KIF11 degrader compounds and uses thereof

Abstract

Tire present disclosure relates to novel compounds with KIF11 degradation activities, pharmaceutical compositions containing such compounds, and their use in prevention and treatment of diseases and conditions.

Description

Attorney Docket No.: 41827-65012 (045WO)KIF11 DEGRADER COMPOUNDS AND USES THEREOF 1. BACKGROUND

[0001] Kinesin-like protein KIF11 (KIF1 l / Kinesin-5 / Eg5 / BinC / KSP) plays a vital role in regulating the cell cycle and is implicated in the tumorigenesis and progression of various cancers. KIF1 lis a homotetramer that cross-links anti-parallel microtubules in the mitotic spindle to maintain spindle bipolarity. Tire motor domain or motor head is at the N-terminus and performs ATP hydrolysis and binds to microtubules. Kinesin-5 motors assemble into a bipolar homotetrameric structure that is capable of sliding apart bundles of anti-parallel oriented microtubules. KIF11 forms and maintains the bipolar spindle during mitosis. Overactivity' of KIF11 has been linked with several types of cancer due to abnormal cell division and uncontrolled proliferation, making it a potential therapeutic target for diseases, such as cancer.

[0002] Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulates key regulatory proteins and degrades misfolded or abnormal proteins, UPP is central to multiple cellular processes, and if defective or imbalanced, leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0003] There are hundreds of known E3 ligases that facilitate the ubiquitination of different proteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s, and multi-subunit E3s (see generally Li et al. (PLOS One, 2008, 3, 1487), Bemdsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307), Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-437), and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347)). Additionally, one of several hundred E3 ubiquitin -ligase enzyme complex components, such as cereblon (CRBN) and von Hippel landau (VHL) (Bricelj et al, Front Chem, 2021, 9:707317), facilitate the transfer of ubiquitin to a lysine on the substrate protein. The CRBN and VHL proteins function as critical components in Cullin RING E3 ubiquitin-ligase complexes (Cai and Wang, Cell Div, 2016, 11). Both CRBN and VHL are widely expressed across tissue types and are evolutionarily conserved among vertebrates. CRBN coordinates the ubiquitination and degradation of ion channels, the MEIS2 developmental transcription factor, the AMPK metabolic-regulating kinase, and glutamine synthase. CRBN can also be induced to degrade transcription factors 1KZF1 and IKZF3 along with casein kinase 1A1 by immunomodulatory compounds (Kronke et al. Science, 2014, 343:301-5; Petzold et al., Nature, 2016, 532: 127-30). VHL normally ubiquitinates hypoxia-inducible factor la (HIF1 A), the primary transcription factor responsible for promoting angiogenesis (Kaelin, Nat Rev Cancer, 2008, 8:865-73).

[0004] Targeted protein degradation (TPD) is a therapeutic modality to modulate proteins that have proved challenging to target with conventional small molecules. Some of these proteins have been intractable because, for example, their active sites are broad, have shallow pockets that are difficult to bridge with small molecules, have ‘smooth’ surfaces that offer few sites for a small molecule to bind,41827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)or may not even possess an active site to which small molecules could bind. Many of these difficult to target proteins play key roles in diseases, such as cancer. Protein-degrading molecules (hereinafter degraders) have the potential to enable the modulation of these difficult to target proteins via TPD. Degraders are heterobifunctional small molecules comprising two ligands (e.g., chemical moieties) joined by a linker. The roles of the two ligands are different. One ligand recruits and binds a protein of interest (i.e., target protein) while the other recruits and binds an E3 ubiquitin ligase. Uris simultaneous binding of the protein of interest and a ligase by the degrader induces ubiquitination of the protein of interest and its subsequent degradation by the ubiquitin-proteasome system (UPS), after which the degrader is available to target another copy of the protein of interest. This catalytic -type mechanism of action and event-driven pharmacology differentiate degraders from classical inhibitors, which have a one-to-one relationship with the protein of interest and whose pharmacology is driven by stoichiometry and, usually, by interactions with an active site (see Bekes, et al, Nature Reviews Diug Discovery 2022, 21, 181-200).

[0005] There remains an unmet medical need for compounds that can degrade certain proteins, such as KIF11, Compounds that can degrade KIF11 may be expected to offer a selective approach to halt the proliferation of cancer cells, minimizing collateral damage to healthy cells.2. SUMMARY

[0006] The present disclosure is directed to novel KIF11 degraders (also known herein as Protein- Protein Interaction Targeted Chimeras (PPI-TACs)), such as KIF11 degraders. PPI-TACs possess many advantages over conventional biochemical enzyme inhibitors and other types of degraders. Unlike other degraders that rely only on proximity’ by projecting one small molecule simultaneously to a targeted protein and E3 ligase, the PPI-TACs disclosed herein not only possess the ability to facilitate target protein and E3 ligase ternary complex formation but are also belie ved to direct protein-protein interactions between the targeted protein and E3 ligase, thus leading to enhanced degradation potency and selectivity. In some embodiments, the PPI-TACs work sub-stoichiometrically by inducing multiple rounds of degradation of target proteins. This is attributed to the PPI-TAC molecule being released from the proteosome-degraded protein to bind another target protein and E3 ubiquitin ligase, which in turn results in a greater potency compared to each isolated moiety binding to its respective target. In some embodiments, PPI-TACs disclosed herein can deplete target proteins that are not responsive to biochemical inhibition by binding accessible pockets that do not affect the biochemical activity of the target but still permit their degradation. It is believed that the PPI-TACs disclosed herein may achieve prolonged pharmacological effects compared to inhibitors.

