, Z is O, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is

[0337] In some embodiments, W is CH, Y is N, Z is O, Ring A is is H, methyl, ethyl, isopropyl,

[0338] In some embodiments, W is CH, Y is N, Z is O, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring is H, methyl, ethyl, isopropyl, or , and n=2.

[0339] In some embodiments, W is CH, Y is N, Z is O, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is , .

[0340] In some embodiments, W is CH, Y is N, Z is O, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring is H, methyl, ethyl, isopropyl, or , and n=2. Attorney Docket No. SYND-062 / 001WO 43707-02983

[0341] In some embodiments, W is CH, Y is N, Z is O, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is

[0342] In some embodiments, W is CH, Y is N, Z is O, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring is H, methyl, ethyl, isopropyl, or , and n=2.

[0343] In some embodiments, W is CH, Y is N, Z is O, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is

[0344] In some embodiments, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is H, and n=2.

[0345] In some embodiments, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is methyl, and n=2.

[0346] In some embodiments, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or

[0347] 31 Attorney Docket No. SYND-062 / 001WO 43707-02983 two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is , R3is ethyl, and n=2.

[0348] In some embodiments, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is JO1, R3is isopropyl, and n=2.

[0349] In some embodiments, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is , R3is

[0350] In some embodiments, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is , R3is

[0351] H, and n=2.

[0352] In some embodiments, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is , R3is methyl, and n=2.

[0353] In some embodiments, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is , R3is ethyl, and n=2.

[0354] In some embodiments, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or Atorney Docket No. SYND-062 / 001WO 43707-02983 two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is isopropyl, and n=2.

[0355] In some embodiments, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is , R3is , and n=2.

[0356] In some embodiments, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is , R3is

[0357] H, and n=2.

[0358] In some embodiments, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is , R3is methyl, and n=2.

[0359] In some embodiments, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is , R3is ethyl, and n=2.

[0360] In some embodiments, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is , R3is isopropyl, and n=2.

[0361] In some embodiments, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or Attorney Docket No. SYND-062 / 001WO 43707-02983 two Rls, each Rlsis independently oxo or =NR4a, R2is isopropyl, Ring A is , R3is ,and n=2.

[0362] In some embodiments, W is CH, Y is N, Z is O, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring

[0363] In some embodiments, W is CH, Y is N, Z is O, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is is methyl, and n=2.

[0364] In some embodiments, W is CH, Y is N, Z is O, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is is ethyl, and n=2.

[0365] In some embodiments, W is CH, Y is N, Z is O, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is is isopropyl, and n=2.

[0366] In some embodiments, W is CH, Y is N, Z is O, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring

[0367] In some embodiments, W is CH, Y is N, Z is O, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally Attorney Docket No. SYND-062 / 001WO 43707-02983 substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is is H, X3is H or methyl, and n=2.

[0368] In some embodiments, W is CH, Y is N, Z is O, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is is methyl, X3is H or methyl, and n=2.

[0369] In some embodiments, W is CH, Y is N, Z is O, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is is ethyl, X3is H or methyl, and n=2.

[0370] In some embodiments, W is CH, Y is N, Z is O, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is is isopropyl, X3is H or methyl, and n=2.

[0371] In some embodiments, W is CH, Y is N, Z is O, R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is , X3is H or methyl, R3is , and n=2.

[0372] In some embodiments, W is CH, Y is N, Z is O, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring

[0373] In some embodiments, W is CH, Y is N, Z is O, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally Atorney Docket No. SYND-062 / 001WO 43707-02983 substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is , R3is methyl, and n=2.

[0374] In some embodiments, W is CH, Y is N, Z is O, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is , R3is ethyl, and n=2.

[0375] In some embodiments, W is CH, Y is N, Z is O, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is , R3is isopropyl, and n=2.

[0376] In some embodiments, W is CH, Y is N, Z is O, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring

[0377] In some embodiments, W is CH, Y is N, Z is O, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is , R3is H, X3is H or methyl, and n=2.

[0378] In some embodiments, W is CH, Y is N, Z is O, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is , R3is methyl, X3is H or methyl, and n=2.

[0379] In some embodiments, W is CH, Y is N, Z is O, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally Attorney Docket No. SYND-062 / 001WO 43707-02983 substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is is ethyl, X3is H or methyl, and n=2.

[0380] In some embodiments, W is CH, Y is N, Z is O, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is is isopropyl, X3is H or methyl, and n=2.

[0381] In some embodiments, W is CH, Y is N, Z is O, R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is , X3is H or methyl, R3is , and n=2.

[0382] In some embodiments, W is CH, Y is N, Z is O, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring

[0383] In some embodiments, W is CH, Y is N, Z is O, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is is methyl, and n=2.

[0384] In some embodiments, W is CH, Y is N, Z is O, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is is ethyl, and n=2.

[0385] In some embodiments, W is CH, Y is N, Z is O, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally Atorney Docket No. SYND-062 / 001WO 43707-02983 substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is , R3is isopropyl, and n=2.

[0386] In some embodiments, W is CH, Y is N, Z is O, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring

[0387] In some embodiments, W is CH, Y is N, Z is O, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is , R3is H, X3is H or methyl, and n=2.

[0388] In some embodiments, W is CH, Y is N, Z is O, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is , R3is methyl, X3is H or methyl, and n=2.

[0389] In some embodiments, W is CH, Y is N, Z is O, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is , R3is ethyl, X3is H or methyl, and n=2.

[0390] In some embodiments, W is CH, Y is N, Z is O, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is isopropyl, Ring A is , R3is isopropyl, X3is H or methyl, and n=2.

[0391] In some embodiments, W is CH, Y is N, Z is O, R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally Attorney Docket No. SYND-062 / 001WO 43707-02983 substituted with one or two Rls, each Rlsis independently oxo, =NH, or =NCHs, R2is jO1isopropyl, Ring A is , X3is H or methyl, R3is , and n=2.

[0392] In some embodiments, the present disclosure is directed to a compound of Formula III: a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0393] R1is 3- to 12-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 12-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a;

[0394] R2is Ci-C6alkyl;

[0395] X3is H or Ci-Ce alkyl;

[0396] R3is H or Ci-Ce alkyl, wherein the Ci-Ce alkyl is optionally substituted with one or more R3a, or R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected; each R3ais independently 3- to 12-membered heterocyclyl; each R4ais independently H or Ci-Ce alkyl; and n is 2.

[0397] In some embodiments, the compound is of Formula I or II combined with any of the embodiments described herein.

[0398] In some embodiments, the compound is of Formula I, II, or III combined with any of the embodiments described herein.

[0399] Any of the groups described above for any variable can be combined with any of the other groups described above, where applicable, for any of the Formulae described herein.

[0400] Representative compounds of the present disclosure are shown in the table below. Attorney Docket No. SYND-062 / 001WO 43707-02983

[0401] Table 1. Representative Compounds of the Present Disclosure Atorney Docket No. SYND-062 / 001WO 43707-02983 Atorney Docket No. SYND-062 / 001WO 43707-02983 Atorney Docket No. SYND-062 / 001WO 43707-02983 Atorney Docket No. SYND-062 / 001WO 43707-02983 Atorney Docket No. SYND-062 / 001WO 43707-02983 Atorney Docket No. SYND-062 / 001WO 43707-02983

[0402] In some embodiments, a compound according to any embodiments herein (e.g., Formulae I, II, III, and Table 1) exhibits an inhibition activity against the binding of menin and MLL. In some embodiments, a compound according to any embodiments herein (e.g., Formulae I, II, III, and Table 1) exhibits an inhibition activity against the binding of menin and MLL. In some embodiments, a compound according to any embodiments herein e.g., Formulae I, II, III, and Table 1) exhibits an inhibition activity against the binding of menin and MLL which is useful in the treatment and / or prevention of one or more diseases in which menin and MLL play a role.

[0403] In some embodiments, a compound according to any embodiments herein (e.g., Formulae I, II, III, and Table 1) exhibits low hERG binding. In some embodiments, a compound according to any embodiments herein (e.g., Formulae I, II, III, and Table 1) minimizes hERG binding and is useful for the treatment of one or more diseases in which menin and MLL play a role. Without being bound to any theory, one of the primary causes of QT prolongation is thought to be blockage of the hERG potassium channel in cardiac myocytes. In some embodiments, the compounds of the present disclosure (e.g., Formulae I,

[0404] II, III, and Table 1) do not significantly block the hERG potassium channel.

[0405] In some embodiments, the compounds of the present disclosure (e.g., Formulae I, II,

[0406] III, and Table 1) do not significantly block the hERG potassium channel (e.g., an ICso greater than 1 pM, 5 pM, 10 pM, 15 pM, 20 pM, 25 pM, 30 pM, 35 pM, 40 pM, or 50 pM) as measured by a standard patch clamp hERG assay.

[0407] In some embodiments, the compounds of the present disclosure (e.g., Formulae I, II, III, and Table 1) do not significantly block the hERG potassium channel (e.g., a compound of the invention has an ICso greater than 1 pM, 5 pM, 10 pM, 15 pM, 20 pM, 25 pM, 30 pM, 35 pM, 40 pM, or 50 pM for the hERG potassium channel).

[0408] In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin-MLL interaction comprising a sulfur-sub stituted benzamide moiety (e.g., Formulae I, II, III, and Table 1) where the sulfur-substituted benzamide moiety has been found to reduce hERG inhibition.

[0409] In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin-MLL interaction (e.g., Formulae I, II, III, and Table 1) which are resistant to metabolism. In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin-MLL interaction (e.g., Formulae I, II, III, and Table 1) which are resistant to metabolism, where the Atorney Docket No. SYND-062 / 001WO 43707-02983 metabolites are inhibitors of the hERG potassium channel. In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin-MLL interaction (e.g., Formulae I, II, III, and Table 1) which are resistant to metabolism, where the metabolism decreases the bioavailability of the inhibitor. In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin-MLL interaction (e.g., Formulae I, II, III, and Table 1) which are resistant to metabolism, where the metabolism decreases the bioavailability of the inhibitor and the corresponding metabolites are more effective (e.g., by ICso, etc.) at binding the hERG potassium channel.

[0410] In some embodiments, a compound according to any embodiments herein (e.g., Formulae I and II, and Table 1) exhibits an inhibition activity against the binding of menin and MLL. In some embodiments, a compound according to any embodiments herein (e.g., Formulae I and II, and Table 1) exhibits an inhibition activity against the binding of menin and MLL. In some embodiments, a compound according to any embodiments herein e.g., Formulae I and II, and Table 1) exhibits an inhibition activity against the binding of menin and MLL which is useful in the treatment and / or prevention of one or more diseases in which menin and MLL play a role.

[0411] In some embodiments, a compound according to any embodiments herein (e.g., Formulae I and II, and Table 1) exhibits low hERG binding. In some embodiments, a compound according to any embodiments herein (e.g., Formulae I and II, and Table 1) minimizes hERG binding and is useful for the treatment of one or more diseases in which menin and MLL play a role. Without being bound to any theory, one of the primary causes of QT prolongation is thought to be blockage of the hERG potassium channel in cardiac myocytes. In some embodiments, the compounds of the present disclosure (e.g., Formulae I and II, and Table 1) do not significantly block the hERG potassium channel.

[0412] In some embodiments, the compounds of the present disclosure (e.g., Formulae I and II, and Table 1) do not significantly block the hERG potassium channel (e.g., an ICso greater than 1 pM, 5 pM, 10 pM, 15 pM, 20 pM, 25 pM, 30 pM, 35 pM, 40 pM, or 50 pM) as measured by a standard patch clamp hERG assay.

[0413] In some embodiments, the compounds of the present disclosure (e.g., Formulae I and II, and Table 1) do not significantly block the hERG potassium channel (e.g., a compound of the invention has an ICso greater than 1 pM, 5 pM, 10 pM, 15 pM, 20 pM, 25 pM, 30 pM, 35 pM, 40 pM, or 50 pM for the hERG potassium channel). Atorney Docket No. SYND-062 / 001WO 43707-02983

[0414] In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin-MLL interaction comprising a sulfursubstituted benzamide moiety (e.g., Formulae I and II, and Table 1) where the sulfursubstituted benzamide moiety has been found to reduce hERG inhibition.

[0415] In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin-MLL interaction (e.g., Formulae I and II, and Table 1) which are resistant to metabolism. In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin-MLL interaction (e.g., Formulae I and II, and Table 1) which are resistant to metabolism, where the metabolites are inhibitors of the hERG potassium channel. In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin- MLL interaction (e.g., Formulae I and II, and Table 1) which are resistant to metabolism, where the metabolism decreases the bioavailability of the inhibitor. In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin- MLL interaction (e.g., Formulae I and II, and Table 1) which are resistant to metabolism, where the metabolism decreases the bioavailability of the inhibitor and the corresponding metabolites are more effective (e.g., by ICso, etc.) at binding the hERG potassium channel.

[0416] In some embodiments the pharmaceutically acceptable salt of the compound of Formula I, II, or III is a hydrochloride salt or a 2, 2, 2, trifluoroacetate salt.

[0417] In some embodiments the pharmaceutically acceptable salt of the compound of Formula I or II is a hydrochloride salt or a 2,2,2,trifluoroacetate salt.

[0418] Another aspect is an isotopically labeled compound of any of the formulae delineated herein. Such compounds have one or more isotopic atoms e.g.,3H,2H,14C,13C,18F,35S,32P,125I, and131I) introduced into the compound. Such compounds are useful for drug metabolism studies and diagnostics, as well as therapeutic applications. In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0419] It is understood that the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.

[0420] 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 Atorney Docket No. SYND-062 / 001WO 43707-02983 incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium.

[0421] It is understood that the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a deuterium labeled reagent for a non-deuterium labeled reagent.

[0422] A compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the disclosure. Further, substitution with deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0423] For the avoidance of doubt, it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

[0424] Potency can also be determined by ICso value. A compound with a lower ICso value, as determined under substantially similar conditions, is more potent relative to a compound with a higher ICso value.

[0425] Potency can also be determined by ECso value. A compound with a lower ECso value, as determined under substantially similar conditions, is more potent relative to a compound with a higher ECso value.

[0426] The compounds of the application are defined herein by their chemical structures and / or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0427] In another aspect, the application provides a method of synthesizing a compound disclosed herein. The synthesis of the compounds of the application can be found herein and in the Examples below. Other embodiments are a method of making a compound of any of the Atorney Docket No. SYND-062 / 001WO 43707-02983 formulae herein using any one, or combination of, reactions delineated herein. The method can include the use of one or more intermediates or chemical reagents delineated herein.

[0428] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0429] At various places in the present specification, substituents of compounds of the disclosure are disclosed in groups or in ranges. It is specifically intended that the disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term “Ci-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, Cs alkyl, and Ce alkyl.

[0430] At various places in the present specification various cycloalkyl, and heterocyclyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “a pyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyri din-3 -yl, or pyridin-4-yl ring.

[0431] For compounds of the disclosure in which a variable appears more than once, each variable can be a different moiety independently selected from the group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound, the two R groups can represent different moieties independently selected from the group defined for R.

[0432] As used herein, “alkyl”, “Ci, C2, C3, C4, Cs or Ce alkyl” or “Ci-Ce alkyl” is intended to include Ci, C2, C3, C4, Cs or Ce straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, Cs or Ce branched saturated aliphatic hydrocarbon groups. For example, C C6alkyl is intends to include C C2, C3, C4, C5and C6alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., Ci-Ce for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

[0433] As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, Atorney Docket No. SYND-062 / 001WO 43707-02983 alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0434] As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and tri chi orom ethoxy .

[0435] As used herein, the term "amino," employed alone or in combination with other terms, refers to a group of formula -NEE. In some embodiments, an amine can be substituted by one or more groups, e.g., -N-(Ci-Ce alkyl)2. In some embodiments, when two groups are attached to an amine they can be the same or different. Each group is selected independently of each other and can be each independently optionally substituted.

[0436] As used herein, the term “halogen” or "halo," employed alone or in combination with other terms, refers to a halogen atom selected from F, Cl, I or Br. In some embodiments, "halo" refers to a halogen atom selected from F, Cl, or Br. In some embodiments, the halo substituent is F. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0437] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms. In some embodiments, the haloalkyl group is fluorinated. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the haloalkyl group is fluoromethyl, difluoromethyl, or trifluorom ethyl. In some embodiments, the haloalkyl group is trifluorom ethyl. 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.

[0438] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms.

[0439] As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0440] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “C3- Atorney Docket No. SYND-062 / 001WO 43707-02983

[0441] Ce” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6 alkenylene linker” or “C2-C6 alkynylene linker” is intended to include C2, C3, C4, Cs or Ce chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2- C6alkenylene linker is intended to include C2, C3, C4, Cs and Ce alkenylene linker groups.

[0442] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl- piperidinyl and 2,2,6,6-tetramethyl-l,2,3,6-tetrahydropyridinyl.

[0443] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be nonaromatic. In some embodiments, cycloalkyl may optionally contain one or more alkenylene groups as part of the ring structure. Cycloalkyl groups can include mono- or polycyclic ring systems. Polycyclic ring systems can include fused ring systems and spirocycles. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused ( / .<?., having a bond in common with) to the cycloalkyl ring, for example, benzo or pyrido derivatives of cyclopentane, cyclopentene, cyclohexane, and the like. A heterocyclyl group that includes a fused aromatic e.g., aryl or heteroaryl) moiety can be attached to the molecule through an atom from either the aromatic or non-aromatic portion. One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized to form carbonyl linkages. In some embodiments, cycloalkyl is C3-10 cycloalkyl, C3-7 cycloalkyl, or C5-6 cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and the like. Further exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Additional example cycloalkyl groups, where the cycloalkyl group has a fused aryl or heteroaryl moiety, include tetrahydronaphthalen-2-yl, 2,3-dihydro-lH-inden-2-yl; 2, 3,4,9- tetrahydro-lH-carbazol-7-yl; 2,6,7,8-tetrahydrobenzo[cd]indazol-4-yl; and 5,6,7,8,9,10- hexahy drocy cl ohepta [b ] indol -3 -y 1. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0444] As used herein, the term “aryl,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon, such as, but not limited to, phenyl, 1 -naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl is Ce-io aryl. In some embodiments, aryl is Ce-u aryl. In some embodiments, the aryl group is a naphthalene ring or phenyl ring. In some embodiments, the aryl group is phenyl.

[0445] As used herein, the term “heteroaryl,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic heterocylic moiety, having one or more heteroatom ring members selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group has 1, 2, 3, or 4 heteroatom ring members. In some embodiments, the heteroaryl group has 1, 2, or 3 heteroatom ring members. In some embodiments, the heteroaryl group has 1 or 2 heteroatom ring members. In some embodiments, the heteroaryl group has 1 heteroatom ring member. In some embodiments, the heteroaryl group is 5- to 10-membered or 5- to 6-membered. In some embodiments, the heteroaryl group is 5-membered. In some embodiments, the heteroaryl group is 6-membered. In some embodiments, the heteroaryl group is 9- or 10-membered bicyclic. In some embodiments, the heteroaryl is 9-member bicyclic. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides. Example heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, furanyl, thiophenyl, triazolyl, tetrazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiopheneyl, benzofuranyl, benzisoxazolyl, benzoimidazolyl, imidazofl, 2-b]thiazolyl, purinyl, triazinyl, and the like. In some embodiments, the heteroaryl group is 9H-carbazol-2- yl; lH-benzo[d]imidazol-6-yl; lH-indol-6-yl; lH-indazol-6-yl; 2H-indazol-4-yl; 1H- benzo[d][l,2,3]triazol-6-yl; benzo[d]oxazol-2-yl; quinolin-6-yl; or benzo[d]thiazol-2-yl.

[0446] Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodi oxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, deazapurine, indolizine.

[0447] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, Atorney Docket No. SYND-062 / 001WO 43707-02983 alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenyl carbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][l,3]dioxole-5-yl).

[0448] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. As used herein, the term “substituted” or “substituted with one or more”, means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto ( / .< ., =0), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g, C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0449] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0450] When any variable (e.g, R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0451] As used herein, the term "heterocyclyl," employed alone or in combination with other terms, refers to a non-aromatic heterocyclic ring system, which may optionally contain one or more unsaturations as part of the ring structure, and which has at least one heteroatom ring member independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heterocyclyl group has 1, 2, 3, or 4 heteroatom ring members. In some embodiments, the heterocyclyl group has 1, 2, or 3 heteroatom ring members. In some embodiments, the heterocyclyl group has 1 or 2 heteroatom ring members. In some embodiments, the heterocyclyl group has 1 heteroatom ring member. When the heterocyclyl group contains more than one heteroatom in the ring, the heteroatoms may be the same or different. Example ringforming members include CH, CH2, C(O), N, NH, O, S, S(O), and S(=O)2. Heterocyclyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems. Polycyclic rings can include both fused systems and spirocycles. Also included in the definition of heterocyclyl are moi eties that have one or more aromatic rings fused ( / .< ., having a bond in common with) to the non-aromatic ring, for example, 1, 2, 3, 4-tetrahydro-quinoline, dihydrobenzofuran and the like. A heterocyclyl group that includes a fused aromatic moiety can be attached to the molecule through an atom from either the aromatic or non-aromatic portion. The carbon atoms or heteroatoms in the ring(s) of the heterocyclyl group can be oxidized to form a carbonyl, sulfinyl, or sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized. In some embodiments, heterocyclyl is 5- to 10-membered, 4- to 10- membered, 4- to 7-membered, 5-membered, or 6-membered. Examples of heterocyclyl groups include 1, 2, 3, 4-tetrahydro-quinolinyl, dihydrobenzofuranyl, azetidinyl, azepanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and pyranyl. Examples of heterocyclyl groups that include one or more fused aromatic groups (e.g., aryl or heteroaryl) include N-(2'-oxospiro[cyclohexane-l,3'-indolin]-6'-yl; l,2,3,4-tetrahydroisoquinolin-6-yl; 2,3-dihydro-lH-benzo[d]imidazol-5-yl; l,3-dihydrospiro[indene-2,3'-indolin]-6'-yl; 2,3- dihydrobenzo[d]oxazol-5-yl; l,2-dihydroquinolin-7-yl; indolin-6-yl; spiro[cyclopentane-l,3'- indolin]-6'-yl; spiro[cyclohexane-l,3'-indolin]-6'-yl; chroman-6-yl; 3,4-dihydro-2H- benzo[b][l,4]oxazin-6-yl; and benzo[d][l,3]dioxol-5-yl.

[0452] As used herein, “ ” represents a bond to the position indicated by the corresponding variable, for example Ring A, R1, R2, R3, Z, W, Y, X3, R3a, R4a, R4b, R4a’, or R4b’. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0453] As used in the embodiments describing Ring A, when Ring A is

[0454] , or , it is intended that the position of the substituents can be at any position allowed by the available valences according to general formulae I and II, or a stereoisomer, or a pharmaceutically acceptable salt thereof, e.g. , or wherein * indicates attachment to Z.

[0455] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[0456] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents.

[0457] As used herein, the term “chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0458] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0459] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.

[0460] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity.

[0461] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

[0462] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

[0463] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0464] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R and S sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereoisomers, are intended unless otherwise indicated. Where a compound name or structure is silent with respect to the stereochemistry of a stereocenter, all possible configurations at the stereocenter are intended. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0465] When the compounds of the disclosure contain a chiral center, the compounds can be any of the possible stereoisomers. In compounds with a single chiral center, the stereochemistry of the chiral center can be (R) or (S). In compounds with two chiral centers, the stereochemistry of the chiral centers can each be independently (R) or (S) so the configuration of the chiral centers can be (R) and (R), (R) and (S); (S) and (R), or (S) and (S). In compounds with three chiral centers, the stereochemistry each of the three chiral centers can each be independently (R) or (S) so the configuration of the chiral centers can be (R), (R) and (R); (R), (R) and (S); (R), (S) and (R); (R), (S) and (S); (S), (R) and (R); (S), (R) and (S); (S), (S) and (R); or (S), (S) and (S). Atorney Docket No. SYND-062 / 001WO 43707-02983

[0466] Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as 0- camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- m ethylephedrine, cyclohexylethylamine, 1, 2-diaminocyclohexane, and the like.

[0467] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

[0468] As used herein, the terms “El” and “E2” correspond to first and second enantiomers to elute from a chiral chromatography column as discussed in the Examples.

[0469] When a disclosed compound is named or depicted without indicating the stereochemistry of one or more stereocenters, each of the stereoisomers resulting from the possible stereochemistries at the undefined stereocenter(s) are intended to be encompassed. For example, if a stereocenter is not designated as R or S, then either or both are intended.

[0470] Compounds of the disclosure also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1, 2, 4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[0471] Compounds of the disclosure can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. Isotopes of constituent atoms of the compounds of the disclosure can be present in natural or non-natural abundance. Examples of isotopes of hydrogen include deuterium and tritium. In some embodiments, the compounds of the Atorney Docket No. SYND-062 / 001WO 43707-02983 disclosure are deuterated, meaning at least one deuterium atom is present in the place of a hydrogen atom. In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogens in a compound of the disclosure are replaced by deuterium. Methods for replacing hydrogen with deuterium in a molecule are known in the art.

[0472] The term "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified (e.g., in the case of purine rings, unless otherwise indicated, when the compound name or structure has the 9H tautomer, it is understood that the 7H tautomer is also encompassed).

[0473] All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated.

[0474] It will be understood that the compounds of the present disclosure and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds.

[0475] In some embodiments, the compounds of the disclosure, or salts thereof, or crystalline forms of any of the aforementioned, are purified or substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in a compound of the disclosure. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the disclosure, or salt thereof. In some embodiments, the compounds of the disclosure, or salts thereof, or crystalline forms of any of the aforementioned, can be prepared with a purity of about 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more.

[0476] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0477] The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is Atorney Docket No. SYND-062 / 001WO 43707-02983 about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C.

[0478] The present disclosure also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" or "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (MeCN) are preferred.

[0479] The compounds disclosed herein include the compounds themselves, as well as their salts, their solvates, and their prodrugs, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., protonated amino) on a compound of this disclosure. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluroacetate). The term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a compound of this disclosure. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. The compounds of this disclosure also include those salts containing quaternary nitrogen atoms. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing active compounds of this disclosure. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0480] Additionally, physiologically acceptable, i.e., pharmaceutically compatible, salts can be salts of the compounds disclosed herein with inorganic or organic acids. Preference is given to salts with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or to salts with organic carboxylic or sulphonic acids, such as, for example, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.

[0481] Other pharmaceutically compatible salts which may be mentioned are salts with customary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts, derived from ammonia or organic amines, such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine or methylpiperidine.

[0482] As used herein, “pharmaceutically acceptable salts” can refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0483] Other examples of pharmaceutically acceptable salts can include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, Atorney Docket No. SYND-062 / 001WO 43707-02983 cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l -carboxylic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, or an alkaline earth metal ion, e.g., an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-m ethylglucamine, diethylamine, diethylaminoethanol, ethylenediamine, imidazole, lysine, arginine, morpholine, 2- hydroxyethylmorpholine, dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine, tetramethylammonium hydroxide and the like.

[0484] It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0485] It is to be understood that, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to provide such treatment or prevention as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to prepare a medicament to treat or prevent such condition. The treatment or prevention includes treatment or prevention of human or non-human animals including rodents and other disease models.

[0486] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment includes use of the compounds to prepare a medicament to treat such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.

[0487] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the subject is a human.

[0488] As used herein, the term “subject in need thereof’ refers to a subject having a disease or having an increased risk of developing the disease. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A Atorney Docket No. SYND-062 / 001WO 43707-02983 subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy.

[0489] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model. It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0490] It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.

[0491] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0492] It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18thedition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure.

[0493] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0494] The compounds of the present disclosure may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the sulfonylurea group in a compound of the any one of the Formulae disclosed herein.

[0495] Accordingly, the present disclosure includes those compounds of the present disclosure as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of the present disclosure that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the present disclosure may be a synthetically-produced compound or a metabolically-produced compound.

[0496] A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, Atorney Docket No. SYND-062 / 001WO 43707-02983

[0497] 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0498] A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the present disclosure containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include Cl -CIO alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Cl -CIO alkoxy carbonyl groups such as ethoxy carbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin- 1-ylmethyl and 4- (C1-C4 alkyl)piperazin- 1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0499] A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-C4 alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl N-methylamine or diethylamine, a C1-C4 alkoxy C2-C4 alkylamine such as 2 methoxyethylamine, a phenyl Ci- C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0500] A suitable pharmaceutically acceptable prodrug of a compound of the present disclosure that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl Atorney Docket No. SYND-062 / 001WO 43707-02983 and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminom ethyl, morpholinomethyl, piperazin- 1-ylmethyl, and 4-(Cl-C4 alkyl)piperazin- 1-ylmethyl.

[0501] The in vivo effects of a compound of the present disclosure may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the present disclosure. As stated hereinbefore, the in vivo effects of a compound of the present disclosure may also be exerted by way of metabolism of a precursor compound (a prodrug).

[0502] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

[0503] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.

[0504] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.

[0505] As use herein, the phrase “compound of the disclosure” refers to those compounds which are disclosed herein, both generically and specifically. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0506] Synthesis

[0507] In some aspects, the present disclosure provides a method of preparing a compound disclosed herein.

[0508] In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps as described herein.

[0509] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound described herein.

[0510] In some aspects, the present disclosure provides an intermediate being suitable for use in a method for preparing a compound described herein.

[0511] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.

[0512] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0513] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilized.

[0514] It will be appreciated that during the synthesis of the compounds of the disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0515] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl (Bn). The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group such as a tert butoxy carbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0516] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0517] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0518] Once a compound of the present disclosure has been synthesized by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound of the present disclosure Atorney Docket No. SYND-062 / 001WO 43707-02983 into another compound of the present disclosure; (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0519] The resultant compounds of the present disclosure can be isolated and purified using techniques well known in the art.

[0520] Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as tri chi or ethylene, 1,2- di chloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methylisobutylketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the said solvents or mixtures with water.

[0521] The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used.

[0522] Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours.

[0523] Moreover, by utilizing the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0524] As will be understood by the person skilled in the art of organic synthesis, compounds of the present disclosure are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples. The skilled person will easily recognize which kind of reagents and reactions conditions are to be used and how they are to be applied and Atorney Docket No. SYND-062 / 001WO 43707-02983 adapted in any particular instance - wherever necessary or useful - in order to obtain the compounds of the present disclosure. Furthermore, some of the compounds of the present disclosure can readily be synthesized by reacting other compounds of the present disclosure under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilled person will apply - whenever necessary or useful - synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well- known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons). The compounds of the disclosure can be synthesized by the methods described in Schemes 1-5 below. The synthesis of various hydroxyl-substituted heterocycles is well documented in the literature and can be synthesized by known literature methods. The depicted intermediates may also be available as commercial reagents from numerous vendors.

[0525] The compounds of the present disclosure can be prepared according to the general methods illustrated in the following Schemes.

[0526] Scheme 1

[0527] Scheme 1 illustrates the general methods for preparing the key intermediate 1-H. The carboxylic acid 1-A can be converted initially to the amide 1-B. Many different conditions have been developed to achieve this type of transformation, and are well-known to those in the art. For instance, carboxylic acid 1-A can be converted to an intermediate acid chloride (not shown), using thionyl chloride, in a neutral solvent like CH2CI2 or THF, and that acid chloride can then be reacted with a suitable amine to afford amide 1-B. Typically, N,N- Atorney Docket No. SYND-062 / 001WO 43707-02983 dimethylamine is the amine of choice for this particular chemistry, which affords the N,N- dimethyl amide (1-B; Ri and R2 = CH3). Amide 1-B is then reacted with a 5-halopyrimidine (1-C), such as 5 -bromopyrimidine or 5-iodopyrimidine, to afford the corresponding diaryl ether 1-D. As an example, amide 1-B can be reacted with 5-bromopyrimidine in the presence of a base, for instance cesium carbonate, in a neutral solvent such as dimethylacetamide, to afford 1-D. The amide group of compound 1-D is subsequently saponified to the corresponding carboxylic acid 1-E. Typically, this transformation is accomplished using LiOH, NaOH or KOH, in an aqueous solvent system, such as methanol / water or THF / water. Heat can be used to increase the reaction rate. The carboxylic acid is then converted to ester 1-F. The transformation of a carboxylic acid to an ester is usually achieved by reacting the carboxylic acid with an alcohol, such as methanol or ethanol, in the presence of an acid catalyst like HC1 or H2SO4. Typically, the alcohol is used as a solvent, and heat can be used to increase the reaction rate. Alternatively, 1-E can be O-alkylated using methyl iodide in the presence of an acid scavenger, oftentimes K2CO3, to afford 1-E. Reaction of 1-E with a suitable oxidizing agent, such as urea hydroperoxide in the presence of trifluoroacetic anhydride, or meto-chloroperoxybenzoic acid (mCPBA), in a suitable solvent, typically CH2CI2 or THF, affords the pyrimidine A-oxide 1-G. This then can be chlorinated to afford compound 1-H using an appropriate chlorinating agent, typically POCI3 or oxalyl chloride, in the presence of an acid scavenger, usually EtsN, (i-Pr)2NEt, in a neutral solvent like CH2CI2, ethyl acetate (EtOAc), or isopropyl acetate.

[0528] Scheme 2 Atorney Docket No. SYND-062 / 001WO 43707-02983

[0529] Scheme 2 illustrates an alternative method to prepare the key intermediate 1-H. A suitably substituted 2-halophenol, for instance 4-fluoro-2-bromophenol (2-A), is reacted with a 5- halopyrimidine (1-C), for example 5-bromopyrimidine or 5-iodopyrimidine, to afford the corresponding diaryl ether (2-B). This reaction is typically conducted in the presence of an acid scavenger like Na2COs, K2CO3, CS2CO3, K3PO4, EtsN (triethylamine) or (i-Pr)2NEt (diispropylethylamine, also known as Hunig’s base), in a suitable, neutral solvent, such as DMA (dimethyl acetamide) or NMP (A-methylpyrrolidinone). In some instances, this transformation can be facilitated by addition of an appropriate catalyst, typically CU2O or Cui, in the presence of a suitable ligand, for example re / -(lA,2A)-A1,A2-bis(2- pyridinylmethylene)-l,2-cyclohexanediamine or 3,4,7,8-tetramethyl-l,10-phenanthroline. Conversion of compound 2-B to compound 1-F can be readily achieved by carbonylation under Pd catalysis, in the presence of an acid scavenger and suitable alcohol (typically used as the solvent in the reaction). Oftentimes, Pd(dppf)C12 (dppf = 1,1- bis(diphenylphosphino)ferrocene) is used as the palladium catalyst, but other catalyst systems, such as Pd(Ph3P)2C12 (PI13P = triphenylphosphine) or Pd(OAc)2 with PI13P, can also be used. Commonly, EtsN or (i-Pr)2NEt are used as the acid scavengers, and methanol is used as the solvent. These reactions are most typically run under an atmosphere of CO, but other CO sources, for example oxalic acid, can be used in some instances. Reaction of 1-F under oxidizing conditions, such as those described in Scheme 1, delivers the A-oxide derivative 1- G, which can be chlorinated, according to the general conditions described in Scheme 1, to afford the key intermediate 1-H. It will be appreciated by those of skill in the art that compound 1-H is a flexible intermediate that can be converted into the compounds of the present invention in a variety of ways.

[0530] Atorney Docket No. SYND-062 / 001WO 43707-02983

[0531] Scheme 3

[0532] Scheme 3 illustrates the general method for the preparation of key intermediates like compound 3-G. A suitable 2-halo-4-hydroxypyridine, for instance 2-chloro-4- hydroxypyridine (3-A), is reacted with an appropriate alkylating or acylating agent, for instance 4-methoxybenzyl chloride, to afford the protected derivative 3-B. The protecting group is selected so that it can be removed selectively when desired. Note that, in some instances, the protecting group might attach to nitrogen, to afford an TV-substituted 4-pyridone derivative (not shown). This would be considered acceptable, as long as the position of the protecting group (O vs. N) does not interfere with the ensuing chemistry. Compound 3-B is subsequently transformed to compound 3-C. Typically, this transformation is accomplished by reacting 3-B with a suitable olefinic boron reagent, for instance potassium vinyltrifluoroborate, vinylboronic acid, vinylboronic acid pinacol ester (also known as 2- vinyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane), isopropenylboronic acid, isopropenylboronic acid pinacol ester (also known as 2-isopropenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane), propenylboronic acid, or propenylboronic acid pinacol ester (also known as 4, 4,5,5- tetramethyl-2-(prop-l-en-l-yl)-l,3,2-dioxaborolane). The corresponding olefinic stannanes, for instance tributylvinyltin (also known as tributyl(vinyl)stannane), might also be used. This reaction is typically mediated by a palladium catalyst, such as PdCh; Pd(OAc)2, or [(Ph3P)]4Pd, oftentimes in the presence of a ligand for Pd, such as dibenzylideneacetone or l,l'-bis(diphenylphosphino)ferrocene (dppf). Typically, an acid scavenger, like EtsN, Hunig’s base, potassium carbonate, or cesium carbonate, is used, and the reaction is conducted in an appropriate solvent, such as ethanol, tetrahydrofuran, or 1,4-di oxane. As an example of this type of reaction, compound 3-B can be reacted with potassium Atorney Docket No. SYND-062 / 001WO 43707-02983 vinyltrifluoroborate, PdC12(dppf), and EtsN in ethanol to afford 3-C (R3 = R4 = H). Reaction of 3-C with an appropriate amine, for instance benzylamine, produces 3-D. This reaction oftentimes requires an acidic catalyst, such as acetic acid, in methanol or ethanol as the solvent. Removal of the protecting group then delivers 3-E. As indicated previously, conditions for adding and removing protecting groups are described in established reference volumes, for instance Greene's Protective Groups in Organic Synthesis, 4thEdition (ISBN:9780470053485). In the case of 3-E, the 4-methoxybenzyl group can be selectively removed using trifluoroacetic acid (TFA) in a neutral solvent like CH2CI2 or 1,2- di chloroethane. Compound 3-E will react with aldehydes in a classic Pictet-Spengler-type reaction. Typical solvents for this type of reaction include methanol, ethanol, n-butanol, or DMSO, and sometimes, a base like EtsN, Hunig’s base, or K2CO3 is used. For example, reaction of 3-E with formalin in methanol or ethanol affords the tetrahydronaphthyridine derivative 3-F. Reaction with other aldehydes, for instance acetaldehyde, would deliver 3-F (Rs = CEE). If desired, the benzyl group on the basic nitrogen of 3-F can be removed by hydrogenolysis over a palladium catalyst, typically using hydrogen gas in the presence of a palladium catalyst (oftentimes palladium on activated carbon). This reaction is typically conducted in a solvent like acetic acid, methanol, ethanol, ethyl acetate, or mixtures thereof. Sometimes, a strong acid (like HC1) is incorporated into the reaction to afford the acid salt of the amine. Alternatively, if this reaction is conducted in the presence of Boc anhydride, in a solvent like methanol, ethanol, ethyl acetate, or mixtures thereof, the A- Boc derivative 3-G would emerge from the reaction. Compounds 3-F and 3-G are both useful intermediates for preparing the compounds of this

[0533] Atorney Docket No. SYND-062 / 001WO 43707-02983

[0534] Scheme 4

[0535] Scheme 4 illustrates the general methods for converting the key intermediate 3-G into the compounds of the present invention (4-F and 4-G) (X and Y = N and / or CH). Compound 3-G (X = N, Y = CH), which can be prepared according to the general procedures described in Scheme 3, can be reacted with an appropriate aliphatic iodo / bromo compound 4-A, under standard O-alkylation conditions, to afford compound 4-B. The O-alkylation reaction can be performed under a wide range of conditions well-known to those of skill in the art. For example, compound 3-G and benzyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate can be combined in the presence of a base, such as Na2COs, K2CO3, or CS2CO3, in a neutral solvent like THF, DMF, DMSO or NMP, at elevated temperature, to afford 4-B. Alternatively, 4-B can be synthesized using 3-G and an appropriate alcohol, for instance, a suitably protected variant of 2-azaspiro[3.3]heptan-6-ol, under Mitsunobu conditions. Typically, a Mitsunobu reaction is conducted using a diazodicarboxylate, typically DEAD (diethyl azodicarboxylate), DIAD (diisopropyl azodicarboxylate), or ADDP (1,1’- (azodicarbonyl)dipiperidine), and an appropriate phosphine, typically PPI13 (triphenylphosphine). Alternatively, the coupling can be mediated by the Tsunoda reagent (2- tributylphosphoranylidene)acetonitrile). The reaction is conducted in a neutral solvent like THF, ACN, CH2CI2 or toluene. On the other hand, one might employ a copper (II) catalyzed Atorney Docket No. SYND-062 / 001WO 43707-02983 coupling reaction to prepare 4-B, using an appropriate boron reagent like a potassium aryltrifluoroborate, and a suitably protected variant of 2-azaspiro[3.3]heptan-6-ol. This type of reaction is usually conducted in the presence of a ligand like TMEDA or 1,10- phenanthroline, in the presence of a base like pyridine or DMAP, in a neutral solvent like CH2CI2. Another approach to prepare compound 4-B could be to react compound 3-G (where, X and Y = N, Cl instead of OH) with an appropriate alcohol 4-A, using a strong base like KOtBu or sodium hydride, in a neutral solvent like THF, DMF, DMSO or NMP. As an example of this type of reaction, compound 3-G (where X and Y = N; Cl instead of OH) can be reacted with benzyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate and sodium hydride in DMF to afford 4-B (where X and Y = N) at RT. Removal of the protecting group then affords compound 4-C, which is a useful intermediate that can be used to make additional compounds. The use of protecting groups in organic synthesis is well-known to those of skill in the art, and conditions for adding and removing protecting groups are described in established reference volumes, for instance, Greene's Protective Groups in Organic Synthesis, 4thEdition (ISBN:9780470053485). For instance, when the protecting group PG2 in 4-B is Cbz, deprotection is oftentimes achieved under hydrogenolysis conditions, to give compound 4-C. Hydrogenolysis is accomplished by reaction with hydrogen gas, generally in the presence of a palladium catalyst, such as palladium on activated carbon (Pd / C) or Pd(OH)2. Sometimes, AcOH or HC1 is added to the reaction mixture, and a suitable solvent, like methanol, ethanol, 2,2,2-trifluoroethanol, ethyl acetate, or a combination thereof, is typically used. Sometimes, PtCh can be used as a hydrogenolysis catalyst. When the protecting group PG2 in 4-B is Boc ( / cvV-butyloxycarbonyl), deprotection is oftentimes accomplished under acidic conditions, using acids like HC1, TFA (trifluoracetic acid), or / ?-TsOH (para- toluenesulfonic acid), in a suitable solvent, oftentimes CH2CI2, THF or 1,4-di oxane. Preferably, the Boc group in compound 4-B is removed with TMSC1 in 2,2,2- trifluoroethanol.