[0007] In an aspect, provided herein is a compound, wherein tire compound is represented by Formula (I) or is a pharmaceutically acceptable salt thereof:241827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)(Z)w(I),wherein:X is CH orN;G is selected from CH2, O, NH, and N(C1-C6 alkyl);each Y is independently selected from halogen, Ci-Cs alkyl, Ci-Cg haloalkyl, hydroxyl, -OCi- C3alkyl, -CN, and -NH2;each Z is independently selected from halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, hydroxyl, -OCi- C3alkyl, -CN, and -NH2;R1is selected from hydrogen, Ci-Co alkyl, Ci-Cg haloalkyl, and -(CH2)Ce-Ci4 ryl;R is selected from hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -(CH2)i-eNH2, -(CH2)i-eN(Rel)(Re2), -C(O)Ci-C6alkyl, -C(O)OH, and -C(O)OCt-C6 alkyl;Re!is hydrogen or Ci-Ce alkyl;Re2is hydrogen or Ci-Ce alkyl;L is a bond or a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(R3')-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, C3-C6cycloalkylene, C5-Ci2bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene, wherein each of the C3-Cg cycloalkylene, C3-Ci2bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 R;;each Ra!is independently selected from Ci-Ce alkyl, oxo, -(CH-)C •( nix L -(CH2)C3- Cscvcloalky 1,-C(O)OCi-C6alkyl, -C(O)OCi-C6haloalkyl, and -C(O)O-(CH2)C6-CI4aryl;each Razis independently selected from hydrogen, halogen, Ci-Ce alkyl, oxo, and C3-Ce cycloalkyl;M is a bond or a divalent group with a backbone of 1-6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, - NH-, -N(RbI)-, -C(O)-, -C(O)-NH-, -C(O)N(Rbi)-, -NH-C(O)-, -N(Rbl)-C(O)-, C3-C6cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene, wherein each of the C3-Ce cycloalkylene, Cs-Ci2bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene are substituted with 0, 1,341827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO), 3, or 4 Rb2;each Rblis independently selected from Ci-Cg alkyl, -(CH2)Cg-Ci:aryl, -(CH )( - Cscycloalkyl, -C(O)OCi-Cg alkyl, -C(O)OCi-Cg haJoalkyl, and -C(O)O-(CH2)Cg-Ci4 aryl;each Rb2is independently selected from hydrogen, halogen, Ci-Cg alkyl, oxo, and C3-Cg cycloalkyl;P is a bond or a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(Rc1)-, -C(O)-, -C(O)-NH-, -C(O)N(Rc1)-, -NH-C(O)-, -N(Rcl)-C(O)-, C3-Cg cycloalkylene, C-( ■ bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene, wherein each of C3-C6 cycloalkylene, ( -( bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 R:each Rc:is independently selected from Ci-Cg alkyl, -(CH2)Cg-Ci4 ryl, -(CH2)C3-Cgcycloalkyl, -C(O)OCi-Cg alkyl, -C(O)OCi-Cg haloalkyl, and -C(O)O-(CH2)C6-C’14 aryl;each Rc2is independently selected from hydrogen, halogen, Ci-C alkyl, oxo, and C3-Cg cycloalkyl;Q is a bond or a divalent group of 1 -6 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from C -Cio monocyclic arylene, Cg-Ci2bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered bicyclic heteroarylene, and wherein each of the C -Cio monocyclic arylene, Cg-Ci2bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered bicyclic heteroarylene is independently substituted with 0, 1, 2, or 3 Rd;each Rdis independently selected from hydrogen, halogen, Ci-Cg alkyl, hydroxyl, -OCi-Cg alkyl, oxo, -C(O)NH-, and -NH2; andn is 0, 1, 2, 3, or 4; andw is 0, 1, 2, 3, or 4.

[0008] In another aspect, provided is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, pharmaceutically acceptable vehicles, pharmaceutically acceptable excipients, or combinations thereof.

[0009] Also disclosed herein are methods of treatment. The disclosed methods may comprise treating a subject (e.g., a human subject) in need thereof, wherein the subject has a disease, such as a KIF 11-mediated disease or disorder. Tire methods may comprise administering to the subject an effective amount of a compound disclosed herein. In an aspect, the KIF 11 -mediated disease or disorder is cancer. In another aspect, the cancer is selected from breast cancer, lung cancer, pancreatic cancer, small bowel cancer, colorectal cancer, gall bladder cancer, thyroid cancer, liver cancer, bile duct441827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, esophageal cancer, and blood cancer.

[0010] In an aspect, provided is a method for inhibiting and / or degrading protein kinesin-like protein KIF11 in a cell, comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0011] In another aspect, provided is use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of medicament for the treatment of a disease or disorder.3. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 illustrates the KIF11 degradation activity of exemplary Compound 1 in the MCF7 cell line 6 hours after administration.

[0013] FIG. 2 illustrates the KIF11 degradation activity of exemplary Compound 1 in the NCI-H441 cell line 6 hours after administration.

[0014] FIG. 3 illustrates the KIF11 degradation activity of exemplary Compound 1 in the Panc 04.03 cell line 6 hours after administration.

[0015] FIG. 4 illustrates the KIF11 degradation activity of exemplar}' Compound 1 in the HCC1954 cell line 6 hours after administration.4. DETAILED DESCRIPTION

[0016] When describing the embodiments of the present disclosure, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated.

[0017] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc,). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and / or “an” should be interpreted to mean “at least 541827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)one” or ‘"one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art w ould understand the convention (e.g., “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive w7ord and / or phrase presenting two or more alternative terms, whether in the description, claims, or draw ings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”

[0018] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0019] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub¬ ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in tire art, a range includes each individual member. Thus, for example, a group having 1-3 articles refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having I, 2, 3, 4, or 5 articles, and so forth.4.1. Definitions

[0020] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following641827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry’ and Physics, 75th Ed. Additionally, general principles of organic chemistry’ are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0021] As used herein, the term “acyl” refers to R-C(O)- groups such as, but not limited to, (alkyl)-C(O)-, (alkenyl)-C(O)-, (alkynyl)-C(O)-, (aryl)-C(O)-, (cycloalkyl)-C(O)-, (heteroaryl)-C(O)-, and (heterocyclyl)-C(O)-, wherein the group is attached to the parent molecular structure through the carbonyl functionality. In some embodiments, it is a Cl -10 acyl radical which refers to the total number of chain or ring atoms of the, for example, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heteroaryl, portion plus the carbonyl carbon of acyl. For example, a C4-acyl has three other ring or chain atoms plus carbonyl.