[0536] The amine compound 4-C can be readily reacted with the chloride of compound 1-H. The ester group is subsequently saponified to the corresponding carboxylic acid (not shown in the scheme). Typically, this transformation is accomplished using LiOH, NaOH or KOH, in an aqueous solvent system, such as methanol / water or THF / water. If desired, the carboxylic acid can also be isolated as the Li, Na, or K salt. The carboxylic acid is then converted to an amide (4-E). Many different conditions have been developed to achieve this type of transformation Atorney Docket No. SYND-062 / 001WO 43707-02983 and will be generally familiar to those of skill in the art. For instance, the carboxylic acid can be reacted with phosphorus trichloride, thionyl chloride or oxalyl chloride, which forms the corresponding acid chloride. This reaction can be conducted in a suitable, neutral solvent like CH2CI2, or if thionyl chloride is used, can be run with thionyl chloride as the reactant and solvent. The acid chloride is subsequently reacted with a suitable amine, R1R2NH (R1 = alkyl and R2 = cyclic / acyclic sulfide, sulfone, sulfoxide or sulfoximine), in the presence of an appropriate acid scavenger, for example, EtsN, (i-Pr)2NEt, or pyridine, in a neutral solvent like CH2CI2 or THF. In some instances, pyridine can be used as the acid scavenger and the solvent for the reaction. Alternatively, the carboxylic acid and amine R1R2NH (R1 = alkyl and R2 = cyclic / acyclic sulfide, sulfone, sulfoxide or sulfoximine) can be combined and coupled using a reagent such as DCC (dicyclohexyl carbodiimide), EDC (l-ethyl-3-(4- dimethylaminopropyl)carbodiimide), HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HBTU (2-(lH-benzotriazol-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate), or T3P (propanephosphonic acid anhydride, 50% in EtOAc), in the presence of an appropriate acid scavenger, for example, EtsN, (i-Pr)2NEt, or pyridine, in a neutral solvent, oftentimes DMF, NMP, CH2CI2 or THF. In some instances, when DCC or EDC is used as the coupling reagent, HOBt (hydroxybenzotriazole) might be added to the reaction to facilitate the desired coupling reaction. In some cases, phosphorus trichloride in combination with DIPEA in a neutral solvent like CftCh.can be used for this transformation. When a protecting group (PG1) is required, it can be removed subsequently according to the nature of the protecting group. For instance, when the protecting group PG1 in 4-E is Boc, deprotection is achieved according to the general methods described for the Boc-deprotection under acidic condition (see 4-B to 4- C), to give compound 4-F. Compound 4-F can be isolated as a salt, where n HX denotes the salt form, or as the free base, following work-up under standard basic conditions. When PG1 = Bn in 4-E, deprotection can be accomplished according to the general methods described for the Cbz-deprotection under hydrogenolysis conditions (see 4-B to 4-C).

[0537] If desired, 4-F can be TV-alkylated to afford compound 4-G (X and Y = N and / or CH, R = an appropriate alkyl group). In this type of reaction, 4-F reacts with an alkyl halide or an alkyl sulfonate (for instance, a tritiate, mesylate, or tosylate) to afford the alkylated product 5-G. This reaction can be conducted in the presence of a base like, Na2COs, K2CO3, CS2CO3, EtsN (tri ethylamine) or (i-Pr)2NEt (diispropylethylamine, also known as Hunig’s base), in a Atorney Docket No. SYND-062 / 001WO 43707-02983 suitable, neutral solvent, such as ACN, THF, DMF, DMA (dimethyl acetamide) or NMP (TV- methylpyrrolidinone). Alternatively, 4-F can react with a suitable aldehyde or ketone in a reductive amination reaction. This reaction can be conducted in the presence of STAB (sodium triacetoxyborohydride) or NaCNBHs (sodium cyanoborohydride) and acetic acid, in a suitable solvent, such as MeOH, DCE, CH2CI2, THF, DMF or NMP or a combination thereof. In a representative example, formaldehyde can be reacted with 4-F in the presence of STAB (sodium triacetoxyborohydride) and AcOH, in DCE to afford the TV-methylated compound 4-G. Alternatively, another approach to convert compound 4-F to 4-G is to react 4-F with a dihaloalkane (like l-bromo-3 -chloropropane) in the presence of Na2COs, K2CO3, CS2CO3, EtsN or (i-Pr)2NEt, in a suitable, neutral solvent, such as ACN, THF, DMF or DMA to obtain the corresponding TV-alkylated halo intermediate (not shown in the scheme). This can further react with another amine R.6R7NH, in the presence of a base, such as EtsN or (i- Pr)2NEt), in a suitable, neutral solvent, such as ACN, THF or DMF, to afford compound 4-G (wherein R contains the ReR?N- group).

[0538] Scheme 5

[0539] Scheme 5 illustrates the general methods for converting compound 5-A into compounds 5-K and 5-L. Compound 5-A can be reacted with aldehydes in a Pictet-Spengler-type reaction, according to the general procedures described in Schemes 4 (see 3-D to 3-E). For example, reaction of 5-A with methyl 4-oxobutanoate in DMSO affords the tetrahydronaphthyridine derivative 5-C. The benzyl group on the basic nitrogen of 5-C can be removed by Atorney Docket No. SYND-062 / 001WO 43707-02983 hydrogenolysis, typically using hydrogen gas with a palladium catalyst (oftentimes palladium on activated carbon), in the presence of catalytic acetic acid, in MeOH or ethanol as solvent. The resulting free amine (not shown in the scheme) typically reacts with the ester in situ to afford the lactam product 5-D. Compound 5-D can be O-alkylated using a suitable alkylating reagent, following the general methods described in Scheme 4 (see 3-G to 4-B). Preferably, 5-D can be reacted with 5-E (tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate) under basic conditions, such as K2CO3, in a neutral solvent, DMF, at elevated temperature, to afford 5-F. The protecting group (Boc or Bn) of 5-F can be removed using the general procedures for removing a Boc or Bn protecting group described in Scheme 4 (see 4-B to 4-C), to afford 5-G. The amide group of 5-G can be subsequently reduced to the corresponding amine. Many different conditions have been developed to achieve this type of transformation and will be generally familiar to those of skill in the art. Typically, this transformation is accomplished using aluminum hydride or boron hydride reducing agents (for example, LiAIFU, BH3.Et2O, BH3.DMS, or 9-BBN), in neutral solvents such as THF, Et2O, DCM, hexane or toluene. As an example, the amide group of 5-G can be reduced to the amine 5-H using LiAlEU in THF. Alternatively, the amide can be reduced to the corresponding amine by initial amide activation using, for instance, Tf2O (trifluoromethanesulfonic anhydride) in the presence of an acid scavenger like 2-fluoropyridine, or a Lewis acid, such as BF3.Et2O, followed by reduction with a reducing agent like NaBH4 or tetramethyldisiloxane. The amines 5-G and 5- H can be isolated as the free base or as a suitable salt form, as discussed in Scheme 4. Compound 5-H is then converted to 5-1 according to the general methods described previously (see earlier Scheme 4). The ester group of 5-1 is subsequently saponified to the corresponding carboxylic acid (not shown). The carboxylic acid is then converted to the racemic amide corresponding to 5-K and 5-L (not shown), according to the general methods for amide formation described in Scheme 4. In a representative example, the carboxylic acid is reacted with a suitable amine, R1R2NH (R1 = alkyl and R2 = cyclic / acyclic sulfide, sulfone, sulfoxide or sulfoximine), using T3P (propanephosphonic acid anhydride, 50% in EtOAc), in the presence of an appropriate acid scavenger, (i-Pr)2NEt, in CH2CI2 to obtain the racemic amide corresponding to 5-K and 5-L (not shown). The pure enantiomers, 5-K and 5- L can be isolated by chiral purification using HPLC or SFC. Typically, this purification is accomplished using a chiral SFC method. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0540] General Biological Methods

[0541] Menin-MLL Competition andMV4;ll Cell Proliferation Assays

[0542] Menin-MLL is a competition assay between human Menin and N-terminal portion of human MLL representing amino acids 4-43 of the protein. The interaction between Menin and MLL peptide was monitored by HTRF employing Terbium labeled anti-His6 antibody directed to the N-terminal His6-tag on recombinant Menin and FITC group covalently attached to the MLL peptide. The N-terminal fragment of MLL, retained in all MLL fusion proteins, is involved in the interactions with Menin, and this protein-protein interaction is critical for the MLL fusion proteins mediated leukemogenic transformations.

[0543] For ICso determination test compounds may be prepared as stock solutions. Lower substocks of 50pM may be prepared from the lOmM stock solution. To test the compounds in assay, 3.16-fold serial dilutions are made in 100% DMSO. Mid-stock of 50x compounds (50pM) were serially diluted (3.16 fold) in 100% DMSO in Polypropylene plate. In assay plate 1 micro-litre of the previously prepared compound dilution was stamped. H-FL-Menin diluted to 4nM in assay buffer (50 mM Tris-HCl, pH 7.4, 50 mM NaCl, freshly prepared 1 mM DTT, 0.01% BSA, 0.005% Triton X-100) was pre-incubated with 8nM anti-His6-Tb for 30 min at room temperature. FITC-MLL-4-43 was diluted to 2nM in assay buffer and 25 pL was dispensed into each well of the assay plate followed by addition of 25 pl of pre-incubated H- FL-Menin and anti-His6-Tb mixture. Final concentration H-FL-Menin diluted to InM in assay plate with 2nM anti-His6-Tb and InM FITC-MLL-4-43. After 1 hr incubation at room temperature, the HTRF signal was measured on the Spark multi-label plate reader. Resulting data were captured as a ratio of RFU520 / RFU485 x 1000. The max values were obtained from 0% inhibition in presence of 2% DMSO and the min. values were 100% inhibition in presence of IpM reference compound.

[0544] Cell Proliferation Assay -MV4; 11

[0545] Compounds were evaluated for its capacity to inhibit the proliferation of the MLLr leukemia cell line MV4-11 that harbors an MLL1-AF4 fusion protein. MV4-11 cells were cultured for 72 hours with limiting dilutions of compounds and viability was measured using CellTiter-Glo.

[0546] Compounds were dissolved to obtain as lOmM solution in DMSO. The stock was diluted 1 :5 to the top concentration of 2mM in 100% DMSO. For IC50 determination, serial 1 :3.16 dilutions were prepared in 100% DMSO by diluting 20pL into 43.5pL of DMSO for 8 Atorney Docket No. SYND-062 / 001WO 43707-02983 concentrations. Each prepared DMSO solution were further diluted 1 :500 in the cell culture media to obtain the 2x dosing solutions. The final concentrations of tested compounds in the cell culture media ranged from 0.632nM to 2000nM.

[0547] MV4-11 cells were cultured in IMDM with 10% FBS and lx Penicillin-Streptomycin at 5% CO2 and 37°C. A cell suspension was prepared containing 15,000cells / ml in the culture medium and lOOpL of this suspension was added per well to a 96-well cell culture plate. Then, 100 pL of 2x dosing media containing test compounds were added bringing the total volume to 200pL. These cells were cultured for 72 hours at 37°C and 5% CO2 in a humidified incubator.

[0548] After 72 hours, the cultured cells were mixed and lOOpL was transferred to a 96-well black plate. Cell Titer Gio (100 pl) was then added to this plate. The plate was mixed with shaking for 15 mins at RT, the luminescence was then measured using Tecan Spark 20M spectrophotometer. Cell Viability (%) was determined by RLU of test / RLU average vehicle control* 100 and % max inhibition was determined by 100-(% cell viability remaining at the top concentration of compound). hERG Patch Clamp Assay

[0549] The hERG inhibition assay uses a high throughput single cell planar patch clamp approach. Chinese hamster ovary cells transfected with the hERG gene (CHO-hERG) are dispensed into the PatchPlate. Amphotericin is used as a perforating agent to gain electrical access to the cells. The hERG tail current is measured prior to the addition of the test compound by perforated patch clamping. Following addition of the test compound at a defined concentration or range of concentrations a second recording of the hERG current is performed. The degree of inhibition (%) is obtained by measuring the tail current amplitude, which is induced by a one second test pulse to - 40 mV after a two second pulse to + 20 mV, before and after drug incubation (the difference current is normalized to control and multiplied by 100 to obtain the percent of inhibition). The patch clamp assay can be used according to the knowledge of a person of ordinary skill in the art to accordingly assess the compounds of the present disclosure.

[0550] In any one of the embodiments described herein, the compound has an IC50 of more than 10, 15, 20, 25, or 30 pM in a standard human ether-a-go-go related gene (hERG) patch clamp assay.

[0551] A number of drugs have been withdrawn from late-stage clinical trials due to cardiotoxic effects, therefore it is important to identify and avoid compounds with potential for cardiotoxic effects early in drug discovery. The cardiovascular toxicity of a compound can be Atorney Docket No. SYND-062 / 001WO 43707-02983 measured using a standard human ether-a-go-go related gene (hERG) assay. The human ether- a-go-go related gene (hERG) encodes the inward rectifying voltage gated potassium channel in the heart (IKr), which is involved in cardiac repolarization. Inhibition of the hERG current causes QT interval prolongation resulting in potentially fatal ventricular tachyarrhythmia called Torsade de Pointes. A compound having an IC50 of more than about 10 pM or more than about 15 pM, in the hERG assay may be considered as free from any cardiovascular toxicity. In some embodiments, the compounds of Formulae I, II, III and / or Table 1 have reduced hERG binding compared to structural analogs. In some embodiments, the compounds of Formulae I and II, and / or Table 1 have reduced hERG binding compared to structural analogs. In some embodiments, the compounds of Formulae I, II, III and / or Table 1 ICso of more than 10 pM, 15 pM, 20 pM, 25 pM, or 30 pM in the standard patch clamp hERG assay. In some embodiments, the compounds of Formulae I and II, and / or Table 1 ICso of more than 10 pM, 15 pM, 20 pM, 25 pM, or 30 pM in the standard patch clamp hERG assay.

[0552] In some embodiments, the compounds of the present disclosure (e.g., Formulae I, II, III and Table 1) do not significantly block the hERG potassium channel (e.g., an ICso greater than 1 pM, pM, 10 pM, 15 pM, 20 pM, 25 pM, 30 pM, 35 pM, 40 pM, or 50 pM) in the standard patch clamp hERG assay.

[0553] In some embodiments, the compounds of the present disclosure (e.g., Formulae I and II, and Table 1) do not significantly block the hERG potassium channel (e.g., an ICso greater than 1 pM, pM, 10 pM, 15 pM, 20 pM, 25 pM, 30 pM, 35 pM, 40 pM, or 50 pM) in the standard patch clamp hERG assay.

[0554] Methods of Use

[0555] The compounds of the invention are inhibitors of the interaction of menin with MLL and MLL fusion proteins. In some embodiments, the present disclosure is directed to a method of inhibiting the interaction between menin and MLL or an MLL fusion protein by contacting menin and MLL or the MLL fusion protein with a compound of the disclosure. The contacting can be carried out in vitro or in vivo. In some embodiments, the compounds of the disclosure can bind to menin, thereby interfering with the binding of MLL to menin. In some embodiments, the present disclosure provides a method of inhibiting the activity of menin by contacting menin with a compound of the disclosure in the presence of MLL or an MLL fusion protein. In further embodiments, the present disclosure provides a method of inhibiting the binding of MLL or an MLL fusion protein to menin, comprising contacting menin with a compound of the disclosure in the presence of the MLL or MLL fusion protein. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0556] In some embodiments, compounds of the present disclosure minimize hERG interactions. In some embodiments, the present disclosure is directed to a method of inhibiting the interaction between menin and MLL or an MLL fusion protein by contacting menin and MLL or the MLL fusion protein with a compound of the disclosure while the compounds of the disclosure minimize hERG activity. In some embodiments, the present disclosure is directed to a method of inhibiting the interaction between menin and MLL or an MLL fusion protein by contacting menin and MLL or the MLL fusion protein with a compound of the disclosure while the compound of the disclosure avoids drug-induced blockade of hERG.

[0557] Evaluating the hERG activity can be accomplished by many methods known in the art. Including, such methods for the assessment of hERG liability is the patch-clamp electrophysiological assay on hERG transfected cells. Various other strategies including radiolabeled binding assays, functional assays, and rubidium efflux assays also quantify hERG potency.

[0558] The compounds of the disclosure are also useful in treating diseases associated with the menin-MLL interaction or menin-MLL fusion protein interaction. For example, diseases and conditions treatable according to the methods of the disclosure include cancer, such as leukemia, and other diseases or disorders mediated by the menin-MLL interaction or menin- MLL fusion protein interaction such as diabetes.

[0559] Accordingly, the compounds of the disclosure are believed to be effective against a broad range of cancers, including, but not limited to, hematological cancer (e.g., leukemia and lymphoma), bladder cancer, brain cancer (e.g., glioma, diffuse intrinsic pontine glioma (DIPG)), breast cancer (e.g., triple-negative breast cancer, estrogen-receptor-positive breast cancer ( / .< ., ER+ breast cancer)), colorectal cancer, cervical cancer, gastrointestinal cancer (e.g., colorectal carcinoma, gastric cancer), genitourinary cancer, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer (e.g., castration resistant prostate cancer), renal cancer (e.g., renal cell carcinoma), skin cancer, thyroid cancer (e.g., papillary thyroid carcinoma), testicular cancer, sarcoma (e.g., Ewing’s sarcoma), and AIDS-related cancers. In some embodiments, the cancer is associated with a rearranged MLL gene. In some embodiments, the pathophysiology of the cancer is dependent on the MLL gene. In some embodiments, the cancer is associated with mutant p53 gain-of- function.

[0560] In some embodiments, the specific cancers that may be treated by the compounds, compositions and methods described herein include cardiac cancers, such as for example, Atorney Docket No. SYND-062 / 001WO 43707-02983 sarcoma (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; lung cancers, including, for example, bronchogenic carcinoma (e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma), alveolar and bronchiolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, bronchial adenomas / carcinoids, and pleuropulmonary blastoma; gastrointestinal cancer, including, for example, cancers of the esophagus (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma), cancers of the stomach (e.g., carcinoma, lymphoma, and leiomyosarcoma), cancers of the pancreas (e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma), cancers of the small bowel (e.g., adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma), cancers of the large bowel or colon, (e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma), and other cancers of the digestive tract (e.g., anal cancer, anorectal cancer, appendix cancer, cancer of the anal canal, cancer of the tongue, gallbladder cancer, gastrointestinal stromal tumor (GIST), colon cancer, colorectal cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, rectal cancer, and small intestine cancer); genitourinary tract cancers, including, for example, cancers of the kidney (e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, and leukemia), cancers of the bladder and urethra (e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma), cancers of the prostate (e.g., adenocarcinoma and sarcoma), cancers of the testis, (e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma), as well as transitional cell cancer, transitional cell cancer of the renal pelvis and ureter and other urinary organs, urethral cancer, and urinary bladder cancer; liver cancers, including, for example, hepatoma (e.g., hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; bone cancers, including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; nervous system cancers, including, for example, cancers of the skull (e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans); cancers of the meninges (e.g., Atorney Docket No. SYND-062 / 001WO 43707-02983 meningioma, meningiosarcoma, and gliomatosis); cancers of the brain (e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors); cancers of the spinal cord (e.g., neurofibroma, meningioma, glioma, and sarcoma), and other nervous system cancers (e.g., brain stem glioma, diffuse intrinsic pontine glioma (DIPG), brain tumor, central nervous system cancer, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, primary central nervous system lymphoma, visual pathway and hypothalamic glioma, nervous system lymphoma, supratentorial primitive neuroectodeimal tumors, pineoblastoma and supratentorial primitive neuroectodermal tumors); gynecological cancers, including, for example, cancers of the uterus (e.g., endometrial carcinoma), cancers of the cervix (e.g., cervical carcinoma, and pre tumor cervical dysplasia), cancers of the ovaries (e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa thecal cell tumors, Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma), cancers of the vulva (e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma), cancers of the vagina (e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma), and cancers of the fallopian tubes (e.g., carcinoma); other reproductive tract cancers, including, for example, endometrial cancer, endometrial uterine cancer, germ cell tumor, gestational trophoblastic tumor, gestational trophoblastic tumor glioma, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, penile cancer, vaginal cancer, vulvar cancer, extracranial germ cell tumor, extragonadal germ cell tumor, uterine cancer, uterine corpus cancer, uterine sarcoma; lymphatic and hematologic cancers, including, for example, cancers of the blood (e.g., acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin's lymphoma, non Hodgkin's lymphoma (malignant lymphoma) and Waldenstrom's macroglobulinemia), and other lymphatic or hematologic cancers including, for example, childhood leukemia, myeloproliferative disorders (e.g., primary myelofibrosis), plasma cell neoplasm / multiple myeloma, myelodysplasia, myelodysplastic syndrome, cutaneous T-cell lymphoma, lymphoid neoplasm, AIDS-related lymphoma, thymoma, thymoma and thymic carcinoma, mycosis fungoides, and Sezary Syndrome; skin cancers, including, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles Atorney Docket No. SYND-062 / 001WO 43707-02983 dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis, merkel cell carcinoma, merkel cell skin carcinoma, melanoma, and carcinoid tumor; adrenal gland cancers, including, for example, neuroblastoma; other cancers associated with the endocrine system including, for example, adrenocortical carcinoma, multiple endocrine neoplasia (e.g., multiple endocrine neoplasia type I), multiple endocrine neoplasia syndrome, parathyroid cancer, pituitary tumor, pheochromocytoma, islet cell pancreatic cancer, and islet cell tumors); connective tissue cancer (e.g., bone cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma); cancer associated with the head, neck, and mouth (e.g., head and neck cancer, paranasal sinus and nasal cavity cancer, metastatic squamous neck cancer, mouth cancer, throat cancer, esophageal cancer, laryngeal cancer, pharyngeal cancer, hypopharyngeal cancer, lip and oral cavity cancer, nasopharyngeal cancer, oral cancer, oropharyngeal cancer, and salivary gland cancer); and cancer associated with the eye (e.g., ocular cancer, intraocular melanoma). In some embodiments, the cancer is Ewing’s sarcoma.