[0022] As used herein, the term “aliphatic” or “aliphatic group” refers to straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocyclyl,” “cycloaliphatic,” or “cycloalky 1”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocy'clyl” or “cycloalkyl”) refers to a monocyclic C3-C7 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cy’cloalkyl)alkenyl.

[0023] As used herein, the term “alkenyl” refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-8 carbon atoms, referred to herein as (C2-Cs)-alkenyl. Exemplary’ alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2 -ethylhexenyl, 2-propyl-2 -butenyl, and 4-(2-methyl-3-butene)-pentenyl.

[0024] As used herein, the term “alkyl” refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1 to 8 carbon atoms, referred to herein as Ci.g alkyl. Exemplary' alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2 -methyl- 1 -propyl, 2-741827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)methyl-2-propyl, 2-methyl-l -butyl, 3 methyl- 1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2- methyl-1 -pentyl, 3 methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl -2 -pentyl, 3-methyl-2-pentyl, 4 methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3, 3 -dimethyl- 1 -butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. In some embodiments, “alkyl” is a straight¬ chain hydrocarbon. In some embodiments, “alkyl” is a branched hydrocarbon. When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-Ce alkyl” is intended to encompass Ci, Cj, C3, C4, Cs, Cs, Cus, C1.5, C1-4, C1.3, C1.2, C2-6, C2-5, C2-4, C2-3, C3.6, C3.5, C3.4, C4.6, C4.5, and C5-6 alkyl.

[0025] As used herein, the term “alkylene” refers to a divalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, for example, from 1 to 6, from 1 to 4, from I to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0026] As used herein, the term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0027] As used herein, the term “alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, e.g., -O(alkyl). Examples of alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, 7-butoxy, or pentoxy groups.

[0028] As used herein, the term “alkylene” refers to a divalent alkyl radical. Representative examples of C1 10 alkylene include, but are not limited to, methylene, ethylene, w-propylene, iso-propylene, n-butylene, xec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3 -methylhexylene, 2,2-dimethyIpentylene, 2,3-dimethylpentylene, n-heptylene, rf-octylene, w-nonylene, and w-decylene.

[0029] As used herein, the term “alkynyl” refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-8 carbon atoms, referred to herein as (C^-Csj-alkynyl. Exemplar}'- alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-l -butynyl, 4-propyl-2-pentynyl, and 4 butyl 2 hexynyl.

[0030] As used herein, the term “ary l” refers to an all carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi- electron system without any heteroatom ring atoms. An aryl group may be selected from: monocyclic carbocyclic aromatic rings, for example, phenyl; bicyclic ring systems such as 7-12 membered, e.g., 9-10 membered, bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, selected.841827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)for example, from naphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and tricyclic ring systems such as 10-15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene. For example, the aryl group may be a 6-membered carbocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl or heterocyclic ring optionally comprising at least one heteroatom selected from N, O, and S, provided that the point of attachment is at the carbocyclic aromatic ring when the carbocyclic aromatic ring is fused with a heterocyclic ring, and the point of attachment can be at the carbocyclic aromatic ring or at the cycloalkyl group when the carbocyclic aromatic ring is fused with a cycloalkyl group. Divalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Divalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.

[0031] As used herein, the term “bivalent Ci.s (or CAo) saturated or unsaturated, straight or branched, hydrocarbon chain,” refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0032] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, abridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless other ise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:941827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0033] As used herein, the tern “cyano” refers to CN.

[0034] Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl bicyclic (fused, bridged, or spirocyclic) or polycyclic (fused, bridged, or spirocyclic) ring systems are defined based on the nature of the ring system and / or point of attachment. For example, if the entire bicyclic or polycyclic ring system is fully non-aromatic and contains at least one ring heteroatom, then the ring system is a heterocycloalkyl bicyclic or polycyclic ring system. If the entire bicyclic or polycyclic ring system is fully aromatic and contains at least one ring heteroatom, then the ring system is considered a heteroaryl bicyclic or polycyclic ring system. If the bicyclic or polycyclic ring system contains a mix of non-aromatic and aromatic ring systems, then it is the point of attachment that dictates the nature of the ring system: if attached to the non-aromatic cycloalkyl or heterocycloalkyl ring, it is considered a cycloalkyl or heterocycloalkyl bicyclic or polycyclic ring system; if it is attached to the aromatic aryl or heteroaryl ring, it is considered an aryl or heteroaryl bicyclic or polycyclic ring system.

[0035] As used herein, the term “cycloalkyl” refers to a non-aromatic saturated or unsaturated, monocyclic, bicyclic, or polycyclic ring system containing 3 to 16 ring carbon atoms, but no heteroatom ring atoms. For example, 3-16 carbons, or 3-8 carbons, referred to herein as “(Cs-Cs)- cycloalkyl,” derived from a cycloalkane. Cycloalkyl can include any number of carbons, such as C3.6, C4-6, C5-6, C3-8, C4-8, C5-8, Cg-8, C3-9, C3-10, C3.11, and C3.12. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, bicyclo [l.l.l]pentane, norbomane, [2.2.2] bicyclooctane, decahydronaphthalene and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and norbomadiene. When cycloalkyl is a saturated monocyclic C3-8 cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl,1041827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When cycloalkyl is a saturated monocyclic C3-6 cycloalkyl, exemplary' groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups may be substituted with an alcohol (hydroxy), alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxylic acid, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, ketone, nitro, oxo (a carbonyl on the ring), phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Cycloalkyl groups can be fused to other cycloalkyl (saturated or partially unsaturated), ary l, or heterocyclyl groups, to form a bicycle, tetracycle, etc. In embodiments, the term cycloalkyl is a monocyclic ring. In embodiments, the term “bicyclic cycloalky 1” may refer to a ring system such as a 1, 1 '-bi (cyclohexyl) ring system:ring system such as a decahydronaphthalene ring system:, In embodiments, the term “bicyclic cycloalkyl” may refer to a spirocy clic ring system such as:

[0036] As used herein, when the terms “cycloalkyl, bicyclic cycloalkyl, fused bicyclic cycloalkyl, and / or spirocy clyl” (or any combination of the preceding) are used alongside in the same embodiment, the terms are mutually exclusive of each other and not considered subgenera of cycloalkyl. In other words, when used in the same embodiment, the term cycloalkyl refers to a monocyclic ring system whereas a bicyclic or fused cycloalkyl refer to polycyclic ring systems.