[0561] In some embodiments, the cancer is a hematological cancer such as leukemia or lymphoma. Example leukemia and lymphomas treatable by the compounds of the disclosure include mixed lineage leukemia (MLL), MLL-related leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage leukemia (MLL- r), leukemia associated with a MLL rearrangement or a rearrangement of the MLL gene, acute leukemia, chronic leukemia, indolent leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, myelogenous leukemia, childhood leukemia, acute lymphocytic leukemia (ALL) (also referred to as acute lymphoblastic leukemia or acute lymphoid leukemia), acute myeloid leukemia (AML) (also referred to as acute myelogenous leukemia or acute myeloblastic leukemia), acute granulocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia (CLL) (also referred to as chronic lymphoblastic leukemia), chronic myelogenous leukemia (CML) (also referred to as chronic myeloid leukemia), therapy related leukemia, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD) (such as primary myelofibrosis (PMF)), myeloproliferative neoplasia (MPN), plasma cell neoplasm, multiple myeloma, myelodysplasia, cutaneous T-cell lymphoma, lymphoid neoplasm, AIDS- related lymphoma, thymoma, thymic carcinoma, mycosis fungoides, Alibert-Bazin syndrome, granuloma fungoides, 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 (malignant lymphoma), and Waldenstrom's macroglobulinemia. In some embodiments, the Atorney Docket No. SYND-062 / 001WO 43707-02983 acute myeloid leukemia (AML) is abstract nucleophosmin (NPMl)-mutated acute myeloid leukemia (i.e., NPMlmutacute myloid leukemia).

[0562] In particular embodiments, compounds of the disclosure are used to treat leukemia associated with a MLL rearrangement, acute lymphocytic leukemia associated with a MLL rearrangement, acute lymphoblastic leukemia associated with a MLL rearrangement, acute lymphoid leukemia associated with a MLL rearrangement, acute myeloid leukemia associated with a MLL rearrangement, acute myelogenous leukemia associated with a MLL rearrangement, or acute myeloblastic leukemia associated with a MLL rearrangement. As used herein, “MLL rearrangement” means a rearrangement of the MLL gene.

[0563] In some embodiments, diseases and conditions treatable with compounds of the disclosure include insulin resistance, pre-diabetes, diabetes (e.g., Type 2 diabetes or Type 1 diabetes), and risk of diabetes. In some embodiments, diseases and conditions treatable with compounds of the disclosure include hyperglycemia. In some embodiments, the hyperglycemia is associated with diabetes, such as Type 2 diabetes. In some embodiments, compounds of the disclosure are used to treat loss of response to other anti-diabetic agents and / or reduced beta cell function in a patient or subject. In some embodiments, compounds of the disclosure are used to restore response to other anti-diabetic agents and / or to restore beta cell function and / or to reduce the need for insulin in a patient or subject. In some embodiments, compounds of the disclosure are used to reduce insulin resistance, reduce the risk of diabetes, or reduce increases in blood glucose caused by a statin in a subject taking a statin. In some embodiments, compounds of the disclosure are used to treat diabetes in a subject taking a statin or to prevent diabetes in a subject taking a statin. Methods of the disclosure include decreasing, reducing, inhibiting, suppressing, limiting or controlling in the patient elevated blood glucose levels. In further aspects, methods of the disclosure include increasing, stimulating, enhancing, promoting, inducing or activating in the subject insulin sensitivity. Statins include, but are not limited to atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rousuvastatin and simvastatin.

[0564] In some embodiments, a patient is treated with (e.g., administered) a compound of the present disclosure in an amount sufficient to treat or ameliorate one or more of the diseases and conditions recited above (e.g., a therapeutically effective amount). The compounds of the disclosure may also be useful in the prevention of one or more of the diseases recited therein. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0565] Combination Therapy

[0566] The disclosure further relates to a combination therapy for treating a disease or a disorder described herein. In some embodiments, the combination therapy comprises administering at least one compound of the present disclosure in combination with one or more other pharmaceutically active agents for treating cancer or other disorders mediated by menin / MLL. In some embodiments, the combination therapy comprises administering at least one compound of the present disclosure in combination with one or more other pharmaceutically active agents, such as for the treatment of cancer. The pharmaceutically active agents can be combined with a compound of the disclosure in a single dosage form, or the therapeutics can be administered simultaneously or sequentially as separate dosage forms.

[0567] In some embodiments, the invention provides a combination therapy comprising a menin inhibitor of the present disclosure (e.g., a compound of Formula I, Formula II, Formula III, etc.) and a CYP3A4 inhibitor. In certain embodiments, the invention provides for a pharmaceutical composition comprising: (a) a menin inhibitor of the present disclosure (e.g., a compound of Formula I, Formula II, Formula III, etc.), and (b) a CYP3A4 inhibitor. In some embodiments, the invention is directed to a method for treating a patient comprising (a) administering a menin inhibitor of the present disclosure e.g., a compound of Formula I, Formula II, Formula III, etc.), and (b) administering a CYP3A4 inhibitor.

[0568] Some embodiments of this invention are directed to combination therapies designed to treat or manage cancer in a subject, wherein the combination therapies comprise administering a menin inhibitor of the present disclosure (e.g., a compound of Formula I, Formula II, Formula III, etc.) in combination with a CYP3A4 inhibitor. In particular, some embodiments of this invention are directed to methods of treating or managing cancer in a subject, comprising administering a menin inhibitor in combination with a therapeutically effective amount of a CYP3 A4 inhibitor administered simultaneously, separately or sequentially.

[0569] In some embodiments, the invention provides a combination therapy comprising a menin inhibitor of the present disclosure (e.g., a compound of Formula I, Formula II, etc.) and a CYP3A4 inhibitor. In certain embodiments, the invention provides for a pharmaceutical composition comprising: (a) a menin inhibitor of the present disclosure (e.g., a compound of Formula I, Formula II, etc.), and (b) a CYP3A4 inhibitor. In some embodiments, the invention is directed to a method for treating a patient comprising (a) administering a menin inhibitor of Atorney Docket No. SYND-062 / 001WO 43707-02983 the present disclosure (e.g., a compound of Formula I, Formula II, etc.), and (b) administering a CYP3A4 inhibitor.

[0570] Some embodiments of this invention are directed to combination therapies designed to treat or manage cancer in a subject, wherein the combination therapies comprise administering a menin inhibitor of the present disclosure (e.g., a compound of Formula I, Formula II, etc.) in combination with a CYP3A4 inhibitor. In particular, some embodiments of this invention are directed to methods of treating or managing cancer in a subject, comprising administering a menin inhibitor in combination with a therapeutically effective amount of a CYP3 A4 inhibitor administered simultaneously, separately or sequentially.

[0571] In some embodiments, the CYP3A inhibitor is: an antiarrhythmic; an antihistamine; an azole antifungal; a benzodiazepine; a calcium channel blocker; a HIV antiviral; a HMG CoA Reductase inhibitor; a macrolide antibiotic; a prokinetic; a protease inhibitor; or any combinations thereof. In some embodiments, the CYP3 A inhibitor is: posaconazole, alprazolam; amiodarone; amlodipine; aprepitant; aripiprazole; astemizole; atorvastatin; boceprevir; buspirone; chloramphenicol; chlorpheniramine; cimetidine; ciprofloxacin; cisapride; clarithromycin; cobicistat (GS-9350); analogs or derivatives of cobicistat (GS- 9350); cyclosporine; delaviridine; 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 combinations thereof.

[0572] In some embodiments, the CYP3A4 inhibitor is posaconazole, cobicistat (GS-9350) or analogs or derivatives of cobicistat (GS-9350). In some embodiments, the CYP3A4 inhibitor is ketoconazole. In some embodiments, the CYP3 A4 inhibitor is ritonavir. In some embodiments, the menin inhibitor and the CYP3A4 inhibitor are in separate dosage forms. In some embodiments, the pharmaceutical composition is in a combined dosage form. In some embodiments, the CYP3 A4 inhibitor is posaconazole.

[0573] In some embodiments, the pharmaceutical composition comprises an amount of the CYP3 A4 inhibitor that is effective to increase the oral bioavailability of the menin inhibitor. The compounds according to the disclosure may also be used in combination with Atorney Docket No. SYND-062 / 001WO 43707-02983 immunotherapies, including but not limited to cell-based therapies, antibody therapies and cytokine therapies, for the treatment of a disease or disorder disclosed herein.

[0574] In certain embodiments, compounds according to the disclosure are used in combination with one or more passive immunotherapies, including but not limited to naked monoclonal antibody drugs and conjugated monoclonal antibody drugs. Examples of naked monoclonal antibody drugs that can be used include, but are not limited to, rituximab (Rituxan®), an antibody against the CD20 antigen; trastuzumab (Herceptin®), an antibody against the HER2 protein; alemtuzumab (Lemtrada®, Campath®), an antibody against the CD52 antigen; cetuximab (Erbitux®), an antibody against the EGFR protein; and bevacizumab (Avastin®) which is an anti-angiogenesis inhibitor of VEGF protein.

[0575] Examples of conjugated monoclonal antibodies that can be used include, but are not limited to, radiolabeled antibody ibritumomab tiuxetan (Zevalin®); radiolabeled antibody tositumomab (Bexxar®); and immunotoxin gemtuzumab ozogamicin (Mylotarg®) which contains calicheamicin; BL22, an anti-CD22 monoclonal antibody-immunotoxin conjugate; radiolabeled antibodies such as OncoScint® and ProstaScint®; brentuximab vedotin (Adcetris®); ado-trastuzumab emtansine (Kadcyla®, also called TDM-1).

[0576] Further examples of therapeutic antibodies that can be used include, but are not limited to, REOPRO® (abciximab), an antibody against the glycoprotein Ilb / IIIa receptor on platelets; ZENAPAX® (daclizumab) an immunosuppressive, humanized anti-CD25 monoclonal antibody; PANOREX™, a murine anti-17-IA cell surface antigen IgG2a antibody; BEC2, a murine anti-idiotype (GD3 epitope) IgG antibody; IMC-C225, a chimeric anti-EGFR IgG antibody; VITAXIN™ a humanized anti-aVp3 integrin antibody; Campath 1H / LDP-03, a humanized anti CD52 IgGl antibody; Smart M195, a humanized anti-CD33 IgG antibody; LYMPHOCIDE™, a humanized anti-CD22 IgG antibody; LYMPHOCIDE™ Y-90; Lymphoscan; Nuvion® (against CD3; CM3, a humanized anti-ICAM3 antibody; IDEC-114 a primatized anti-CD80 antibody; IDEC-131 a humanized anti-CD40L antibody; IDEC-151 a primatized anti-CD4 antibody; IDEC-152 a primatized anti-CD23 antibody; SMART anti- CD3, a humanized anti-CD3 IgG; 5G1.1, a humanized anti-complement factor 5 (C5) antibody; D2E7, a humanized anti-TNF-a antibody; CDP870, a humanized anti-TNF-a Fab fragment; IDEC-151, a primatized anti-CD4 IgGl antibody; MDX-CD4, a human anti-CD4 IgG antibody; CD20-streptdavidin (+biotin-yttrium 90); CDP571, a humanized anti-TNF-a IgG4 antibody; LDP-02, a humanized anti-a4p7 antibody; OrthoClone OKT4A, a humanized anti- Atorney Docket No. SYND-062 / 001WO 43707-02983

[0577] CD4 IgG antibody; ANTOVA™, a humanized anti-CD40L IgG antibody; ANTEGREN™, a humanized anti-VLA-4 IgG antibody; and CAT-152, a human anti-TGF-P? antibody.

[0578] In certain embodiments, compounds according to the disclosure are used in combination with one or more targeted immunotherapies containing toxins but not an antibody, including but not limited to denileukin diftitox (Ontak®), IL-2 linked to diphtheria toxin.

[0579] The compounds according to the disclosure may also be used in combination with adjuvant immunotherapies for the treatment of a disease or disorder disclosed herein. Such adjuvant immunotherapies include, but are not limited to, cytokines, such as granulocytemacrophage colony-stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G- CSF), macrophage inflammatory protein (MIP)-l -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 (IF A); QS-21; DETOX; Levamisole; and Dinitrophenyl (DNP), and combinations thereof, such as, for example, combinations of interleukins, for example IL-2, with other cytokines, such as IFN-alpha.

[0580] In certain embodiments, compounds according to the disclosure are used in combination with vaccine therapy, including but not limited to autologous and allogeneic tumor cell vaccines, antigen vaccines (including polyvalent antigen vaccines), dendritic cell vaccines, and viral vaccines.

[0581] In another embodiment, the present disclosure comprises administering to a subject with cancer an effective amount of a compound of the disclosure and one or more additional anti-cancer therapies selected from: surgery, anti-cancer agents / drugs, biological therapy, radiation therapy, anti-angiogenesis therapy, immunotherapy, adoptive transfer of effector cells, gene therapy or hormonal therapy. Examples of anti-cancer agents / drugs are described below.

[0582] In some embodiments, the anti-cancer agents / drug is, for example, adriamycin, aactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; Atorney Docket No. SYND-062 / 001WO 43707-02983 carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride; palbociclib; Yervoy® (ipilimumab); Mekinist™ (trametinib); peginterferon alfa-2b, recombinant interferon alfa-2b; Sylatron™ (peginterferon alfa-2b); Tafinlar® (dabrafenib); Zelboraf® (vemurafenib); or nivolumab.

[0583] The compounds according to the present disclosure can be administered in combination with existing methods of treating cancers, for example by chemotherapy, irradiation, or Atorney Docket No. SYND-062 / 001WO 43707-02983 surgery. Thus, there is further provided a method of treating cancer comprising administering an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt form thereof, to a subject in need of such treatment, wherein an effective amount of at least one additional cancer chemotherapeutic agent is administered to the subject. Examples of suitable cancer chemotherapeutic agents include any of: abarelix, ado-trastuzumab emtansine, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, emtansine, epirubicin, eribulin, erlotinib, estramustine, etoposide phosphate, etoposide, everolimus, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fruquintinib, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, ixabepilone, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed di sodium, pentostatin, pertuzuma, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, sorafenib, streptozocin, sulfatinib, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, volitinib, vorinostat, and zoledronate.

[0584] In particular embodiments, compounds according to the disclosure are used in combination with one or more anti-cancer agent selected from methotrexate, paclitaxel albumin-stabilized nanoparticle formulation, ado-trastuzumab emtansine, eribulin, doxorubicin, fluorouracil, everolimus, anastrozole, pamidronate disodium, exemestane, capecitabine, cyclophosphamide, docetaxel, epirubicin, toremifene, fulvestrant, letrozole, gemcitabine, gemcitabine hydrochloride, goserelin acetate, trastuzumab, ixabepilone, lapatinib Atorney Docket No. SYND-062 / 001WO 43707-02983 ditosylate, megestrol acetate, tamoxifen citrate, pamidronate disodium, palbociclib, and pertuzumab for the treatment of breast cancer.

[0585] Other anti-cancer agents / drugs include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1; antiandrogen; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bi saziridinyl spermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors; castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophy cin 8; cryptophycin A derivatives; curacin A; cyclin-dependent kinase inhibitors; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9- dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate;fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; Atorney Docket No. SYND-062 / 001WO 43707-02983 ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitors; microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras famesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; Atorney Docket No. SYND-062 / 001WO 43707-02983 roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfm; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfm; vinorelbine; vinxaltine; vitaxin; zanoterone; zilascorb; zinostatin stimalamer; 5 -fluorouracil; and leucovorin.

[0586] In some embodiments, the anti-cancer agent / drug is an agent that stabilizes microtubules. As used herein, a "microtubulin stabilizer" means an anti-cancer agent / drug which acts by arresting cells in the G2-M phases due to stabilization of microtubules. Examples of microtubulin stabilizers include ACLITAXEL® and Taxol® analogues. Additional examples of microtubulin stabilizers include without limitation the following marketed drugs and drugs in development: Discodermolide (also known as NVP-XX-A-296); Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA); Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B); Epothilone E; Epothilone F; Epothilone B N-oxide; Epothilone A N-oxide; 16-aza-epothilone B; 21- aminoepothilone B (also known as BMS-310705); 21 -hydroxy epothilone D (also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone); FR-182877 (Fujisawa, also known as WS-9885B), BSF-223651 (BASF, also known as ILX-651 and LU-223651); AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HC1); AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A); Fijianolide B; Atorney Docket No. SYND-062 / 001WO 43707-02983

[0587] Laulimalide; Caribaeoside; Caribaeolin; Taccalonolide; Eleutherobin; Sarcodictyin; Laulimalide; Dictyostatin-1; Jatrophane esters; and analogs and derivatives thereof.

[0588] In another embodiment, the anti-cancer agent / drug is an agent that inhibits microtubules. As used herein, a "microtubulin inhibitor" means an anti-cancer agent which acts by inhibiting tubulin polymerization or microtubule assembly. Examples of microtubulin inhibitors include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104); Dolastatin 10 (also known as DLS-10 and NSC-376128); Mivobulin isethionate (also known as CI-980); Vincristine; NSC-639829; ABT-751 (Abbott, also known as E-7010); Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C); Spongistatins (such as Spongi statin 1, Spongi statin 2, Spongi statin 3, Spongi statin 4, Spongi statin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9); Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356); Auristatin PE (also known as NSC-654663); Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577); LS- 4578 (Pharmacia, also known as LS-477-P); LS-4477 (Pharmacia), LS-4559 (Pharmacia); RPR-112378 (Aventis); Vincristine sulfate; DZ-3358 (Daiichi); GS-164 (Takeda); GS-198 (Takeda); KAR-2 (Hungarian Academy of Sciences); SAH-49960 (Lilly / Novartis); SDZ- 268970 (Lilly / Novartis); AM-97 (Armad / Kyowa Hakko); AM- 132 (Armad); AM-138 (Armad / Kyowa Hakko); IDN-5005 (Indena); Cryptophycin 52 (also known as LY-355703); Vitilevuamide; Tubulysin A; Canadensol; Centaureidin (also known as NSC-106969); T- 138067 (Tularik, also known as T-67, TL-138067 and TL138067); COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHL261); H10 (Kansas State University); Hl 6 (Kansas State University); Oncocidin Al (also known as BTO-956 and DIME); DDE-313 (Parker Hughes Institute); SPA-2 (Parker Hughes Institute); SPA-1 (Parker Hughes Institute, also known as SPIKET-P); 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-569); Narcosine (also known as NSC-5366); Nascapine, D-24851 (Asta Medica), A- 105972 (Abbott); Hemiasterlin; 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-191); TMPN (Arizona State University); Vanadocene acetyl acetonate; T- 138026 (Tularik); Monsatrol; Inanocine (also known as NSC-698666); 3-IAABE (Cytoskeleton / Mt. Sinai School of Medicine); A-204197 (Abbott); T-607 (Tularik, also known as T-900607); RPR-115781 (Aventis); Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin); Halichondrin B; D-64131 (Asta Medica); D-68144 (Asta Medica); Diazonamide A; A-293620 (Abbott); NPI-2350 (Nereus); TUB-245 (Aventis); A-259754 (Abbot); Diozostatin; (-)-Phenylahistin (also known as NSCL- Atorney Docket No. SYND-062 / 001WO 43707-02983

[0589] 96F037); D-68838 (Asta Medica); D-68836 (Asta Medica); Myoseverin B; D-43411 (Zentaris, also known as D-81862); A-289099 (Abbot); A-318315 (Abbot); HTI-286 (also known as SPA-110, trifluoroacetate salt) (Wyeth); D-82317 (Zentaris); D-82318 (Zentaris); SC-12983 (NCI); Resverastatin phosphate sodium; BPR-0Y-007 (National Health Research Institutes); SSR-250411 (Sanofi); Combretastatin A4; eribulin (Halaven®); and analogs and derivatives thereof.

[0590] In further embodiments, compounds according to the disclosure are used in combination with one or more alkylating agents, antimetabolites, natural products, or hormones.

[0591] Examples of alkylating agents useful in the methods of the disclosure include but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, efc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, efc.), or triazenes (decarbazine, etc. .

[0592] Examples of antimetabolites useful in the methods of the disclosure include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, fl oxouridine, cytarabine), and purine analogs (e.g., mercaptopurine, thioguanine, pentostatin). Examples of natural products useful in the methods of the disclosure include but are not limited to vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide, teniposide), antibiotics (e.g., actinomycin D, daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin) or enzymes (e.g., L-asparaginase).

[0593] Examples of hormones and antagonists useful for the treatment of cancer include but are not limited to adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), and gonadotropin releasing hormone analog (e.g., leuprolide).

[0594] Other agents that can be used in combination with the compounds of the disclosure for the treatment of cancer include platinum coordination complexes (e.g., cisplatin, carboblatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), and adrenocortical suppressant (c.g, mitotane, aminoglutethimide). Other anti-cancer agents / drugs that can be used in combination with the compounds of the disclosure include, but are not limited to, liver X receptor (LXR) modulators, Atorney Docket No. SYND-062 / 001WO 43707-02983 including LXR agonists and LXR beta- selective agonists; aryl hydrocarbon receptor (AhR) inhibitors; inhibitors of the enzyme poly ADP ribose polymerase (PARP), including olaparib, iniparib, rucaparib, veliparib; inhibitors of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including cediranib; programmed cell death protein 1 (PD-1) inhibitors, including nivolumab (Bristol-Myers Squibb Co.) and pembrolizumab (Merck & Co., Inc.; MK- 3475); MEK inhibitors, including cobimetinib; B-Raf enzyme inhibitors, including vemurafenib; cytotoxic T lymphocyte antigen (CTLA-4) inhibitors, including tremelimumab; programmed death-ligand 1 (PD-L1) inhibitors, including MEDI4736 (AstraZeneca); inhibitors of the Wnt pathway; inhibitors of epidermal growth factor receptor (EGFR) including AZD9291 (AstraZeneca), erlotinib, gefitinib, panitumumab, and cetuximab; adenosine A2A receptor inhibitors; adenosine A2B receptor inhibitors; colony-stimulating factor-1 receptor (CSF1R) inhibitors, including PLX3397 (Plexxikon), and inhibitors of CD73.

[0595] The compounds of the disclosure can be used in combination with one or more therapeutic strategies including immune checkpoint inhibitors, including inhibitors of PD-1, PD-L1, and CTLA-4.

[0596] The compounds of the disclosure can be used in combination with one or more anticancer agents selected from MCL-1 inhibitors, e.g., homoharringtonin (HHT) and omacetaxine; BCL-2 inhibitors, e.g., venetoclax (ABT-199), navitoclax (ABT-263), ABT-737, gossypol (AT- 101), apogossypolone (ApoG2) and obatoclax; selective inhibitors of nuclear export (SINEs), e.g., selinexor (KPT-330).

[0597] In particular embodiments, the compounds of the disclosure are used in combination with one or more anti-cancer agents selected from methotrexate (Abitrexate®; Fol ex®; Fol ex PFS®; Mexate®; Mexate-AQ®); nelarabine (Arranon®); blinatumomab (Blincyto®); rubidomycin hydrochloride or daunorubicin hydrochloride (Cerubidine®); cyclophosphamide (Clafen®; Cytoxan®; Neosar®); clofarabine (Clofarex®; Clolar®); cytarabine (Cytosar-U®; Tarabine PFS®); dasatinib (Sprycel®); doxorubicin hydrochloride; asparaginase Erwinia chrysanthemi (Erwinaze); imatinib mesylate (Gleevec®); ponatinib hydrochloride (Iclusig®); mercaptopurine (Purinethol; Purixan); pegaspargase (Oncaspar®); prednisone; vincristine sulfate (Oncovin®, Vincasar PFS®, Vincrex®); vincristine sulfate liposome (Marqibo®); hyper- CVAD (fractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone); arsenic trioxide (Trisenox®); idarubicin hydrochloride (Idamycin®); mitoxantrone hydrochloride; thioguanine (Tabloid®); ADE (cytarabine, daunorubicin, and etoposide); alemtuzumab (Lemtrada®, Campath®); chlorambucil (Ambochlorin®, Amboclorin®, Leukeran®, Atorney Docket No. SYND-062 / 001WO 43707-02983

[0598] Linfolizin®); ofatumumab (Arzerra®); bendamustine hydrochloride (Treanda®); fludarabine phosphate (Fludara®); obinutuzumab (Gazyva®); ibrutinib (Imbruvica®); idelalisib (Zydelig®); mechlorethamine hydrochloride (Mustargen®); rituximab (Rituxan®); chlorambucilprednisone; CVP (cyclophosphamide, vincristine, and prednisone); bosutinib (Bosulif®); busulfan (Busulfex®; Myleran®); omacetaxine mepesuccinate (Synribo®); nilotinib (Tasigna®); Intron® A (recombinant interferon Alfa-2b); DOT IL inhibitors, including EPZ-5676 (Epizyme, Inc.); and inhibitors of bromodomain and extra-terminal motif (BET) proteins (BET inhibitors), including MS417, JQ1, LBET 762, and I-BET 151 for the treatment of leukemia.

[0599] Compounds of the disclosure can be used in combination with one or more other agents or therapies for the treatment of insulin resistance, pre-diabetes, diabetes (e.g., Type 2 diabetes or Type 1 diabetes), and risk of diabetes, including but not limited to insulins and insulin analogues, such as Humulin® (Eli Lilly), Lantus® (Sanofi Aventis), Novolin® (Novo Nordisk), and Exubera® (Pfizer); Avandamet® (metformin HCI and rosiglitazone maleate, GSK); Avandaryl® (glimepiride and rosiglitazone maleate, GSK); Metaglip® (glipizide and metformin HCI, Bristol Myers Squibb); Glucovance® (glyburide and metformin HCI, Bristol Myers Squibb); PPAR gamma agonists, such as Avandia® (rosiglitizone maleate, GSK) and Actos® (pioglitazone hydrochloride, TakedaZEli Lilly); sulfonylureas, such as Amaryl® (glimepiride, Sanofi Aventis), Diabeta® (glyburide, Sanofi Aventis), Micronase® / Glynase® (glyburide, Pfizer), and Glucotrol® / Glucotrol XL® (glipizide, Pfizer); meglitinides, such as Prandin® / NovoNorm® (repaglinide, Novo Nordisk), Starlix® (nateglinide, Novartis), and Glufast® (mitiglinide, Takeda); biguanides, such as Glucophase® / Glucophase XR® (metformin HCI, Bristol Myers Squibb) and Glumetza® (metformin HCI, Depomed); thiazolidinediones; amylin analogs; GLP-1 analogs; DPP-IV inhibitors such as Januvia® (sitagliptin, Merck) and Galvus® (vildagliptin, Novartis); PTB-1 B inhibitors; protein kinase inhibitors (including AMP-activated protein kinase inhibitors); glucagon antagonists, glycogen synthase kinase-3 beta inhibitors; glucose-6-phoshatase inhibitors; glycogen phosphorylase inhibitors; sodium glucose co-transporter inhibitors; and alpha-glucosidase inhibitors, such as Glycet® (miglitol, Pfizer); statins, fibrates, and Zetia® (ezetimibe); alpha-blockers; beta-blockers; calcium channel blockers; diuretics; angiotensin converting enzyme (ACE) inhibitors; dual ACE and neutral endopeptidase (NEP) inhibitors; angiotensin-receptor blockers (ARBs); aldosterone synthase inhibitors; aldosterone-receptor antagonists; endothelin receptor antagonists; orlistat; phentermine; sibutramine; Acomplia® (rimonabant); thiazolidinediones (e.g., rosiglitazone, pioglitazone); SGLT 2 inhibitors (e.g., dapagliflozin, remogliflozin etabonate, sergliflozin, Atorney Docket No. SYND-062 / 001WO 43707-02983 canagliflozin, and 1 -chloro-4-(P-D- glucopyranos-l-yl)-2-[4-(('S)-tetrahydrofuran-3-yloxy)- benzyl] -benzene); PPAR-gamma-agonists (e.g., G1 262570) and antagonists; PPAR- gamma / alpha modulators (e.g., KRP 297); alpha-glucosidase inhibitors (e.g., acarbose, voglibose); DPPIV inhibitors (e.g., Januvia® (sitagliptin), Galvus® / Zomelis® (vildagliptin), Onglyza® (saxagliptin), Nesina® / Vipidia® (alogliptin), and Tradjenta® / Trajenta® (linagliptin)); alpha2-antagonists; glucagon-like protein-1 (GLP-1) receptor agonists and analogues (e.g., exendin-4); amylin; inhibitors of protein tyrosinephosphatase 1; substances that affect deregulated glucose production in the liver, e.g., inhibitors of glucose-6-phosphatase, or fructose- 1 ,6- bisphosphatase, glycogen phosphorylase; glucagon receptor antagonists; inhibitors of phosphoenol pyruvate carb oxy kinase; 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 the derivatives thereof, PPAR-alpha agonists, PPAR-delta agonists; ACAT inhibitors (e.g., avasimibe); cholesterol absorption inhibitors such as ezetimibe; bile acid-binding substances such as cholestyramine; inhibitors of ileac bile acid transport; HDL-raising compounds such as CETP inhibitors and ABC1 regulators; active substances for treating obesity such as sibutramine and tetrahydrolipostatin; SDRIs; axokine; leptin; leptin mimetics; antagonists of the cannabinoid 1 receptor; and MCH-1 receptor antagonists; MC4 receptor agonists; NPY5 and NPY2 antagonists; beta3 adrenergic agonists such as SB- 418790 and AD-9677; agonists of the 5HT2c receptor; GABA-receptor antagonists; Na-channel blockers; topiramate; protein-kinase C inhibitors; advanced glycation end product inhibitors; and aldose reductase inhibitors.

[0600] Pharmaceutical Formulations, Administration, and Dosage Forms

[0601] When employed as pharmaceuticals, the compounds of the disclosure can be administered in the form of a pharmaceutical composition which refers to a combination of a compound of the disclosure, or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction Atorney Docket No. SYND-062 / 001WO 43707-02983 by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0602] This disclosure also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of the disclosure above in combination with one or more pharmaceutically acceptable carriers. In making the compositions of the disclosure, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0603] Compounds or compositions described herein may be administered to a patient using any amount and any route of administration effective for treating or lessening the severity of one or more of the diseases and conditions described herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, disease or disorder, the particular agent, its mode of administration, and the like. Provided compounds are preferably formulated in a particular unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated.

[0604] The therapeutic dosage of the compounds of the present disclosure can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the disclosure in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical Attorney Docket No. SYND-062 / 001WO 43707-02983 characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the disclosure can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration.

[0605] EXAMPLES As depicted in the Examples below, compounds of the disclosure were prepared and isolated according to the following general procedures. It will be appreciated that, although the general methods may depict the synthesis of certain compounds of the present disclosure, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein. Atorney Docket No. SYND-062 / 001WO 43707-02983 Atorney Docket No. SYND-062 / 001WO 43707-02983

[0606] LCMS

[0607] Instrument names: Shimadzu LC2020 Nexera Series; Shimadzu MS2020 N-Series;

[0608] Agilent 1290 Infinity II series with 1260 MSD.

[0609] Method A: Mobile Phase A: 5 mM NH4HCO3 in water, mobile phase B: ACN; Column: Phenomenex Kinetex EVO Cl 8 (50 x 3.0) mm, 2.6 pm.

[0610] Method B: Mobile Phase A: 0.1% FA in water, mobile phase B: 0.05% FA in ACN; Column: ZORB AX ECLIPSE PLUS C18 (50 x 2.1) mm, 1.8 pm.

[0611] Method C: Mobile Phase: A: 0.05% TFA in water, mobile phase B: ACN; Column: ZORB AX ECLIPSE PLUS C18 (50 x 2.1) mm, 1.8 pm.

[0612] Method D: Mobile Phase A: 10 mM NH4HCO3 in water, mobile phase B: ACN; Column: Phenomenex Kinetex EVO Cl 8 (50 x 3.0) mm, 2.6 pm.

[0613] Method E: Mobile Phase A: 5 mM NH4HCO3 in water, mobile phase B: ACN; Column: X Bridge C8 (50 x 4.6) mm, 3.5 pm.

[0614] Method F: Mobile Phase A: 5 mM NH4HCO3 in water, mobile phase B: ACN; Column: Acquity UPLC BEH C18 (50 x 2.1) mm, 1.7 pm.

[0615] Method G: Mobile Phase A: 5 mM NH4HCO3 in water, mobile phase B: ACN; Column: X Bridge BEH C18 (50 x 2.1) mm, 2.5 pm.

[0616] Method H: Mobile Phase: A: 0.1% TFA in water, mobile phase B: ACN; Column: ZORB AX ECLIPSE PLUS C18 (50 x 2.1) mm, 1.8 pm.

[0617] HPLC Atorney Docket No. SYND-062 / 001WO 43707-02983

[0618] Instrument names: Shimadzu LC; Prominence-I series instruments as followed using % with UV detection (Maxplot).

[0619] Method A: Mobile Phase AMO mM NH4HCO3 in water, mobile phase B: ACN; Flow Rate: 2.0 mL / min; Column: X-Bridge C18 (150 x 4.6) mm, 5 pm.

[0620] Prep HPLC

[0621] Method A: Mobile Phase A: 10 mM NH4HCO3 in water; mobile phase B: ACN; Flow Rate: 18.0 mL / min; Column: X-Timate C18 (250 x 21.2) mm, 5 pm.

[0622] Method B: Mobile Phase AMO mM NH4HCO3 in water; mobile phase B: ACN; Flow Rate: 15.0 mL / min; Column: X-Select CSH C18 (250 x 19) mm, 5 pm.

[0623] Method C: Mobile Phase AMO mM NH4HCO3 in water; mobile phase B: ACN; Flow Rate: 15.0 mL / min; Column: SHIMPACK GIST C18 (150 x 19.0) mm, 5 pm.

[0624] Method D: Mobile Phase AMO mM NH4HCO3 in water; mobile phase B: ACN; Flow Rate: 18.0 mL / min; Column: SHIMPACK GIST C18 (150 x 19.0) mm, 5 pm.

[0625] Method E: Mobile Phase AMO mM NH4HCO3 in water; mobile phase B: ACN; Flow Rate: 18.0 mL / min; Column: XTIMATE C18 (250 x 21.2) mm, 5 pm.

[0626] Chiral SFC

[0627] Instrument names: Shimadzu Nexera UC SFC Analytical; PIC- SFC Analytical- 10.

[0628] Method A: Mobile Phase A: CO2; Co-solvent - 0.5% Isopropylamine in [ACN: MeOH (1 : 1)] (55:45); Flow Rate: 4.0 mL / min; % Co-Solvent: 45%; Column: Whelk-(R,R) (250 x 4.6) mm, 5 pm.

[0629] Method B: Mobile Phase A: CO2; Co-solvent - 0.5% Isopropylamine in MeOH (70:30); Flow Rate: 4.0 mL / min; % Co-Solvent: 30%; Column: LCellulose Z (250 x 4.6) mm, 5 pm.

[0630] Method C: Mobile Phase A: CO2; Co-solvent - 0.5% Isopropylamine in MeOH (50:50); Flow Rate: 4.0 mL / min; % Co-Solvent: 50%; Column: LCellulose Z (250 x 4.6) mm, 5 pm.

[0631] Method D: Mobile Phase A: CO2; Co-solvent - 0.5% Isopropylamine in MeOH (75:25); Flow Rate: 4.0 mL / min; % Co-Solvent: 25%; Column: LCellulose B (250 x 4.6) mm, 5 pm. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0632] Method E: Mobile Phase A: CO2; Co-solvent - 0.5% Isopropylamine in IPA (50:50);

[0633] Flow Rate: 4.0 mL / min; % Co-Solvent: 50%; Column: LUX-I-Amylose3 (250 x 4.6) mm, 5 pm.

[0634] Method F: Mobile Phase A: CO2; Co-solvent - 0.5% Isopropylamine in MeOH (65:35); Flow Rate: 4.0 mL / min; % Co-Solvent: 35%; Column: C Cellulose B (250 x 4.6) mm, 5 pm.

[0635] Method G: Mobile Phase A: CO2; Co-solvent - 0.5% Isopropylamine in MeOH (50:50); Flow Rate: 4.0 mL / min; % Co-Solvent: 50%; Column: LUX-I-Amylose3 (250 x 4.6) mm, 5 pm.

[0636] Method H: Mobile Phase A: CO2; Co-solvent - 0.5% Isopropylamine in MeOH (50:50); Flow Rate: 4.0 mL / min; % Co-Solvent: 50%; Column: Whelk-(R,R) (250 x 4.6) mm, 5 pm.

[0637] Method I: Mobile Phase A: CO2; Co-solvent - 0.5% Isopropylamine in MeOH (60:40); Flow Rate: 4.0 mL / min; % Co-Solvent: 40%; Column: Whelk-(R,R) (250 x 4.6) mm, 5 pm.

[0638] Method J: Mobile Phase A: CO2; Co-solvent - 0.5% Isopropylamine in MeOH (55:45); Flow Rate: 4.0 mL / min; % Co-Solvent: 40%; Column: Whelk-(R,R) (250 x 4.6) mm, 5 pm.

[0639] Method K: Mobile Phase A: CO2; Co-solvent - 0.5% Isopropylamine in [ACN: MeOH (60:40)] (50:50);

[0640] Flow Rate: 4.0 mL / min; % Co-Solvent: 50%; Column: I-Cellulose Z (250 x 4.6) mm, 5 pm.

[0641] Chiral Prep SFC

[0642] Method A: Mobile Phase A: CO2; Co-solvent - 0.5% Isopropylamine in [IPA: ACN (1:1) (50:50)]; Flow Rate: 100 mL / min; % Co-Solvent: 50%; Column: LCellulose Z (250 x 30) mm, 5 pm.

[0643] Method B: Mobile Phase A: CO2; Co-solvent - 0.5% Isopropylamine in MeOH (70:30); Flow Rate: 100 mL / min; % Co-Solvent: 30%; Column: I-Cellulose Z (250 x 30) mm, 5 pm.

[0644] Method C: Mobile Phase A: CO2; Co-solvent - 0.5% Isopropylamine in IPA (50:50); Flow Rate: 60 mL / min; % Co-Solvent: 50%; Column: LUX-I Amylose 3 (250 x 21) mm, 5 pm. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0645] Method D: Mobile Phase A: CO2: Co-solvent - 0.5% Isopropylamine in MeOH (55:45); Flow Rate: 60 mL / min; % Co-Solvent: 45%; Column: RR WHELK (250 x 21) mm, 5 pm.

[0646] Synthesis of Intermediates

[0647] Intermediate 1. Methyl 2-((4-chloropyrimidin-5-yl)oxy)-5-fluorobenzoate (Procedure 1)

[0648] A 40% aqueous dimethylamine solution (140.0 L, 1200.0 mol) was heated at 60-65 °C for 2- 3 h to release dimethylamine gas, which was purged into a cooled solution (0-5 °C) of THF (250.0 L).

[0649] In another reactor, thionyl chloride (41.0 kg, 347.4 moles) was added to a solution of 5- fluorosalicylic acid (30.0 kg, 192.0 moles) in THF (100.0 L) over a period of 1-2 h. The reaction mixture was heated to 50-60 °C for 5-6 h. After completion of the reaction, as judged by TLC, the reaction mixture was concentrated completely. THF was added and distilled out to remove the remaining thionyl chloride. The acid chloride thus obtained was dissolved in THF (30.0 L) and was added to the dimethylamine-THF solution at 0-5 °C. The reaction mixture was stirred at RT for 4-5 h. After completion of the reaction, the reaction mixture was concentrated under a vacuum below 40 °C. Ice water was added, and the mixture was stirred for 1-2 h at room temperature to precipitate a solid. The solid was filtered and washed with water. The solid was triturated with cyclohexane and centrifuged to give 5- fluoro-2-hydroxy-A,A-dimethylbenzamide (28.5 kg, 81% yield) as a solid. 'H NMR (400 MHz, DMSO-tL): 6 2.81 (s, 3H), 2.94 (s, 3H), 6.83-6.87 (m, 1H), 6.92-6.95 (m, 1H), 7.02- 7.07 (m, 1H), 9.76 (br, 1H); HPLC (% purity): 99.63%. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0650] To a solution of 5-fluoro-2-hydroxy-A,A-dimethylbenzamide (28.0 kg, 153.0 moles) and 5- bromopyrimidine (29.16 kg, 183.0 moles) in dimethyl acetamide (180.0 L) was added cesium carbonate (89.73, 270.0 moles). The reaction mixture was heated to 125-130 °C for 22-24 h. After complete consumption of starting material, as judged by TLC, the reaction mixture was cooled to 35-40 °C and filtered to remove the cesium carbonate. The reaction mixture was concentrated under a vacuum. The residue thus obtained was dissolved in water (84.0 L) and extracted with DCM (2 x 56.0 L). The DCM layer was washed with 10% aqueous sodium hydroxide solution, followed by dilute HC1 solution, dried over sodium sulfate, filtered, and concentrated to give 5-fluoro-A,A-dimethyl-2-(pyrimidin-5-yloxy)benzamide (24.0 kg, 60.1% yield) as a semisolid. 'H NMR (400 MHz, DMSO-t / 6): 6 8.94 (s, 1H), 8.54 (s, 2H), 7.25-7.34 (m, 3H), 2.85 (s, 3H), 2.84 (s, 3H); HPLC (% purity): 86.75%.

[0651] Step 3. 5-Fluoro-2-(pyrimidin-5-yloxy)benzoic acid

[0652] To a solution of 5-fluoro-A,A-dimethyl-2-(pyrimidin-5-yloxy)benzamide (23.5 kg, 90.03 moles) in 6: 1 MeOJWLO (140.0 L) was added LiOH.H2O (15.5 kg, 360.0 moles), and the reaction was heated at 60-65 °C for 48 h. The reaction mixture was cooled to 40 °C, and the methanol was distilled out in vacuum below 40 °C. The residue thus obtained was dissolved in water. The aqueous layer was washed with ethyl acetate. The aqueous layer was treated with activated carbon and filtered on Hyflo. The aqueous layer was acidified with concentrated HC1 (1.5 L) to pH ~1.0-2.0 to precipitate a solid. This solid was filtered, washed with water, and dried at 40-45 °C to give 5-fluoro-2-(pyrimidin-5-yloxy)benzoic acid (13.5 kg, 64.1% yield) as a solid. *HNMR (400 MHz, DMSO-t / 6): 6 13.40 (br s, 1H), 8.92 (s, 1H), 8.46 (s, 2H), 7.69-7.71 (m, 1H), 7.52- 7.57 (m, 1H), 7.38- 7.42 (m, 1H); HPLC (% purity): 96.94%. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0653] Step 4. Methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate

[0654] To a cooled solution of 5-fluoro-2-(pyrimidin-5-yloxy)benzoic acid (13.5 kg, 57.69 moles) in methanol (90.0 L) was added sulfuric acid (2.16 L), and the reaction was heated at 60-65 °C for 24 h. The reaction mixture was cooled to room temperature, and the methanol was distilled out completely under reduced pressure. The residue thus obtained was dissolved in DCM (54.0 L). The DCM layer was washed with 5% sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate (9.6 kg, 67.1% yield) as a solid. 'H NMR (400 MHz, DMSO-t / 6): 6 8.94 (s, 1H), 8.50 (s, 2H), 7.72-7.75 (m, 1H), 7.57- 7.62 (m, 1H), 7.41- 7.45 (m, 1H), 3.73 (s, 3H); HPLC (% purity): 98.37%; assay by Q-NMR (%): 99.21%.

[0655] Step 5. 5-(4-Fluoro-2-(methoxycarbonyl)phenoxy)pyrimidine 1-oxide

[0656] To a cooled solution of methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate (9.6 kg, 38.7 moles) in THF (150 L) was added UHP (7.64 kg, 81.2 moles) at 0-5 °C (over a period of 30 min), and the reaction was stirred for 10 min at 0-5 °C. TFAA (17.0 kg, 81.0 moles) was then added dropwise over 30-40 min at 0-5 °C. The reaction was stirred at 0-5 °C for 12-14 h. After complete consumption of starting material, as judged by TLC, the reaction mixture was quenched by the addition of 5% NaHCCh solution at 0-5 °C. DCM (60.0 L) was then added at 5-10 °C, and the mixture was stirred for 20 min. The aqueous and organic layers were separated. The organic layer was washed with 5% NaHCCh. Aqueous sodium thiosulfate solution was then added to the organic layer (DCM layer), and the mixture was stirred for 12 hours at 10 °C. The organic layer was separated, dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to give 5-(4-fluoro-2- (methoxycarbonyl)phenoxy)pyrimidine- 1-oxide (5.12 kg, 50.0% yield) as solid.1HNMR Atorney Docket No. SYND-062 / 001WO 43707-02983

[0657] (400 MHz, DMSO-tL): 6 8.86 (s, 1H), 8.44 (s,lH), 8.01 (s, 1H), 7.72-7.75 (m, 1H), 7.59- 7.64 (m, 1H), 7.49 - 7.52 (m, 1H), 3.76 (s, 3H); HPLC (% purity): 99.60%.