[0037] As used herein, the term “halo” or “halogen” refers to -F, -Cl, -Br, and / or -I.

[0038] As used herein, “haloalkyl” refers to an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0039] As used herein, the term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or a substituted nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrroIyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)). In embodiments, the heteroatom is selected from oxygen, sulfur, nitrogen, and phosphorus. In another1141827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)embodiment, the heteroatom is selected from oxygen, sulfur, and nitrogen. In embodiments, the heteroatom is independently oxygen or nitrogen.

[0040] As used herein, the term “heteroaryi” refers to a monovalent aromatic radical of 5-, 6-, or 7-membered rings, and includes fused ring systems (at least one of which is aromatic) of 5-20 atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. In embodiments, the heteroaryl is a -membered heteroaromatic ring. In embodiments, the heteroaryl is a 6-membered heteroaromatic ring. In embodiments, the heteroaryi is a 7-membered heteroaromatic ring. In embodiments, the heteroaryi is a 8-membered heteroaromatic ring. In embodiments, the heteroaryi is a 9-membered heteroaromatic ring. In embodiments, the heteroaryi is a 10-membered heteroaromatic ring. Examples of heteroaryi groups are pyridinyl (including, for example, 2- hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In some embodiments, a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (or in the case of a divalent fused heteroarylene ring system, at least one radical or point of attachment is on a heteroaromatic ring). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbozolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydrquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryi group may be mono-, bicyclic, or tricyclic. The term “heteroaryi” may be used interchangeably with the terms “heteroaryi ring,” “heteroaryi group,” “heteroaromatic,” or “heteroaromatic ring” any of which terms include rings that are optionally substituted. In some embodiments, the heteroaryi is an 8-12 membered bicyclic heteroaryi or a 10-14 membered tricyclic heteroaryi. In embodiments, the term “bicyclic heteroaryi” may refer to a ring system such as a 2-phenylpyridinyl ring system:. In embodiments, the term “bicyclic heteroaryi” may refer to a fused ring system such as an idolyl ring system:1241827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)If the bicyclic or polycyclic ring system contains a mix of non -aromatic and aromatic ring systems, then it is the point of attachment that dictates the nature of the ring system: if attached to the non -aromatic cycloalkyl or heterocycloalkyl ring, it is considered a cycloalkyl or heterocycloalkyl bicyclic or polycyclic ring system; if it is atached to the aromatic aryl or heteroaryl ring, it is considered an aryl or heteroaryl bicyclic or polycyclic ring system.

[0041] As used herein, when the terms “heteroaryl, bicyclic heteroaryl, and / or fused heteroaryl” (or any combination of the preceding) are used alongside in the same embodiment, the terms are mutually exclusive of each other and not considered subgenera of heteroaryl. In other words, when used in the same embodiment, the term heteroaryl refers to a monocyclic ring system whereas a bicyclic or fused heteroaryl refer to polycyclic ring systems.

[0042] As used herein, a “heterocyclyl,” “heterocyclic,” or “heterocycloalkyl” group refers to a ring structure having from 3 to 14 atoms, for example 4 to 13 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S wherein the ring N atom may be oxidized to N-O, and the ring S atom may be oxidized to SO or SO2, the remainder of tire ring atoms being carbon. In embodiments, the heterocycloal kyl is a 3- to 9-membered heterocycloalkyl ring. In embodiments, the heterocycloalkyl is a 4- to 9-membered heterocycloalkyl ring. In embodiments, the heterocycloalkyl is a 5- to 9-membered heterocycloalkyl ring. In embodiments, the heterocycloalkyl is a 6- to 9-membered heterocycloalkyl ring. In embodiments, tire heterocycloalkyl group is a 3 -membered ring. In embodiments, the heterocycloalkyl group is a 4-membered ring. In embodiments, the heterocycloalkyl group is a 5-membered ring. In embodiments, the heterocycloalkyl group is a 6-membered ring. In embodiments, the heterocycloalkyl group is a 7-membered ring. In embodiments, the heterocycloalkyl group is an 8-membered ring. In embodiments, the heterocycloalkyl group is a 9- membered ring. In embodiments, the heterocycloalkyl group is a 10-membered ring. In embodiments, the heterocycloalkyl group is a 11-membered ring. In embodiments, the heterocycloalkyl group is a 12-membered ring. In embodiments, the heterocycloalkyl group is a 13 -membered ring. In embodiments, the heterocycloalkyl group is a 14-membered ring. The heterocyclyl may be a monocyclic, a bicyclic, a tricyclic, a spirocyclic, or a bridged ring system. The heterocyclic group is independently optionally substituted on a ring nitrogen atom with alkyl, aralkyl, alkylcarbonyl, or on sulfur with lower alkyl. Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro- 1H, 3H, 5H-oxazolo[3, 4-1341827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)c]oxazolyl, tetrahydro- 1 spiro [cyclopropane- 1,2'-pyrrolizine], hexahydro- 1 / 7-pyrrolizinyl, hexahydro- lEf-pyrrolo[2, 1 - c] [ 1,4]oxaz iny 1, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(1 )-oxide, tetrahydro- 2H-thiopyranyl 1 -oxide and tetrahydro-2#-thiopyranyl 1,1 -dioxide. Specifically excluded from the scope of this term are compounds having adjacent annular O anchor S atoms. In embodiments, the term “’bicyclic heterocycloalkyl” may refer to a ring system such as a 1 -(piperidin-4-yl)piperazinyl ring system:<\ > >. -r / \ \ > f / embodiments, the term “bicyclic heterocycloalkyl” may refer to a fused ring system such as a 3,4-dihydro-2#-l -benzopyran:. In embodiments, the term “bicyclic heterocycloalkyl” may refer to a heterospirocyclic ring system such as:H_^. N H> >. If the bicyclic or polycyclic ring system contains a mix of non -aromatic and aromatic ring systems, then it is the point of attachment that dictates the nature of the ring system: if attached to the non-aromatic cycloalkyl or heterocycloalkyl ring, it is considered a cycloalkyl or heterocycloalkyl bicyclic or polycyclic ring system; if it is attached to the aromatic aryl or heteroaryl ring, it is considered an aryl or heteroaryl bicyclic or polycyclic ring system.

[0043] As used herein, when the terms “heterocycloalkyl, bicyclic heterocycloalkyl, fused heterocycloalkyl, and / or hetero-spirocyclyl” (or any combination of the preceding) are used alongside in the same embodiment, the terms are mutually exclusive of each other and not considered subgenera of heterocycloalkyl. In other ords, -when used in the same embodiment, the term heterocycloalkyl refers to a monocyclic ring system whereas a bicyclic or fused heterocycloalkyl refer to polycyclic ring systems.

[0044] As used herein, the tern “lower alkyl” refers to aCu straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0045] As used herein, the term “lower haloalkyl” refers to a Cj.4 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0046] As used herein, the term “hydroxy” and “hydroxyl” are used interchangeably and refer to -OH

[0047] As used herein, the term “KIF11” includes any of the recombinant or naturally occurring forms of Kinesin-like protein KIF 11 or variants or homologs thereof that maintain KIF 11 activity1441827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)(e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to KIF11). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% ammo acid sequence identity across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring KIF11 protein. In embodiments, tlie KIF 11 protein is substantially identical to the protein identified by the UniProt reference number P52732 or a variant or homolog having substantial identity thereto.

[0048] As used herein, the term “oxo” refers to an oxygen that is double bonded to a carbon atom thereby forming a carbonyl. In embodiments, oxo is represented as follows:\=0%. In embodiments, a compound that is substituted by an “oxo” is depicted as follows:Oxzz'Z''s\ substituted with JLoxo S'.

[0049] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties, as herein defined,

[0050] A “spirocycle,” “spirocyclyl,” or “spirocyclylene” refers to a chemical entity having two heterocyclyl or two cycloalkyl moieties as defined herein, or to a combination of one or more heterocyclyl and one or more cycloalkyl moiety, having one ring atom in common, i.e., the two rings are connected via one common ring atom. Some exemplary’ spirocyclic ring systems, yet non-limiting

[0051] As used herein and unless otherwise specified, the suffix “-ene” is used to describe a divalent group. Thus, any of the terms above can be modified with the suffix “-ene” to describe a divalent version of that moiety. For example, a divalent carbocycle is “carbocyclylene,” a divalent aryl ring is1541827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)“arylene,” a divalent benzene ring is “phenylene,” a divalent heterocycle is “heterocyclylene,” a divalent heteroaryl ring is “heteroarylene,” a divalent alkyl chain is “alkylene,” a divalent alkenyl chain is “alkylene,” a divalent alkynyl chain is “alkynylene,” and so forth.

[0052] As used herein, “stereoisomer” or “optical isomer” refers to a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structure exist in the compounds of the disclosure which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof. The compounds of the disclosure and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As discussed in more detail below, individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry^ are either commercially available or are made by the methods described below and resolved by techniques well-known in the art.

[0053] It is well-known in tire art that the biological and pharmacological activi ty of a compound is sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like. Thus, one skilled in the art will appreciate that one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer. Additionally, one skilled in the art would know how to separate, enrich, or selectively prepare the enantiomers of the compounds of this disclosure and the knowledge of the prior art.

[0054] Thus, although the racemic form of drug may be used, it is often less effective than administering an equal amount of enantiomerically pure drag; indeed, in some cases, one enantiomer may be pharmacologically inactive and would merely serve as a simple diluent. For example, although ibuprofen had been previously administered as a racemate, it has been shown that only the S-isomer of ibuprofen is effective as an anti-inflammatory agent (in the case of ibuprofen, however, although the R-isomer is inactive, it is converted in vivo to the S-isomer, thus, the rapidity of action of the racemic form of the drug is less than that of the pure S-isomer). Furthermore, the pharmacological1641827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)activities of enantiomers may have distinct biological activity. For example, S -penicillamine is a therapeutic agent for chronic arthritis, while R-penicillamine is toxic. Indeed, some purified enantiomers have advantages over the racemates, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to the racemic mixture.

[0055] In some embodiments, the compound is a racemic mixture of (S)- and (R)-isomers. In other embodiments, provided herein is a mixture of compounds wherein individual compounds of tire mixture exist predominately in an (S)- or (R)-isomeric configuration. For example, the compound mixture has an (S)-enantiomeric excess of greater than 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or more. In other embodiments, the compound mixture has an (S)-enantiomeric excess of greater than 55% to 99.5%, greater than 60% to 99.5%, greater than 65% to 99.5%, greater than 70% to 99,5%, greater than 75% to 99.5%, greater than 80% to 99.5%, greater than 85% to 99.5%, greater than 90% to 99.5%, greater than 95% to 99.5%, greater than 96% to 99.5%, greater than 97% to 99.5%, greater than 98% to greater than 99.5%, greater than 99% to 99.5%, or more. In other embodiments, the compound mixture has an (R) -enantiomeric purity of greater than 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5% or more. In some other embodiments, the compound mixture has an (R)-enantiomeric excess of greater than 55% to 99.5%, greater than 60% to 99.5%, greater than 65% to 99.5%, greater than 70% to 99.5%, greater than 75% to 99.5 %, greater than 80% to 99.5%, greater than 85% to 99.5%, greater than 90% to 99.5%, greater than 95% to 99.5%, greater than 96% to 99.5%, greater than 97% to 99,5%, greater than 98% to greater than 99.5%, greater than 99% to 99.5% or more.