[0658] Step 6. Methyl 2-((4-chloropyrimidin-5-yl)oxy)-5-fluorobenzoate

[0659] In a 100 mL two neck round bottom flask under a nitrogen atmosphere, 5-(4-fluoro-2- (methoxycarbonyl)phenoxy)pyrimidine 1 -oxide (20 g, 76 mmol) was dissolved in EtOAc (200 mL). To this solution, DIPEA (65.3 mL, 378 mmol) was added at 0 °C, and the reaction was stirred at the same temperature for 15 min. To this reaction mixture, POCh (14.15 mL, 151 mmol) was added dropwise at 0 °C. The reaction was warmed to RT and stirred for 1 h. The reaction was monitored by TLC (50% EtOAc in hexane). The reaction was concentrated under reduced pressure to afford crude compound. The crude compound was purified by silica gel flash column chromatography using EtOAc in hexane (product eluted at 25% EtOAc in hexane) to obtain methyl 2-((4-chloropyrimidin-5-yl)oxy)-5-fluorobenzoate (16.5 g, 72.2% yield) as a solid.1HNMR (400 MHz, DMSO-t / 6): 6 8.81 (s, 1H), 8.30 (s, 1H), 7.76 (dd, J= 3.1, 8.8 Hz, 1H), 7.61 (ddd, J= 3.3, 7.9, 9.0 Hz, 1H), 7.46 (dd, J= 4.6, 9.0 Hz, 1H), 3.75 (s, 3H); LCMS (Method A): Rt = 1.74 min, m / z = 283.1 [M+H]+; 93.65%.

[0660] Intermediate 1. Methyl 2-((4-chloropyrimidin-5-yl)oxy)-5-fluorobenzoate (Procedure 2)

[0661] Step 1. 5-(4-Fluoro-2-(methoxycarbonyl)phenoxy)pyrimidine 1-oxide

[0662] To a stirred solution of methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate (5 g, 20.14 mmol) in THF (10 mL), urea hydrogen peroxide (3.79 g, 40.3 mmol) was added, followed by dropwise addition of TFAA (8.46 g, 40.3 mmol) at 0 °C. The reaction was allowed to stir at RT for 2 h. The reaction was monitored by TLC (5% MeOH in DCM). The reaction was diluted with Atorney Docket No. SYND-062 / 001WO 43707-02983 saturated sodium bicarbonate solution (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with saturated sodium thiosulfate (100 mL) and brine solution (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford crude 5-(4-fluoro-2

[0663] (methoxy carbonyl)phenoxy)pyrimidine 1 -oxide (5.32 g, 93% yield) as a sticky solid.JH NMR (400 MHz, DMSO-tfc): 6 8.86 (d, J= 1.5 Hz, 1H), 8.44 (dd, J= 1.7, 2.3 Hz, 1H), 8.01 (d, J= 2.1 Hz, 1H), 7.74 (dd, J= 3.3, 8.8 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.51 (dd, J= 4.6, 9.1 Hz, 1H), 3.77 (s, 3H); LCMS (Method D): Rt = 1.30 min, m / z = 265.2 [M+H]+; 94.67%. This material was used without further purification.

[0664] Step 2. Methyl 2-((4-chloropyrimidin-5-yl)oxy)-5-fluorobenzoate

[0665] In a dried, 500 mL three neck round bottom flask under nitrogen atmosphere, 5-(4-fluoro-2- (methoxycarbonyl)phenoxy)pyrimidine 1-oxide (5.9 g, 22.33 mmol) was dissolved in EtOAc (50 mL). To this reaction mixture, DIPEA (19.45 mL, 112 mmol) and POCh (4.18 mL, 44.7 mmol) were added at 0 °C. The reaction was stirred at RT for 2 h. The reaction was monitored by TLC (100% EtOAc). The reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel flash column chromatography using EtOAc in hexane (product eluted at 30% EtOAc in hexane) to obtain methyl 2-((4-chloropyrimidin-5-yl)oxy)-5-fluorobenzoate (2.5 g, 39.6% yield) as a solid. 'H NMR (400 MHz, DMSO ): 6 8.81 (s, 1H), 8.30 (s, 1H), 7.77 (dd, J= 3.2, 8.8 Hz, 1H), 7.61 (ddd, J= 3.2, 7.8, 9.1 Hz, 1H), 7.46 (dd, J= 4.6, 9.0, 1H), 3.75 (s, 3H); LCMS (Method B): Rt = 2.41 min, m / z = 283.0 [M+H]+, 93.55%.

[0666] Intermediate 2. 2-(2-(Benzylamino)ethyl)pyridin-4-ol 2,2,2-trifluoroacetic acid Atorney Docket No. SYND-062 / 001WO 43707-02983 0 °C-RT, 1 h

[0667] Step 4

[0668] Step 1. 2-Chloro-4-((4-methoxybenzyl)oxy)pyridine

[0669] The reaction was performed following the same procedure in two batches (2 x 150 g).

[0670] In a 10 L three neck round bottom flask under nitrogen atmosphere, 2-chloropyridin-4-ol (150 g, 1158 mmol) was dissolved in acetone (2.5 L) at RT, and the reaction was cooled to 0 °C. To this cooled solution, CS2CO3 (415 g, 1274 mmol) was added, then 4-methoxybenzyl chloride (0.189 L, 1390 mmol) was added slowly using a dropping funnel. The reaction was stirred at RT for 18 h. The progress of the reaction was monitored by TLC (30% EtOAc in hexane). After completion, the two batches were combined and filtered, and the filter pad was washed with acetone (2 x 1 L). The filtrate was concentrated under reduced pressure, and the residue was diluted with water (1 L) and extracted with EtOAc (3 x 2.5 L). The combined organic layer was washed with brine solution (2 x 1 L), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude compound. The crude was purified by silica gel flash column chromatography using EtOAc in hexane (product was eluted at 20% EtOAc in hexane) to obtain 2-chloro-4-((4- methoxybenzyl)oxy)pyridine (275 g, 44.3% yield, combined yield for 300 g batch) as a solid. 'HNMR (400 MHz, DMSO-< 8 8.21 (d, J= 5.79 Hz, 1 H), 7.40 (d, J= 8.55 Hz, 2 H), 7.18 (d, J= 2.10 Hz, 1 H), 7.06 (dd, J= 5.79, 2.24 Hz, 1 H), 6.97 (d, J= 8.68 Hz, 2 H), 5.15 (s, 2 H), 3.76 (s, 3 H); LCMS (Method A): Rt = 1.96 min, m / z = 250.0 [M+H]+, 93.16%.

[0671] Step 2. 4-((4-Methoxybenzyl)oxy)-2-vinylpyridine Atorney Docket No. SYND-062 / 001WO 43707-02983

[0672] In a 10 L three neck round bottom flask, ethanol (3.5 L) was degassed by purging with argon gas for 15 min. To this solution, 2-chloro-4-((4-methoxybenzyl)oxy)pyridine (170 g, 681 mmol), potassium trifluoro(vinyl)borate (109 g, 817 mmol), TEA (96 mL, 681 mmol), and PdC12(dppf) (24.91 g, 34.0 mmol) were added at RT. The reaction was stirred at 100 °C for 16 h under argon atmosphere. The progress of the reaction was monitored by TLC (50% EtOAc in hexane). After completion, the reaction was filtered through a Celite® pad, and the pad was washed with EtOAc (2 x 500 mL). The filtrate was concentrated under reduced pressure to obtain the crude compound. The crude was purified by flash column chromatography using EtOAc and hexane (product was eluted at 20% EtOAc in hexane) to obtain 4-((4-methoxybenzyl)oxy)-2-vinylpyridine (110 g, 63.4% yield) as a solid.JH NMR (400 MHz, DMSO-tfc): 6 8.35 (d, J= 5.66 Hz, 1H), 7.41 (d, J= 8.55 Hz, 2H), 7.14 (d, J = 2.37 Hz, 1H), 6.96 (d, J= 8.68 Hz, 2H), 6.92 (dd, J= 2.50, 5.66 Hz, 1H), 6.75 (dd, J= 10.72, 17.43 Hz, 1H), 6.24 (dd, J= 1.64, 17.43 Hz, 1H), 5.45 (dd, J= 1.64, 10.72 Hz, 1H), 5.13 (s, 2 H), 3.77 (s, 3 H); LCMS (Method A): Rt = 1.97 min, m / z = 242.2 [M+H]+, 94.67%.

[0673] Step 3. N-Benzyl-2-( 4-( 4-methoxybenzyl)oxy)pyridin-2-yl)ethan-l-amine

[0674] To a stirred solution of 4-((4-methoxybenzyl)oxy)-2-vinylpyridine (100 g, 414 mmol) in ethanol (2 L), benzylamine (91 mL, 829 mmol) and acetic acid (23.73 mL, 414 mmol) were added at RT under nitrogen atmosphere. The reaction was stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC (10% MeOH in DCM). After completion, the reaction was cooled to RT and concentrated under reduced pressure to obtain the crude compound. The crude was purified by silica gel flash column chromatography using MeOH in DCM (product was eluted at 10% MeOH in DCM) to afford A-benzyl-2-(4-((4- methoxybenzyl)oxy)pyridin-2-yl)ethan-l -amine (102 g, 56.1% yield) as a semi-solid. 'H NMR (400 MHz, DMSO-tfc): 6 8.26 (d, J= 5.75 Hz, 1H), 7.38 (d, J= 8.76 Hz, 2H), 7.34 - 7.33 (m, 2H), 7.31 - 7.29 (m, 5H), 6.96 - 6.94 (m, 2H), 5.07 (s, 2H), 3.76 (s, 3H), 3.75 (s, 2H), 2.83 - 2.81 (m, 4H), one proton merged with solvent peaks; LCMS (Method D): Rt = 1.96 min, m / z = 349.0 [M+H]+, 79.48%.

[0675] Step 4. 2-(2-(Benzylamino)ethyl)pyridin-4-ol 2,2,2-trifluoroacetic acid Atorney Docket No. SYND-062 / 001WO 43707-02983

[0676] To a stirred solution of 7V-benzyl-2-(4-((4-methoxybenzyl)oxy)pyridin-2-yl)ethan-l -amine (50 g, 143 mmol) in DCM (320 mL), TFA (439 mL, 5740 mmol) was added over 20 min at 0 °C. The reaction was slowly warmed to RT and stirred for 1 h. The reaction turned purple from its initial pale-yellow color. The progress of the reaction was monitored by TLC (15% MeOH in DCM). After completion, the reaction was concentrated under reduced pressure to obtain the crude compound. The crude was purified by silica gel flash column chromatography using MeOH in DCM (product was eluted at 15% MeOH in DCM) to obtain 2-(2-(benzylamino)ethyl)pyridin-4-ol 2,2,2-trifluoroacetic acid (48.5 g, 75% yield) as a semisolid. LCMS (Method A): Rt = 1.15 min, m / z = 229.1 [M+H]+, 76.16%.

[0677] Intermediate 3. Benzyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate

[0678] In a 3 L three neck round bottom flask under a nitrogen atmosphere, tert-butyl 6-hydroxy-2- azaspiro[3.3]heptane-2-carboxylate (200 g, 938 mmol) was dissolved in 2,2,2- trifluoroethanol (2.5 L). The reaction was cooled to 0 °C, and TMSCI (0.476 L, 3751 mmol) was added slowly through a dropping funnel. The reaction was stirred at RT for 2 h. The progress of the reaction was monitored by TLC (100% EtOAc). After completion, the reaction was concentrated under reduced pressure to obtain the crude compound. The crude was triturated with ethyl acetate (2 x 500 mL) and dried under reduced pressure to obtain 2- azaspiro[3.3]heptan-6-ol hydrochloride (130 g, 92% yield) as a solid. 'HNMR (400 MHz, DMSO-tfc): 6 9.15 (br s, 2H), 5.11 (d, J= 6.00 Hz, 1H), 3.99 - 3.90 (m, 1H), 3.88 (s, 2H), Atorney Docket No. SYND-062 / 001WO 43707-02983

[0679] 3.84 (s, 2H), 2.49 - 2.43 (m, 2H), 2.01 - 1.91 (m, 2H); LCMS (Method A): Rt = 0.41 min, m / z = 114.1 [M+H]+, 99.40%. This material was used without further purification.

[0680] Step 2. Benzyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate.

[0681] Cbz

[0682] In a 3 L three neck round bottom flask under a nitrogen atmosphere, 2-azaspiro[3.3]heptan-6- ol hydrochloride (130 g, 869 mmol) was dissolved in THF (1 L) and water (800 mL) at RT. The reaction was cooled to 0 °C, and K2CO3 (240 g, 1738 mmol) was added. To this reaction mixture, benzyl chloroformate (0.147 L, 1043 mmol) was added slowly using a dropping funnel. The reaction was stirred at RT for 16 h. The progress of the reaction was monitored by TLC (100% EtOAc). After completion, the reaction was diluted with water (1.5 L) and extracted with EtOAc (2 x 2.5 L). The combined organic layer was washed with brine solution (1 L), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude was purified by silica gel flash column chromatography using EtOAc in hexane (the product was eluted at 80% EtOAc in hexane) to obtain benzyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (210 g, 93% yield) as a solid. *H NMR (400 MHz, DMSO-tfc): 6 7.40 - 7.28 (m, 5H), 5.03 - 4.99 (m, 3H), 3.98 - 3.79 (m, 5H), 2.45 - 2.36 (m, 2H), 1.98 - 1.89 (m, 2H); LCMS (Method A): Rt = 1.47 min, m / z = 248.2 [M+H]+, 95.12%.

[0683] Step-3. Benzyl 6-(tosyloxy)-2-azaspiro[3.3 ]heptane-2-carboxylate

[0684] Cbz

[0685] In a 5 L three neck round bottom flask under a nitrogen atmosphere, benzyl 6-hydroxy-2- azaspiro[3.3]heptane-2-carboxylate (210 g, 849 mmol) was dissolved in DCM (2 L). The reaction was cooled to 0 °C, and TEA (0.355 L, 2548 mmol) and DMAP (20.75 g, 170 mmol) were added. To this reaction mixture, -toluenesulfonyl chloride (194 g, 1019 mmol) was added portion-wise at the same temperature. The resulting reaction was stirred at RT for Atorney Docket No. SYND-062 / 001WO 43707-02983

[0686] 3 h. The progress of the reaction was monitored by TLC (100% EtOAc). After completion, the reaction was diluted with water (I L) and extracted with DCM (2 x 2 L). The combined organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude was purified by silica gel flash column chromatography using EtOAc in_hexane followed by DCM (product was eluted at 100% DCM) to obtain benzyl 6-(tosyloxy)-2-azaspiro[3.3]heptane-2- carboxylate (270 g, 79% yield) as a solid. 'H NMR (400 MHz, DMSO-tfc): 6 7.77 (d, J= 8.00 Hz, 2H), 7.48 (d, J= 8.00 Hz, 2H), 7.39 - 7.28 (m, 5H), 4.99 (s, 2H), 4.79 - 4.67 (m, 1H), 3.97 - 3.78 (m, 4H), 2.48 - 2.44 (m, 2H), 2.43 (s, 3H), 2.27 - 2.20 (m, 2H); LCMS (Method B): Rt = 2.66 min, m / z = 402.2 [M+H]+, 99.59%.

[0687] Step-4. Benzyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate

[0688] In a 3 L three neck round_-botom flask under a nitrogen atmosphere, benzyl 6-(tosyloxy)-2- azaspiro[3.3]heptane-2-carboxylate (270 g, 673 mmol) was dissolved in ethyl methyl ketone (2 L). To this solution, sodium iodide (403 g, 2690 mmol) was added portion-wise at RT, and the reaction was heated to 100 °C for 16 h. The progress of the reaction was monitored by TLC (100% EtOAc). After completion, the reaction was cooled to RT, diluted with water (2 L), and extracted with EtOAc (3 x 1.5 L). The combined organic layer was washed with brine solution (1 L), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude was purified by silica gel flash column chromatography using MeOH in DCM (product was eluted at 5% MeOH in DCM) to obtain benzyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (205 g, 81% yield) as a solid. 'H NMR (400 MHz, DMSO-tfc): 6 7.40 - 7.29 (m, 5H), 5.01 (s,2 H), 4.43 (p, J= 8Hz, 1H), 4.03 - 3.89 (m, 4H), 2.96 - 2.87 (m, 2H), 2.72 - 2.62 (m, 2H); LCMS (Method D): Rt = 2.54 min, m / z = 358.1 [M+H]+, 94.78%.

[0689] Intermediate 4. / ‘c / 7- Butyl 4-((2-azaspiro[3.3]heptan-6-yl)oxy)-7,8-dihydro-l,6- naphthyridine-6(5H)-carboxylate Attorney Docket No. SYND-062 / 001WO 43707-02983 Formalin (Aq. 37%), (1.5 eq), MeOH, Boc anhydride (3 eq) reflux, 16 h RT, 16 h

[0690] Step 1. 6-Benzyl-5,6, 7,8-tetrahydro-l, 6-naphthyridin-4-ol

[0691] To a stirred solution of 2-(2-(benzylamino)ethyl)pyridin-4-ol 2,2,2-trifluoroacetic acid (90 g, 263 mmol) in MeOH (2.5 L), formaldehyde solution (29.4 mL, 394 mmol; 37 wt% in water) was added slowly at RT. The reaction was stirred at 70 °C for 16 h. The progress of the reaction was monitored by TLC (10% MeOH in DCM). After completion, the reaction was concentrated under reduced pressure to obtain the crude compound. The crude was purified by silica gel flash column chromatography using MeOH in DCM (product was eluted at 15% MeOH in DCM) to obtain 6-benzyl-5,6,7,8-tetrahydro-l,6-naphthyridin-4-ol (63 g, 99% yield) as semisolid. 'HNMR (400 MHz, methanol-t ) 8 11.91 (brs, 1H), 7.74 (d, J= 7.2 Hz, 1H), 7.56 - 7.42 (m, 5H), 6.17 (d, J= 6.8 Hz, 1H), 4.33 (br s, 2H), 3.78 (br s, 2H), 3.33 (br s, 2H), 2.99 - 2.90 (m, 2H); LCMS (Method A): Rt = 1.26 min, m / z = 241.1 [M+H]+, 98.99%. Step 2. tert-Butyl 4-hydroxy-7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate

[0692] In a 2 L three neck round bottom flask under an argon atmosphere, 6-benzyl-5, 6,7,8- tetrahydro-l,6-naphthyridin-4-ol (35 g, 146 mmol) was dissolved in MeOH (350 mL). To this solution, Pd-C (17.5 g, 16.44 mmol) and (Boc)2O (101 mL, 437 mmol) were added, and the Attorney Docket No. SYND-062 / 001WO 43707-02983 reaction was stirred at RT for 16 h under a hydrogen atmosphere (balloon pressure). The progress of the reaction was monitored by TLC (10% MeOH in DCM). After completion, the reaction was filtered through a Celite® pad, and the pad was washed with MeOH (2 x 100 mL). The filtrate was concentrated under reduced pressure to obtain the crude compound. The crude was purified by silica gel flash column chromatography using MeOH in DCM (product eluted at 10% MeOH in DCM) to obtain tert-butyl 4-hydroxy-7,8-dihydro-l,6- naphthyridine-6(5H)-carboxylate (28 g, 74.8% yield) as fluffy solid. 1H NMR (400 MHz, DMSO-tfc): 6 7.99 (br s, 1 H), 6.57 (br s, 1 H), 4.25 (s, 2 H), 3.61 (br t, J= 5.32 Hz, 2 H), 2.79 (br t, J= 4.94 Hz, 2 H), 1.43 (m, 9 H), -OH proton not observed; LCMS (Method D): Rt = 1.16 min, m / z = 251.2 [M+H]+, 97.33%.

[0693] Step 3. tert-Butyl 4-((2-((benzyloxy)carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)-7,8-dihydro- l,6-naphthyridine-6(5H)-carboxylate

[0694] Cbz

[0695] To a stirred solution of tert-butyl 4-hydroxy-7,8-dihydro-l,6-naphthyridine-6(5H)- carboxylate (50 g, 200 mmol, 0.599 mmol) and benzyl 6-iodo-2-azaspiro[3.3]heptane-2- carboxylate (143 g, 400 mmol) in DMF (500 mL), K2CO3 (138 g, 999 mmol) was added at RT. The reaction was stirred at 100 °C for 16 h. The progress of the reaction was monitored by LCMS. After completion, the reaction was diluted with cold water (I L) and extracted with EtOAc (2 x 1 L). The combined organic layer was washed with brine solution (1 L), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude compound. The crude was purified by silica gel flash column chromatography using MeOH in DCM (the product was eluted in 10% MeOH in DCM) to obtain tert-butyl 4-((2-((benzyloxy)carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)-7,8- dihydro-l,6-naphthyridine-6(5H)-carboxylate (90 g, 85% yield) as a solid. 'H NMR. (400 MHz, DMSO-tfc): 6 8.24 (d, J= 5.6 Hz, 1H), 7.41 - 7.29 (m, 5H), 6.73 (d, J= 5.7 Hz, 1H), 5.03 (s, 2H), 4.76 (quin, J= 6.4 Hz, 1H), 4.36 (br s, 2H), 4.07 - 3.90 (m, 4H), 3.61 (br t, J = Atorney Docket No. SYND-062 / 001WO 43707-02983

[0696] 5.8 Hz, 2H), 2.82 - 2.75 (m, 4H), 2.30 - 2.20 (m, 2H), 1.42 (s, 9H).LCMS (Method G): Rt = 2.18 min, m / z = 480.3 [M+H]+, 93.85%.