[0056] Individual stereoisomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic / chiral centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary' skill in the art. These methods of resolution are exemplified by: (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary'; (2) salt formation employing an optically active resolving agent; or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0057] Tirus, if one enantiomer is pharmacologically more active, less toxic, or has a preferred disposition in the body than the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially.1741827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0058] As described herein, compounds of the disclosure may, when specified, contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogen s of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from theI!! J R1may, unless otherwise indicated, replace a hydrogen on any individual ring (e.g.,R1R1R1R1refers to at least). Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every' position. Combinations of substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their purification, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0059] Some of the compounds may exist with different points of attachment of hydrogen, referred to as “tautomers.” For example, compounds including carbonyl -CH2C(O)- groups (keto forms) may undergo tautomerism to form hydroxyl -CH:C(OH)- groups (enol forms). Both keto and enol forms, individually as well as mixtures thereof, are also intended to be included where applicable. By way of example, the process of tautomerization is as follows:

[0060] The compounds, tautomers, solvates, or pharmaceutically acceptable salts of the disclosure may contain an asymmetric center and may thus exist as enantiomers. For example, where the compounds possess two or more asymmetric centers, they may additionally exist as diastereoisomers.1841827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)Enantiomers and diastereoisomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereoisomers are intended to be included in this disclosure. All stereoisomers of the compounds, tautomers, solvates, and pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.

[0061] Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.

[0062] Those skilled in the art will appreciate that a bond designated as “ in a small molecule structure, as used herein, refers to a bond that, in some embodiments, is a single (e.g., saturated) bond, and in some embodiments, is a double (e.g., unsaturated) bond. For example, the following structure:is intended to encompass bothand

[0063] As used herein, “subject” refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In some embodiments, the subject is a human.

[0064] As used herein, the term “treat,” “treating” and “treatment” refers to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to tire patient; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of the symptom. Tire treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, e.g., the result of a physical examination.

[0065] As used herein, “therapeutically effective amount,” “therapeutically effective amount or dose,” “therapeutically sufficient amount or dose,” “effective amount or dose,” or “sufficient amount or dose” are used interchangeably to refer to a dose that produces therapeutic effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques.

[0066] As used herein, the term “unsaturated” refers to a moiety has one or more units of unsaturation.1941827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)4.2. Compounds

[0067] Provided herein is a compound, wherein the compound is represented by Formula (I) or is a pharmaceutically acceptable salt thereof:wherein:X is CH or N;G is selected from CH2, O, NH, and N(G-G alkyl);each Y is independently selected from halogen, G-G alkyl, G-G haloalkyl, hydroxyl, -OCj-C alkyl, -CN, and -NH2;each Z is independently selected from halogen, -G alkyl, -G haloalkyl, hydroxyl, -OG-G alkyl, -CN, and -NH2;R’ is selected from hydrogen, -G alkyl, G-G alkyl, and -(CH2)Cg-Cj4aryl;R2is selected from hydrogen, Ci-Cg alkyl, G-G haloalkyl, -(CH2)i-gNH2, -(CH2)I-6N(Rel)(Re2), -C(O)G-G alkyl, -C(O)OH, and -C(O)OG-G alkyl;Re‘ is hydrogen or G-G alkyl;R is hydrogen or Ci -Cg alkyl;L is a bond or a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, C3-Cg cycloalkylene, G-C12bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene, wherein each of the Cs-G cycloalkylene, C5-G2 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 R:each Ralis independently selected from Ci-Cg alkyl, oxo, -(( 11 )G-G:;uy L -(CII2)C3- Cgcycloalkyl,-C(O)OCi-Cg alkyl, -C(O)OCi-Cg haloalkyl, and -C(O)O-(CH2)Cg-Ci4 aryl;each Ra2is independently selected from hydrogen, halogen, G-G alkyl, oxo, and G-G cycloalkyl;M is a bond or a divalent group with a backbone of 1-6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, - NH-, -N(Rbi)-, -C(O)-, -C(O)-NH-, -C(O)N(Rbi)-, -NH-C(O)-, -N(Rbl)-C(O)-, G-G cycloalkylene,2041827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene, wherein each of the C3-Cg cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 Rb2;each Rb1is independently selected from C1-C6alkyl, -(CH2)C6-C14aryl, -(CH2)C3-C8cycloalkyl, -C(O)OC1-C6alkyl, -C(O)OC1-C6haloalkyl, and -C(O)O-(CH2)C6-C14aryl;each Rb2is independently selected from hydrogen, halogen, C1-C6alkyl, oxo, and C3-C6cycloalkyl;P is a bond or a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(Rc1)-, -C(O)-, -C(O)-NH-, -C(O)N(Rc1)-, -NH-C(O)-, -N(Rcl)-C(O)-, C3-C6cycloalkylene, C5-C12bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene, wherein each of C3-C6cycloalkylene, C5-C12bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 Rc2;each Rc1is independently selected from C1-C6alkyl, -(CH2)C6-C14aryl, -(CH2)C3-C8cycloalkyl, -C(O)OC1-C6alkyl, -C(O)OC1-C6haloalkyl, and -C(O)O-(CH2)C6-C14aryl;each Rc2is independently selected from hydrogen, halogen, C1-C6alkyl, oxo, and C3-C6cycloalkyl;Q is a bond or a divalent group of 1-6 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from C6-C10monocyclic arylene, C8-C12bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered bicyclic heteroarylene, and wherein each of the C6-C10monocyclic arylene, C8-C12bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered bicyclic heteroarylene is independently substituted with 0, 1, 2, or 3 Rd;each Rdis independently selected from hydrogen, halogen, C1-C6alkyl, hydroxyl, -OC1-C6alkyl, oxo, -C(O)NH-, and -NH2; andn is 0, 1, 2, 3, or 4; andw is 0, 1, 2, 3, or 4.

[0068] In embodiments, at least one or more of the variables L, M, P, and Q of Formula (I) is not a bond.

[0069] In embodiments, at least two or more of the variables L, M, P, and Q of Formula (I) is not a bond.

[0070] In embodiments, the compound of Formula (I) is represented by Formula (F):2141827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0071] In embodiments, the compound of Formula (I) is represented by Formula (la):wherein:X is CH or N;R1is H or C1-C6alkyl;each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is bond or a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, - NH-, -NCR3’1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, C3-C6cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-mcmbcrcd heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene;M is a bond or a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, - NH-, -N(Rb1)-, -C(O)-, -C(O)-NH-, -C(O)N(Rb1)-, -NH-C(O)-, -N(Rb1)-C(O)-, C3-C6cycloalkylene, C5-C12bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, 7- to 14-membered bicyclic heterocyclylene;Q is a bond or a divalent group of 1 -6 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from C6-C10monocyclic arylene, C8-C12bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered heteroarylene, and wherein each of C6-C10monocyclic arylene, C8-C12bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered bicyclic heteroarylene is independently substituted with 0, 1, 2, or 3 Rd; andRdis independently selected from hydrogen, halogen, C1-C3 alkyl, hydroxyl, -OC1-C4 alkyl, oxo, and -2241827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0072] In embodiments, the compound of Formula (I) is represented by Formula (la-1):wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, - N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, C3-C6cycloalkylene, 3- to 9-membered heterocyclylene and 7- to 14-membered bicyclic heterocyclylene; and M is a divalent group with a backbone of 1-6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, C3-C6cycloalkylene, 3- to 9-membered heterocyclylene and 7- to 14-membered bicyclic heterocyclylene.

[0073] In embodiments, each Y is independently selected from F, Cl, Br, and I. In embodiments, each Y is F. In embodiments, each Y is Cl. In embodiments, each Y is Br. In embodiments, each Y is I.

[0074] In embodiments, L is selected from2341827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0075] In embodiments, L is. In embodiments, L is. In embodiments, L is. In embodiments, L is O. In embodiments, L isQ. In embodiments, L is O. In embodiments, L isO H O N. In embodiments, L is H. In embodiments, L is o O HNIn embodiments, L is H. In embodiments, L is O. Inembodiments, L is*. In embodiments, L is. In embodiments, L is. In embodiments, L is. In embodiments, L is. Inembodiments, L is. In embodiments, L is. In embodiments, L is. In embodiments, L is. In embodiments, L is. Inembodiments, L is. In embodiments, L is. in embodiments, L isO. In embodiments, L is. In embodiments, L is

[0076] In embodiments, M is selected fromH OA n NO 0 H2441827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0077] In embodiments, M is. In embodiments, M isIn embodiments, M is O. In embodiments, M is. In embodiments, M isH. In embodiments, M isO. In embodiments, M isembodiments, M isIn embodiments, M. In embodiments. M is

[0078] In embodiments, the compound of Formula (I) is represented by Formula (la-2):wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, C3-C6cycloalkylene, C3-C6cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic2541827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)heterocyclylene;M is a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, C3-C6cycloalkylene, 3- to 9-membered heterocyclylene and 7- to 14-membered bicyclic heterocyclylene; andRdis selected from hydrogen, -CH3, -CH2CH3, and -CH2CH2CH3

[0079] In embodiments, each Y is independently selected from F, Cl, Br, and I. In embodiments, each Y is F. In embodiments, each Y is Cl. In embodiments, each Y is Br. In embodiments, each Y is I.

[0080] In embodiments, L is selected fromOy N, In embodiments, L is In embodiments, L is BIn embodiments, L is, In embodiments, L is. In embodiments, L is

[0081] In embodiments, M is selected from

[0082] In embodiments, the compound of Formula (I) is represented by Formula (la-3):2641827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene;M is a divalent group with a backbone of 1-4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene; andRdis hydrogen or Ci-Cg alkyl.

[0083] In embodiments, each Y is independently selected from F, Cl, Br, and 1. In embodiments, each Y is F. In embodiments, each Y is Cl. In embodiments, each Y is Br. In embodiments, each Y is I

[0084] In embodiments,L is -1-0 ' — '4

[0085] In embodiments,M is ’

[0086] In embodiments, the compound of Formula (I) is represented by Formula (la-4):wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1-4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, 3- to 9-membered heterocyclylene, and 7-2741827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)to 14-membered bicyclic heterocyclylene; andM is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, - C(O)-NIL, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra’)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene.

[0087] In embodiments, each Y is independently selected from F, Cl, Br, and I. In embodiments, each Y is F. In embodiments, each Y is Cl. In embodiments, each Y is Br. In embodiments, each Y is I.

[0088] In embodiments,L is

[0089] In embodiments,M is

[0090] In embodiments, the compound of Formula (I) is represented by Formula (la-5):wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NIL, -N(Ral)-, -C(O)-, - C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra’)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene; andM is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NIL, -N(Ra1)-, -C(O)-, - C(O)-NIL, -C(O)N(Ra’)-, -NILC(O)-, -N(Ral)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene.

[0091] In embodiments, each Y is independently selected from F, Cl, Br, and I. In embodiments, each Y is F. In embodiments, each Y is Cl. In embodiments, each Y is Br. In embodiments, each Y is I.