[0697] Step 4. tert-Butyl 4-((2-azaspiro [3.3]heptan-6-yl)oxy)-7 ,8-dihydro-l ,6-naphthyridine-6(5H)~ carboxylate

[0698] In a 100 mL single neck round botom flask under nitrogen atmosphere, tert-butyl 4-((2- ((benzyloxy)carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)-7,8-dihydro-l,6-naphthyridine- 6(5rt)-carboxylate (25 g, 52.1 mmol) was dissolved in 2,2,2-trifluoroethanol (250 mL). To this reaction mixture, Pd-C (24.96 g, 23.46 mmol) was added, and the reaction was stirred at RT for 16 h under a hydrogen atmosphere (balloon pressure). The progress of the reaction was monitored by TLC (100% EtOAc). After completion, the reaction was filtered through a Celite® pad, and the filtrate pad was washed with 10% MeOH in DCM (3 x 200 mL). The filtrate was concentrated under reduced pressure to obtain tert-butyl 4-((2- azaspiro[3.3]heptan-6-yl)oxy)-7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate (18 g, 94% yield) as a semi-solid. LCMS (Method G): Rt = 1.35 min, m / z = 346.1 [M+H]+, 93.78%.

[0699] Intermediate 5. 4-((2-Azaspiro[3.3]heptan-6-yl)oxy)-6-benzyl-5,6,7,8-tetrahydro-l,6- naphthyridine hydrochloride

[0700] Step 1. tert-Butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate Attorney Docket No. SYND-062 / 001WO 43707-02983 Boc

[0701] To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (tert-butyl 6- hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (25 g, 117 mmol) in toluene (250 mL), imidazole (23.94 g, 352 mmol), triphenylphosphine (61.5 g, 234 mmol) and iodine (44.6 g, 176 mmol)) were added at RT. The reaction was stirred at 110 °C for 1.5 h. The progress of the reaction was monitored by TLC (30% EtOAc in hexane). After completion, the reaction was cooled to RT, and the solvent was evaporated under reduced pressure. To this residue, water (500 mL) was added, and the mixture was extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine solution (100 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude was purified by silica gel flash column chromatography using EtOAc in hexane (product was eluted at 20-25% EtOAc in hexane) to obtain tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (25 g, 63.4% yield) as a solid. 'HNMR (400 MHz, DMSO-< 84.43 (p, J= 7.8 Hz, 1H), 3.85 (br s, 4H), 2.95 - 2.83 (m, 2H), 2.70 - 2.60 (m, 2H), 1.36 (s, 9H); LCMS (Method A): Rt = 2.11 min, m / z: 268.1 [M- 56]+, 96.11%.

[0702] Step 2. tert-Butyl 6-((6-benzyl-5,6, 7,8-tet^cihydro-l ,6-naphthyridin-4-yl)oxy)-2- azaspiro[ 3.3 ]heptane-2-carboxylate i Boc

[0703] To a stirred solution of 6-benzyl-5,6,7,8-tetrahydro-l,6-naphthyridin-4-ol (104 g, 433 mmol) dissolved in DMF (1000 ml), powdered K2CO3 (179 g, 1298 mmol) was added at RT under a nitrogen atmosphere. The reaction was stirred at RT for 5 min. To this solution, tert-butyl 6- iodo-2-azaspiro[3.3]heptane-2-carboxylate (280 g, 866 mmol) was added at RT. The resulting mixture was stirred at RT for 10 min and then stirred at 100 °C for 16 h. The Atorney Docket No. SYND-062 / 001WO 43707-02983 reaction was monitored by TLC (100% EtOAc). The reaction was quenched with water (3000 mL) and extracted with EtOAc (4500 mL). The organic layer was washed with cool brine (3 x 4500 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using 100% EtOAc, and then with 10% MeOH in EtOAc, to afford tert- butyl 6-((6-benzyl-5,6,7,8-tetrahydro-l,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptane-2- carboxylate (122 g, 64.4 % yield) as a solid. 'H NMR (400 MHz, DMSO 8 8.20 (d, J = 5.7 Hz, 1H), 7.38 - 7.32 (m, 4H), 7.31 - 7.23 (m, 1H), 6.65 (d, J= 5.5 Hz, 1H), 4.68 (quin, J = 6.7 Hz, 1H), 3.93 - 3.76 (m, 4H), 3.69 (s, 2H), 3.45 (s, 2H), 2.84 - 2.77 (m, 2H), 2.75 - 2.67 (m, 4H), 2.18 - 2.13 (m, 2H), 1.37 (s, 9H); LCMS (Method A): Rt = 2.10 min, m / z = 436.2 [M+H]+, 99.49%.

[0704] Step 3. 4-((2-Azaspiro[3.3]heptan-6-yl)oxy)-6-benzyl-5,6, 7 ,8-tetrahydro-l ,6-naphthyridine hydrochloride

[0705] To a stirred solution of tert-butyl 6-((6-benzyl-5,6,7,8-tetrahydro-l,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptane-2-carboxylate (70 g, 161 mmol) in 2,2,2-trifluoroethanol (700 mL), TMSC1 (82 mL, 643 mmol) was added slowly at 0 °C. The reaction was stirred at RT for 1.5 h. The progress of the reaction was monitored by LCMS. After completion, the reaction was concentrated under reduced pressure to obtain crude 4-((2-azaspiro[3.3]heptan-6-yl)oxy)-6- benzyl-5,6,7,8-tetrahydro-l,6-naphthyridine hydrochloride (60 g, 97% yield) as a solid. This material was used without further purification. LCMS (Method G): Rt = 1.23 min, m / z = 336.1 [M+H]+, 96.69%.

[0706] Intermediate 6. 2-((4-(6-((6-Benzyl-5,6,7,8-tetrahydro-l,6-naphthyridin-4-yl)oxy)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoic acid Attorney Docket No. SYND-062 / 001WO 43707-02983

[0707] Step 3

[0708] Step 1. Methyl 2-((4-(6-((6-benzyl-5,6, 7,8-tetrahydro-l,6-naphthyridin-4-yl)oxy)-2- azaspiro[ 3.3 ]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate To a stirred solution of methyl 2-((4-chloropyrimidin-5-yl)oxy)-5-fluorobenzoate (14.93 g, 52.8 mmol) in 2-propanol (150 mL), TEA (22.09 mL, 158 mmol) and 4-((2- azaspiro[3.3]heptan-6-yl)oxy)-6-benzyl-5,6,7,8-tetrahydro-l,6-naphthyridine hydrochloride (19.64 g, 52.8 mmol) were added at RT. The reaction was stirred at 80 °C for 2 h. The reaction progress was monitored by TLC (10% MeOH in DCM). After completion, the reaction was concentrated under reduced pressure and the residue was diluted with water (100 mL). The mixture was extracted with DCM (2 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under Atorney Docket No. SYND-062 / 001WO 43707-02983 reduced pressure. The crude compound was purified by silica gel flash column chromatography using MeOH in DCM (product eluted at 7% MeOH in DCM) to obtain methyl 2-((4-(6-((6-benzyl-5,6,7,8-tetrahydro-l,6-naphthyridin-4-yl)oxy)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate (26 g, 82% yield) as a solid. 'HNMR (400 MHz, DMSO-tfc): 6 8.29 (s, 1H), 8.19 (d, J= 5.7 Hz, 1H), 7.70 - 7.63 (m, 2H), 7.49 (ddd, J= 3.2, 7.9, 9.0 Hz, 1H), 7.35 (d, J= 4.3 Hz, 4H), 7.27 (qd, J= 4.2, 8.5 Hz, 1H), 7.11 (dd, J= 4.5, 9.2 Hz, 1H), 6.67 (d, J= 5.7 Hz, 1H), 4.72 (quin, J= 6.6 Hz, 1H), 4.26 (s, 2H), 4.16 (s, 2H), 3.81 (s, 3H), 3.67 (s, 2H), 3.45 (s, 2H), 2.84 - 2.73 (m, 4H), 2.69 (br t, J = 5.2 Hz, 2H), 2.27 - 2.18 (m, 2H); LCMS (Method F): Rt = 2.17 min, m / z = 582.4 [M+H]+, 97.31%.

[0709] Step 2. Methyl 5-fluoro-2-((4-(6-((5,6, 7,8-tetrahydro-l,6-naphthyridin-4-yl)oxy)-2- azaspiro[ 3.3 ]heptan-2-yl)pyrimidin-5-yl)oxy)benzoate

[0710] In a round botom flask, methyl 2-((4-(6-((6-benzyl-5,6,7,8-tetrahydro-l,6-naphthyridin-4- yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate (10 g, 17.19 mmol) was dissolved in TFE ( 180 mL). To this solution, Pd-C (5.49 g, 5.16 mmol) was added under a nitrogen atmosphere. The reaction was stirred at RT for 16 h under a hydrogen atmosphere (balloon pressure). The reaction progress was monitored by TLC (10% MeOH in DCM). After completion, the reaction was filtered through a Celite® pad, and the pad was washed with MeOH (2 x 100 mL). The filtrate was concentrated under reduced pressure to obtain crude methyl 5-fluoro-2-((4-(6-((5,6,7,8-tetrahydro-l,6-naphthyridin-4-yl)oxy)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzoate (8.4 g, 97% yield) as a solid. This material was used without further purification.1H NMR (400 MHz, DMSO-tL): 8 8.30 (s, 1H), 8.17 (d, J= 5.6 Hz, 1H), 7.70 - 7.64 (m, 2H), 7.49 (ddd, J= 3.3, 7.9, 9.0 Hz, 1H), 7.10 (dd, J= 4.5, 9.1 Hz, 1H), 6.66 (d, J= 5.6 Hz, 1H), 4.73 (quin, J = 6.6 Hz, 1H), 4.31 - 4.15 Atorney Docket No. SYND-062 / 001WO 43707-02983

[0711] (m, 4H), 3.82 (s, 3H), 3.72 (s, 2H), 2.98 (t, J= 5.8 Hz, 2H), 2.83 - 2.74 (m, 2H), 2.70 (br t, J = 5.7 Hz, 2H), 2.30 - 2.18 (m, 2H), one proton merged with solvent peaks; LCMS (Method A): Rt = 1.56 min, m / z = 492.2 [M+H]+, 97.21%.

[0712] Step 3. Methyl 5-fluoro-2-((4-(6-((6-methyl-5,6, 7,8-tetrahydro-l,6-naphthyridin-4-yl)oxy)-2- azaspiro[ 3.3 ]heptan-2-yl)pyrimidin-5-yl)oxy)benzoate

[0713] In a dried, 500 mL round bottom flask under a nitrogen atmosphere, methyl 5-fluoro-2-((4- (6-((5,6,7,8-tetrahydro-l,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzoate (8.4 g, 17.09 mmol) was dissolved in MeOH (90 mL). To this solution, formaldehyde (2.354 mL, 85 mmol) and AcOH (0.489 mL, 8.54 mmol) were added at 0 °C. The reaction was stirred at RT for 1 h. To this reaction mixture, sodium triacetoxyborohydride (7.24 g, 34.2 mmol) was added at 0 °C, and the reaction was stirred at RT for 16 h. The reaction progress was monitored by TLC (10% MeOH in DCM). After completion, the reaction was concentrated under reduced pressure. The residue was quenched with saturated sodium bicarbonate solution (100 mL) and the mixture was extracted with DCM (2 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude compound was purified by reverse phase chromatography using a SiliCycle SiliaSep C18 column (120 g) on Biotage isolera one (Mobile phase A: 10 mM NH4HCO3 in water, B: ACN). The fractions were concentrated under reduced pressure to afford methyl 5-fluoro-2-((4-(6-((6- methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin- 5-yl)oxy)benzoate (6.7 g, 75% yield) as a solid. 'HNMR (400 MHz, DMSO-t / e): 8 8.30 (s, 1H), 8.18 (d, J= 5.6 Hz, 1H), 7.69 - 7.65 (m, 2H), 7.49 (ddd, J= 3.3, 7.8, 9.1 Hz, 1H), 7.11 (dd, J= 4.4, 9.1 Hz, 1H), 6.67 (d, J= 5.8 Hz, 1H), 4.75 (quin, J= 6.7 Hz, 1H), 4.27 (s, 2H), Atorney Docket No. SYND-062 / 001WO 43707-02983

[0714] 4.18 (s, 2H), 3.82 (s, 3H), 3.35 (s, 2H), 2.84 - 2.76 (m, 4H), 2.65 - 2.59 (m, 2H), 2.36 (s, 3H), 2.30 - 2.23 (m, 2H); LCMS (Method A): Rt = 1.69 min, m / z = 506.3 [M+H]+, 96.85%.

[0715] Step 4. 5-Fluoro-2-((4-(6-((6-methyl-5,6, 7,8-tetrahydro-l,6-naphthyridin-4-yl)oxy)-2- azaspiro[ 3.3 ]heptan-2-yl)pyrimidin-5-yl)oxy)benzoic acid

[0716] Procedure 1: To a stirred solution of methyl 5-fluoro-2-((4-(6-((6-methyl-5,6,7,8-tetrahydro- l,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzoate (7.2 g, 14.24 mmol) in THF:water (55 mL:23.57 mL), lithium hydroxide monohydrate (0.682 g, 28.5 mmol) was added at 0 °C. The reaction was stirred at RT for 2 h. The reaction progress was monitored by TLC (10% MeOH in DCM). After completion, the reaction was concentrated under reduced pressure, the residue was dissolved in water (15 mL), and the mixture was acidified with 1.5 N HC1 (pH ~2). The solvent was removed under reduced pressure, and the residue was reconcentrated from toluene (2 x 100 mL) then from EtOAc (2 x 100 mL). The resulting residue was lyophilized to afford crude 5-fluoro-2-((4-(6-((6-methyl-5, 6,7,8- tetrahydro-l,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzoic acid. xHCl (6.2 g, 87% yield) as a solid. This material was used without further purification. 'HNMR (400 MHz, DMSO ): 6 8.18 (d, J= 5.6 Hz, 1H), 8.14 (s, 1H), 7.38 (s, 1H), 7.26 (dd, J= 2.5, 9.1 Hz, 1H), 7.05 (dt, J= 3.2, 8.5 Hz, 1H), 6.92 (dd, J= 4.6, 8.9 Hz, 1H), 6.69 (d, J= 5.6 Hz, 1H), 4.76 (quin, J= 6.8 Hz, 1H), 4.39 - 4.30 (m, 2H), 4.29 - 4.20 (m, 2H), 3.37 (s, 2H), 2.85 - 2.76 (m, 4H), 2.66 - 2.60 (m, 2H), 2.36 (s, 3H), 2.30 - 2.25 (m, 2H), acid proton -was not observed; LCMS (Method A): Rt = 1.19 min, m / z = 492.2 [M+H]+; HPLC (Method A): Rt = 3.42 min, 98.12%.

[0717] Procedure 2: To a stirred solution of methyl 5-fluoro-2-((4-(6-((6-methyl-5,6,7,8-tetrahydro- l,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzoate (8 g, Atorney Docket No. SYND-062 / 001WO 43707-02983

[0718] 15.82 mmol) in THF:water (40 mL: 17.14 mL), lithium hydroxide monohydrate (1.328 g, 31.6 mmol) was added at 0 °C. The reaction was stirred at RT for 2 h. The reaction progress was monitored by TLC (10% MeOH in DCM). After completion, the reaction was concentrated under reduced pressure, the residue was dissolved in water (20 mL), and the mixture was acidified with 1.5 N HC1 (pH ~2). The solvent was removed under reduced pressure, the residue was dissolved in water (30 mL), and the mixture was neutralized with solid NaHCCh at 0 °C. The precipitated solid was filtered and washed with water (20 mL) to afford 5-fluoro- 2-((4-(6-((6-methyl-5,6,7,8-tetrahydro-l,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2- yl)pyrimidin-5-yl)oxy)benzoic acid (6.1 g, 76% yield) as a solid. 'H NMR (400 MHz, DMSO-tfc): 6 8.30 - 8.23 (m, 1H), 8.21 (d, J= 5.7 Hz, 1H), 7.61 (s, 1H), 7.55 (dd, J= 3.2, 8.7 Hz, 1H), 7.36 (dt, J= 3.3, 8.4 Hz, 1H), 7.02 (br dd, J= 4.3, 8.9 Hz, 1H), 6.69 (d, J= 5.8 Hz, 1H), 4.77 (quin, J= 6.2 Hz, 1H), 4.26 (br s, 2H), 4.19 (br s, 2H), 3.53 (s, 2H), 2.91 - 2.71 (m, 6H), 2.48 (s, 3H), 2.29 - 2.17 (m, 2H), acid proton was not observed; LCMS (Method A): Rt = 1.21 min, m / z = 492.1 [M+H]+, 97.99%.

[0719] Intermediate 7. 2-((4-(6-((6-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydro-l,6-naphthyridin-

[0720] 4-yl)oxy)-2-azaspiro [3.3] heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoic acid

[0721] Step 1. tert-Butyl 4-((2-((benzyloxy)carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)-7,8-dihydro- l,6-naphthyridine-6(5H)-carboxylate Atorney Docket No. SYND-062 / 001WO 43707-02983

[0722] To a stirred solution of tert-butyl 4-hydroxy-7,8-dihydro-l,6-naphthyridine-6(5Z / )- carboxylate (47 g, 188 mmol) in DMF (750 mL), benzyl 6-iodo-2-azaspiro[3.3]heptane-2- carboxylate (87 g, 244 mmol), and K2CO3 (78 g, 563 mmol) were added at RT. The reaction was stirred at 100 °C for 16 h. The reaction progress was monitored by TLC (100% EtOAc). After completion, the reaction was quenched with water (I L) and the mixture was extracted with EtOAc (2 x 1.5 L). The combined organic layer was washed with brine (2 x 1.5 L), dried over sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The crude was purified by silica gel flash column chromatography using MeOH in DCM (product eluted at 10% MeOH in DCM) to obtain tert-butyl 4-((2-((benzyloxy)carbonyl)-2- azaspiro[3.3]heptan-6-yl)oxy)-7,8-dihydro-l,6-naphthyridine-6(5J7)-carboxylate (71.82 g, 77% yield) as a gummy liquid. 'H NMR (400 MHz, DMSO-tfc): 6 8.24 (d, J= 5.6 Hz, 1H), 7.44 . 7.28 (m, 5H), 6.73 (d, J= 5.8 Hz, 1H), 5.03 (s, 2H), 4.76 (quin, J= 6.3 Hz, 1H), 4.36 (s, 2H), 4.14 - 3.88 (m, 4H), 3.62 (br t, J= 5.8 Hz, 2H), 2.84 - 2.72 (m, 4H), 2.30 - 2.21 (m, 2H), 1.42 (s, 9H); LCMS (Method A): Rt = 2.23 min, m / z = 480.4 [M+H]+, 96.28%.

[0723] Step 2. tert-Butyl 4-((2-azaspiro [3.3]heptan-6-yl)oxy)-7 ,8-dihydro-l ,6-naphthyridine-6(5H)~ carboxylate

[0724] In a 250 mL round bottom flask under a nitrogen atmosphere, tert-butyl 4-((2- ((benzyloxy)carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)-7,8-dihydro-l,6-naphthyridine- 6(5J7)-carboxylate (5 g, 10.43 mmol) was dissolved in TFE (50 mL). To this solution, Pd-C Atorney Docket No. SYND-062 / 001WO 43707-02983

[0725] (2.219 g, 2.085 mmol) was added and the reaction was stirred at RT for 5 h under a hydrogen atmosphere (balloon pressure). The reaction progress was monitored by TLC (10% MeOH in DCM). After completion, the reaction was filtered through a Celite® pad, and the pad was washed with MeOH (80 mL). The filtrate was concentrated under reduced pressure to obtain crude tert-butyl 4-((2-azaspiro[3.3]heptan-6-yl)oxy)-7,8-dihydro-l,6-naphthyridine-6(5Z / )- carboxylate (3.5 g, 74.4% yield) as a gummy liquid. This material was used without further purification. LCMS (Method A): Rt = 1.44 min, m / z = 346.1 [M+H]+, 76.51%.

[0726] Step 3. tert-Butyl 4-((2-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2- azaspiro[3.3]heptan-6-yl)oxy)-7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate

[0727] To a stirred solution of tert-butyl 4-((2-azaspiro[3.3]heptan-6-yl)oxy)-7,8-dihydro-l,6- naphthyridine-6(5J7)-carboxylate (2.017 g, 5.84 mmol) in 2-propanol (20 mL), TEA (2.219 mL, 15.92 mmol), and methyl 2-((4-chloropyrimidin-5-yl)oxy)-5-fluorobenzoate (1.5 g, 5.31 mmol) were added at RT. The reaction was stirred at 80 °C for 2 h. The reaction progress was monitored by TLC (100% EtOAc). When complete, the reaction was concentrated under reduced pressure. The crude was purified by silica gel flash column chromatography using MeOH in DCM (product eluted at 5-10% MeOH in DCM) to obtain tert-butyl 4-((2-(5-(4- fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-yl)oxy)-7,8- dihydro-l,6-naphthyridine-6(5J7)-carboxylate (1.9 g, 50.1% yield) as a solid. 'H NMR (400 MHz, CDCh): 6 8.38 (s, 1H), 8.28 (d, J= 5.7 Hz, 1H), 7.70 - 7.62 (m, 2H), 7.26 - 7.16 (m, 1H), 6.88 (dd, J= 4.3, 9.1 Hz, 1H), 6.46 (d, J= 5.8 Hz, 1H), 4.67 (quin, J= 6.5 Hz, 1H), 4.48 (br s, 2H), 4.35 (s, 2H), 4.32 (s, 2H), 3.90 (s, 3H), 3.71 (br t, J= 5.8 Hz, 2H), 2.95 (br t, J = 5.6 Hz, 2H), 2.87 - 2.77 (m, 2H), 2.50 - 2.36 (m, 2H), 1.50 (s, 9H); LCMS (Method A): Rt = 2.07 min, m / z = 592.2 [M+H]+, 82.78%. Atorney Docket No. SYND-062 / 001WO 43707-02983

[0728] Step 4. 2-((4-(6-((6-(tert-Butoxy carbonyl) -5, 6, 7 ,8-tetrahydro-l ,6-naphthyridin-4-yl)oxy)-2- azaspiro[ 3.3 ]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoic acid

[0729] To a stirred solution of tert-butyl 4-((2-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin- 4-yl)-2-azaspiro[3.3]heptan-6-yl)oxy)-7,8-dihydro-l,6-naphthyridine-6(5J7)-carboxylate (1.9 g, 3.21 mmol) in THF:H2O (2:1, 21 mL), LiOH.ffcO (0.404 g, 9.63 mmol) was added at 0 °C. The reaction was stirred at RT for 2 h. The reaction progress was monitored by TLC (10% MeOH in DCM). After completion, the reaction was concentrated and the residue was reconcentrated from toluene (3 x 15 mL) to afford crude lithium 2-((4-(6-((6-(tert- butoxycarbonyl)-5,6,7,8-tetrahydro-l,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2- yl)pyrimidin-5-yl)oxy)-5-fluorobenzoate (1.8 g, 88% yield) as a solid. The crude material (1 g, 1.714 mmol) was diluted with water (10 mL), cooled to 0 °C, and neutralized with 1.5 N HC1 (2.285 mL, 3.43 mmol) to pH ~7. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain crude 2-((4-(6-((6-(ter / -butoxycarbonyl)- 5,6,7,8-tetrahydro-l,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)-5-fluorobenzoic acid (380 mg, 37.7% yield) as a solid. This material was used without further purification. 'H NMR (400 MHz, DMSO-t / e): 8 13.32 (br s, 1H), 8.26 (s, 1H), 8.23 (d, J= 5.6 Hz, 1H), 7.64 - 7.59 (m, 1H), 7.58 (s, 1H), 7.47 - 7.39 (m, 1H), 7.11 (dd, J = 4.5, 9.1 Hz, 1H), 6.75 (d, J= 5.8 Hz, 1H), 4.79 (quin, J= 6.5 Hz, 1H), 4.36 (s, 2H), 4.30 (br s, 2H), 4.22 (br s, 2H), 3.61 (br t, J= 5.8 Hz, 2H), 2.86 - 2.76 (m, 4H), 2.32 - 2.26 (m, 2H), 1.42 (s, 9H); LCMS (Method G): Rt = 1.54 min, m / z = 578.3 [M+H]+, 98.27%.

[0730] Example 1. 5-Fluoro-7V-isopropyl-2-((4-(6-((6-methyl-5,6,7,8-tetrahydro-l,6- naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-A-(thietan-3- yl)benzamide (Compound No. 1) Attorney Docket No. SYND-062 / 001WO 43707-02983 -10 °C-RT, 1 h Step 2 Step 3 -HCI

[0731] Step 1

[0732] Step 4 The reaction was performed following the same procedure in two batches (2 x 20 g).

[0733] In a dried, 500 mL round bottom flask under a nitrogen atmosphere, tert-butyl (1,3- dihydroxypropan-2-yl)carbamate (20 g, 105 mmol) was dissolved in DCM (200 mL). To this solution, EtiN (35.7 mL, 261 mmol) and methanesulfonyl chloride (17.93 mL, 230 mmol) were added at -10 °C and the reaction was stirred at RT for 1 h. The reaction progress was monitored by TLC (10% MeOH in DCM). After completion, the reactions were combined and diluted with water (100 mL), and the mixture was extracted with DCM (2 x 100 mL).

[0734] The combined organic layer was washed with brine (200 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude 2-((te / Z- butoxycarbonyl)amino)propane-l,3-diyl dimethanesulfonate (75 g, quantitative combined yield) as a solid. This material was used without further purification. 'H NMR (400 MHz,

[0735] DMSO-tfc): 6 7.29 (br d, J= 8.0 Hz, 1H), 4.28 - 4.14 (m, 4H), 4.09 - 3.97 (m, 1H), 3.21 (s, 6H), 1.40 (s, 9H); LCMS (Method A): Rt = 1.66 min, m / z = 247.9 [M+H-100]+, 99.66%.

[0736] Step 2. tert-Butyl thietan-3-ylcarbamate Atorney Docket No. SYND-062 / 001WO 43707-02983

[0737] To a solution of 2-((tert-butoxycarbonyl)amino)propane- 1,3 -diyl dimethanesulfonate (10.0 g, 28.8 mmol) in ethanol (200 mL), Na2S.9H2O (7.26 g, 30.2 mmol) was added and the reaction was stirred at 55 °C for 1 h. The reaction progress was monitored by TLC (50% EtOAc in hexane). After completion, the reaction was concentrated under reduced pressure and the residue was dissolved in ice-cold water (50 mL). The mixture was extracted with MTBE (2 x 200 mL) and the combined organic layer was washed with brine (100 mL), dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude was purified by silica gel flash column chromatography using EtOAc in hexane (product was eluted at 5-10% EtOAc in hexane) to obtain tert-butyl thi etan-3 -ylcarbamate (2.2 g, 32.2% yield) as a solid. 'H NMR (400 MHz, DMSO-tfc): 6 7.60 (br d, J= 7.6 Hz, 1H), 4.81 - 4.58 (m, 1H), 3.38 - 3.32 (m, 2H), 3.18 - 3.09 (m, 2H), 1.37 (s, 9H); LCMS (Method A): Rt = 1.71 min, m / z = 188.0 [M-H]’, 79.82%.

[0738] Step 3. Thietan-3-amine hydrochloride

[0739] In a 100 mL round bottom flask under a nitrogen atmosphere, tert-butyl thi etan-3 - ylcarbamate (2.2 g, 11.62 mmol) was dissolved in TFE (20 mL). To this solution, TMSC1 (5.94 mL, 46.5 mmol) was added at 0 °C and the reaction was stirred at RT for 1 h. The reaction progress was monitored by TLC (30% EtOAc in hexane). After completion, the reaction was concentrated under pressure to obtain crude thi etan-3 -amine hydrochloride (1.7 g, quantitative yield) as a solid. This material was used without further purification. *HNMR (400 MHz, DMSO-tfc): 6 8.54 (br s, 3H), 4.49 (quin, J= 8.3 Hz, 1H), 3.56 - 3.47 (m, 2H), 3.21 - 3.12 (m, 2H).

[0740] Step 4. N-Isopropylthietan-3-amine hydrochloride Atorney Docket No. SYND-062 / 001WO 43707-02983

[0741] In a 100 mL two neck round bottom flask under a nitrogen atmosphere, thi etan-3 -amine hydrochloride (1.7 g, 13.53 mmol) was dissolved in MeOH (30 mL). To this solution, acetone (9.94 mL, 135 mmol) and acetic acid (0.077 mL, 1.353 mmol) were added at 0 °C and the reaction was stirred at RT for 1 h. To this reaction mixture, STAB (4.30 g, 20.30 mmol) was added at 0 °C and the reaction was stirred at RT for 16 h. The reaction progress was monitored by 'H-NMR. After completion, the reaction was diluted with EtOAc (100 mL) and filtered through a Celite® pad, and the pad was washed with EtOAc (2 x 25 mL). The filtrate was acidified with 4 M HC1 in 1,4 dioxane to pH ~4 and the mixture was concentrated under reduced pressure to obtain crude A-isopropylthi etan-3 -amine hydrochloride (2.25 g, 94% yield) as a solid. This material was used without further purification.1H NMR (400 MHz, DMSO-tfc): 69.62 (br s, 2H), 4.61 (quin, J= 8.5 Hz, 1H), 3.71 (t, J= 9.3 Hz, 2H), 3.21 - 3.11 (m, 3H), 1.21 (d, J= 6.5 Hz, 6H); LCMS (Method A): Rt = 1.29 min, m / z = 132.1 [M+H]+, 94.47%.

[0742] Step 5. 5-Fluoro-N-isopropyl-2-( ( 4-( 6-(( 6-methyl-5, 6, 7, 8-tetrahydro-l, 6-naphthyridin-4- yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-N-(thietan-3-yl)benzamide

[0743] To a stirred solution of 5-fluoro-2-((4-(6-((6-methyl-5, 6, 7, 8-tetrahydro-l, 6-naphthyridin-4- yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzoic acid (0.5 g, 1.017 mmol) and A-isopropylthietan-3-amine hydrochloride (0.341 g, 2.034 mmol) in DCM (5 mL), DIPEA (4.43 mL, 25.4 mmol) and POCh (0.571 mL, 6.10 mmol) were added at 0 °C. The reaction was stirred at 0 °C for 30 min. The reaction progress was monitored by TLC (10% MeOH in DCM). After completion, the reaction was quenched with aq. NaHCOs solution (20 mL) and Atorney Docket No. SYND-062 / 001WO 43707-02983 the mixture was extracted with DCM (2 x 50 mL). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude was purified by reverse phase chromatography using a SiliCycle SiliaSep Cl 8 column (80 g) on Biotage isolera one (Mobile phase A: l 0 mM NH4HCO3 in water, B: ACN) to obtain 5-fluoro-A-isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- tetrahydro-l,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-A- (thi etan-3 -yl)benzamide (0.324 g, 50.9% yield) as a solid.JH NMR (400 MHz, DMSO-t / e): 8 8.33 - 8.25 (m, 1H), 8.18 (d, J= 5.6 Hz, 1H), 7.84 - 7.75 (m, 1H), 7.40 - 7.20 (m, 2H), 7.17 - 7.00 (m, 1H), 6.67 (d, J= 5.6 Hz, 1H), 4.91 - 4.68 (m, 2H), 4.40 (br t, J= 8.1 Hz, 1H), 4.36 - 4.05 (m, 5H), 3.71 - 3.51 (m, 2H), 3.39 (br s, 2H), 3.16 - 2.92 (m, 2H), 2.87 - 2.75 (m, 4H), 2.68 - 2.62 (m, 1H), 2.38 (s, 3H), 2.30 - 2.21 (m, 2H), 1.54 - 0.91 (m, 6H); LCMS (Method A): Rt = 1.85 min, m / z = 605.1 [M+H]+; HPLC (Method A): Rt = 5.48 min, 97.06%.

[0744] Example 2. 7V-(1, l-Dioxidothietan-3-yl)-5-fluoro-7V-isopropyl-2-((4-(6-((5, 6,7,8- tetrahydro-l,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide (Compound No. 2) Atorney Docket No. SYND-062 / 001WO 43707-02983

[0745] Step 1. 3-(Isopropylamino)thietane 1,1-dioxide

[0746] In a dried, 25 mL round botom flask under a nitrogen atmosphere, 3-aminothietane 1,1- dioxide hydrochloride (600 mg, 3.81 mmol) was taken up in DCM (2 mL). To this mixture, EtsN (0.690 mL, 4.95 mmol) was added, and the reaction was stirred at RT for 5 min. The reaction was concentrated under reduced pressure. To this crude material, MeOH (8 mL) was added, then AcOH (9.96 mL, 174 mmol) and acetone (2.236 mL, 30.5 mmol) were added at 0 °C. The reaction was stirred at RT for 1 h, then STAB (2.02 g, 9.52 mmol) was added at 0 °C and the reaction was stirred at RT for 6 h. The reaction progress was monitored by TLC (5% MeOH in DCM). After completion, the reaction was quenched with saturated sodium bicarbonate solution (10 mL), and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain crude 3-(isopropylamino)thietane 1,1- dioxide (500 mg, 80% yield) as a viscous liquid. This material was used without further purification. 'H NMR (400 MHz, DMSO-tfc): 6 4.36 - 4.22 (m, 2H), 3.93 - 3.82 (m, 2H), 3.67 - 3.55 (m, 1H), 2.68 (spt, J= 6.2, 1H), 0.97 (d, J= 6.3 Hz, 6H), one proton merged with solvent peaks.

[0747] Step 2. tert-Butyl 4-((2-(5-(2-((l,l-dioxidothietan-3-yl)(isopropyl)carbamoyl)-4- fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[ 3.3 ]heptan-6-yl)oxy)~ 7, 8-dihydro-l, 6- naphthyridine-6(5H)-carboxylate Atorney Docket No. SYND-062 / 001WO 43707-02983

[0748] Step 2 was performed following the same procedure in two batches (50 mg and 220 mg). In a dried, 25 mL round bottom flask under a nitrogen atmosphere, 2-((4-(6-((6-(tert- butoxycarbonyl)-5,6,7,8-tetrahydro-l,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2- yl)pyrimidin-5-yl)oxy)-5-fluorobenzoic acid (220 mg, 0.381 mmol) and 3- (isopropylamino)thietane 1,1-dioxide (93 mg, 0.571 mmol) were dissolved in DCM (6 mL). To this reaction mixture, DIPEA (0.333 mL, 1.904 mmol) and POCh (0.053 mL, 0.571 mmol) were added at 0 °C and the reaction was stirred at RT for 3 h. The reaction progress was monitored by TLC (10% MeOH in DCM). After completion, the reaction was quenched with water (10 mL) and the mixture was extracted with DCM (2 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude from both batches were mixed and purified by silica gel flash column chromatography using MeOH in DCM (product was eluted at 4% MeOH in DCM) to obtain tert-butyl 4-((2-(5-(2-((l,l-dioxidothietan-3- yl)(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-yl)oxy)- 7,8-dihydro-l,6-naphthyridine-6(5rt)-carboxylate (250 mg, 74% combined yield) as a solid. LCMS (Method G): Rt = 1.98 min, m / z = 723.4 [M+H]+, 97.92%.

[0749] Step 3. N-(l,l-Dioxidothietan-3-yl)-5-fluoro-N-isopropyl-2-((4-(6-((5,6, 7,8-tetrahydro-l,6- naphthyridin-4-yl)oxy)-2-azaspiro[ 3.3 ]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[0750] In a 25 mL round botom flask under a nitrogen atmosphere, tert-butyl 4-((2-(5-(2-((l,l- dioxidothietan-3-yl)(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2- azaspiro[3.3]heptan-6-yl)oxy)-7,8-dihydro-l,6-naphthyridine-6(5rt)-carboxylate (80 mg, 0.111 mmol) was dissolved in TFE (3 mL). To this solution, TMSC1 (0.057 mL, 0.443 mmol) was added at 0 °C and the reaction was stirred at RT for 1 h. The reaction progress was monitored by TLC (10% MeOH in DCM). After completion, the reaction was concentrated Atorney Docket No. SYND-062 / 001WO 43707-02983 under reduced pressure. The crude was triturated with EtOAc (2 x 10 mL), and the supernatant was decanted. The residue was dried under reduced pressure to obtain crude N- (l,l-dioxidothietan-3-yl)-5-fluoro-A-isopropyl-2-((4-(6-((5,6,7,8-tetrahydro-l,6- naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride. Th...

Claims

Attorney Docket No. SYND-062 / 001WO 43707-02983CLAIMSWhat is claimed is:

1. A compound of Formula I,a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:W is N or CH;Y is N or CH;R1is 3- to 12-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 12-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a;R2is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R2s; each R2Sis independently halo, OH, oxo, CN, or N(R4a’)(R4b’);Z is O, CH2, or NH;Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more RAS; each RAsis independently Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy;X3is H or Ci-Ce alkyl, wherein the Ci-Ce alkyl, is optionally substituted with one or more X3s; each X3sis independently halo, OR4a, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b);Attorney Docket No. SYND-062 / 001WO 43707-02983R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3aor R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected; each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; each R4aand R4bis independently H, CN, or Ci-Ce alkyl; each R4a’ and R4b’ is independently H, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and n is 1, 2, or 3.

2. The compound of claim 1, wherein R2is H, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more R2s; each R2sis independently halo, OH, oxo, CN, or N(R4a’)(R4b’).

3. The compound of claim 1 or 2, wherein R2is Ci-Ce alkyl optionally substituted with one or more R2s; each R2sis independently halo, OH, oxo, CN, or N(R4a’)(R4b’).

4. The compound of any one of claims 1-3, wherein W is CH.

5. The compound of any one of the preceding claims, wherein Y is N.

6. The compound of any one of the preceding claims, wherein Z is O.

7. The compound of any one of the preceding claims, wherein R2is isopropyl.

8. A compound of Formula II,Attorney Docket No. SYND-062 / 001WO 43707-02983a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:R1is 3- to 12-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 3- to 12-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a;R2is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R2s; each R2Sis independently halo, OH, oxo, CN, or N(R4a’)(R4b’);Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more RAS; each RAsis independently Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy;X3is H or Ci-Ce alkyl, wherein the Ci-Ce alkyl, is optionally substituted with one or more X3s; each X3sis independently halo, OR4a, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b);R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3aor R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected;Attorney Docket No. SYND-062 / 001WO 43707-02983 each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; each R4aand R4bis independently H, CN, or Ci-Ce alkyl; each R4a’ and R4b’ is independently H, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and n is 1, 2, or 3.

9. The compound of any one of the preceding claims, wherein R1is 4-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 4-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

10. The compound of any one of claims 1-8, wherein R1is 5-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 5-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

11. The compound of any one of claims 1-8, wherein R1is 6-membered heterocyclyl comprising a sulfur atom, wherein the sulfur atom of the 6-membered heterocyclyl is optionally substituted with one or two Rls; each Rlsis independently oxo or =NR4a.

12. The compound of any one of claims 1-9, wherein13. The compound of any one of claims 1-8 and 10, whereinAttorney Docket No. SYND-062 / 001WO 43707-0298314. The compound of any one of claims 1-8 and 11, wherein15. The compound of any one of the preceding claims, wherein Ring A is 6- to 10- membered aryl optionally substituted with one or more RAs; each RAsis independently Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy.

16. The compound of any one of the preceding claims, wherein Ring A is 6- to 10- membered aryl.

17. The compound of any one of claims 1-14, wherein Ring A is 6- to 10-membered heteroaryl optionally substituted with one or more RAs; each RAsis independently Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy.

18. The compound of any one of claims 1-14 and 17, wherein Ring A is 6- to 10-membered heteroaryl.

19. The compound of any one of claims 1-14, 17, and 18, wherein Ring A isAttorney Docket No. SYND-062 / 001WO 43707-0298321. The compound of any one of the preceding claims, wherein X3is H or Ci-Ce alkyl, wherein the Ci-Ce alkyl is optionally substituted with one or more X3s; each X3sis independently halo, OR4a, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b).

22. The compound of any one of the preceding claims, wherein X3is H.

23. The compound of any one of claims 1-21, wherein X3is Ci-Ce alkyl.

24. The compound of any one of claims 1-21 and 23, wherein X3is methyl.

25. The compound of any one of the preceding claims, wherein R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3a, wherein: each R3ais independently halo, OR4a, oxo, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12- membered heterocyclyl, or 5- to 10-membered heteroaryl; and each R4ais independently H, CN, or Ci-Ce alkyl.Attorney Docket No. SYND-062 / 001WO 43707-0298326. The compound of any one of the preceding claims, wherein R3is Ci-Ce alkyl that is optionally substituted with one or more R3a, and wherein each R3ais independently 3- to 12- membered heterocyclyl.

27. The compound of any one of the preceding claims, wherein R3is methyl, ethyl, or isopropyl.

28. The compound of any one of claims 1-26, wherein R3is29. The compound of any one of claims 1-25, wherein R3is H.

30. The compound of any one of claims 1-29, wherein n is 2.

31. A compound as shown in Table 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

32. A compound as shown in Table 1 or a pharmaceutically acceptable salt thereof.

33. A compound as shown in Table 1.

34. A compound as shown in Table 1 or a pharmaceutically acceptable salt thereof, wherein the salt is hydrochloric acid.

35. The compound according to any one of the preceding claims, wherein the compound is useful for the treatment of cancer and wherein the compound minimizes hERG binding.

36. A pharmaceutical composition comprising a compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.Attorney Docket No. SYND-062 / 001WO 43707-0298337. A pharmaceutical composition comprising a salt or crystalline form of any one of claims 1-35, and at least one pharmaceutically acceptable carrier.

38. A method of inhibiting the interaction between menin and MLL comprising contacting the menin and MLL with a compound of any one of claims 1-35 or the pharmaceutical composition of claim 36 or 37.

39. A method of treating cancer in a patient comprising administering to the patient a compound of any one of claims 1-35 or the pharmaceutical composition of either claim 36 or 37.

40. The method of claim 39, wherein the cancer is a hematological cancer.

41. The method of claim 39, wherein the cancer is a leukemia or lymphoma.

42. The method of claim 39, wherein the cancer is mixed lineage leukemia (MLL), MLL- related leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage (KMT2A-rearranged) leukemia (MLL-r), leukemia associated with a MLL rearrangement or a rearrangement of the MLL gene, acute leukemia, chronic leukemia, indolent leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, myelogenous leukemia, childhood leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute granulocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), therapy related leukemia, myelodysplastic syndrome (MDS), myeloproliferative disease (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, granuloma 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 (malignant lymphoma), or Waldenstrom's macroglobulinemia.Attorney Docket No. SYND-062 / 001WO 43707-0298343. The method of claim 39, wherein the cancer is an abstract nucleophosmin (NPM1)- mutated acute myeloid leukemia (i.e., NPMlmutacute myloid leukemia) or a rearranged mixed lineage (KMT2A-rearranged) leukemia (MLL-r).

44. The compound of any one of claims 1-35 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 36 or 37, for use in treating or preventing a disease caused by, or associated with, menin expression, activity, and / or function.

45. The compound of any one of claims 1-35 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 36 or 37, for use in treating or preventing cancer.

46. Use of the compound of any one of claims 1-35 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 36 or 37, for treating or preventing a disease caused by, or associated with, menin expression, activity, and / or function.

47. Use of the compound of any one of claims 1-35 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 36 or 37, in the manufacture of a medicament for treating or preventing a disease caused by, or associated with, menin expression, activity, and / or function.

48. Use of a compound of any one of claims 1-35 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 36 or 37, for treating or preventing cancer.

49. Use of the compound of any one of claims 1-35 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 36 or 37, in the manufacture of a medicament for treating or preventing cancer.

50. A kit comprising the compound of any of claims 1-35 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 36 or 37 and instructions for its use.

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