[0092] In embodiments, L is [image]2841827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0093] In embodiments,M is

[0094] In embodiments, the compound of Formula (I) is represented by Formula (la-6):wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1-4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene;M is a divalent group with a backbone of 1-4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene;each X’ is independently selected from hydrogen, halogen, Ci-Cs alkyl, and -OCj-Cs alkyl; and p is 0, 1, or 2.

[0095] In embodiments, each Y is independently selected from F, Cl, Br, and I. In embodiments, each Y is F. In embodiments, each Y is Cl. In embodiments, each Y is Br. In embodiments, each Y is I

[0096] In embodiments, Lis

[0097] In embodiments,M is

[0098] In embodiments, the compound of Formula (I) is represented by Formula (la-7):2941827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NIL, -N(Ral)-, -C(O)-, - C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra’)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene;M is a divalent group with a backbone of 1-4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene;each X1is independently selected from hydrogen, halogen, C1-C6alkyl, and -OC1-C3alkyl;Rdis hydrogen or C1-C6alkyl; andp is 0, 1, 2, 3, or 4.

[0099] In embodiments, each Y is independently selected from F, Cl, Br, and I. In embodiments, each Y is F. In embodiments, each Y is Cl. In embodiments, each Y is Br. In embodiments, each Y is I.

[0100] In embodiments,L is

[0101] In embodiments,M is

[0102] In embodiments, the compound of Formula (I) is represented by Formula (la-8):wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, - N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, C3-C6cycloalkylene, 3- to 9-membered heterocyclylene and 7- to 14-membered bicyclic heterocyclylene;M is a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, - N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, C3-C6cycloalkylene,3041827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)3- to 9-membered heterocyclylene and 7- to 14-membered bicyclic heterocyclylene; and Rdis hydrogen or Ci-Cs alkyl.

[0103] In embodiments, X is CH. In embodiments, X is N.

[0104] In embodiments, Rdis Ci-Cg alkyl. In embodiments, Rdis selected from -CH3, -CH2CH3, and -CH2CH2CH3. In embodiments, Rdis -CH3. In embodiments, Rdis -CH2CH3. In embodiments, Rdis -CH2CH2CH3.

[0105] In embodiments, each Y is independently selected from F, Cl, Br, and I. In embodiments, each Y is F. In embodiments, each Y is Cl. In embodiments, each Y is Br. In embodiments, each Y is I.

[0106] In embodiments, L is selected from

[0107] In embodiments, L is. In embodiments, L is. In embodiments, L is. In embodiments, L is In embodiments, L isembodiments, L is. In embodiments, L isO ". In embodiments, L is. In embodiments, L is. In embodiments, L isON ”embodiments, L is H. in embodiments, L is. In embodiments, L is3141827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)In embodiments, L is. In embodiments, L isembodiments, Lis. In embodiments, L is

[0108] In embodiments, L is selected fromHN' N-:Hand

[0109] In embodiments, L is. In embodiments, L is. In embodiments, L is HN “ N--•r. In embodiments, L is H. In embodiments, L is5. Inembodiments, L is, In embodiments, L is, In embodiments, L is

[0110] In embodiments, M is selected fromH OX nO. NO O O H O O H N N NH H3241827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0111] In embodiments, M is. In embodiments, M isIn embodiments, M is. In embodiments, M is. In embodiments, M is o o N A A N A O 47 H. In embodiments, M is '. In embodiments, M is. In embodiments, M is embodiments, Mis. In embodiments, M is. In embodiments, M is

[0112] In embodiments, M is selected from3341827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)\ — / XN4 N N' — / . In embodiments, M is '. In embodiments, M isk — ' ’.

[0113] In embodiments, Reiand R are hydrogen. In embodiments, Relis hydrogen and R is Ci-Ce alkyl. In embodiments, Reland R are Cj-Ce alkyl. In embodiments, the Ci-Cg alkyl is selected from -CH -CH2CH3, and -CH2CH2CH3. In embodiments, the C1-C5 alkyl is -CH3. In embodiments, the Ci-Ct, alkyl is -CH2CH3. In embodiments, the Ci-CC alkyl is -CH (’H CH 3.

[0114] In embodiments, the compound of Formula (I) is represented by Formula (la-9):wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, - C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, C3-C6cycloalkylene, 3- to 9- membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene; andM is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, - C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene.

[0115] In embodiments, Rdis selected from -CH3, -CH2CH3, and -CH2CH2CH3. In embodiments, Rdis -CH3. In embodiments, Rdis -CH2CH3. In embodiments, R“ is -CH2CH2CH3.

[0116] In embodiments, each Y is independently selected from F, Cl, Br, and I. In embodiments, each Y is F. In embodiments, each Y is Cl. In embodiments, each Y is Br. In embodiments, each Y is I.

[0117] In embodiments, L is selected from3441827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0118] In embodiments, L is. In embodiments, L is. In embodiments, L is. In embodiments, L isembodiments, L isIn embodiments, L is, In embodiments, L is. In embodiments, L is H. In embodiments, L is«■ Hembodiments, L isIn embodiments, L is O, In embodiments, L isIn embodiments, L is. In embodiments, L is. In embodiments, L is. In embodiments, L is / ' embodiments, L isJ. In embodiments, L isembodiments, L isembodiments,L is3541827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0119] In embodiments, L is selected from

[0120] In embodiments, L is. In embodiments, L is. in embodiments, L is. In embodiments, L is H. In embodiments, L isembodiments, L isIn embodiments, L isIn embodiments, L is i.. In embodiments, L is

[0121] In embodiments, M is selected from

[0122] In embodiments, M is. In embodiments, M isIn embodiments, M is. In embodiments, M is. In embodiments, M isM. In embodiments, M isMIn embodiments, M is3641827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO). In embodiments, M is O. In embodiments, M iss. In embodiments, M isembodiments, M is. In embodiments, M isN~£'. In embodiments, M isembodiments, M is. In embodiments, M isembodiments, Misembodiments, Mis

[0123] In embodiments, M is selected from

[0124] In embodiments, M isIn embodiments, M isembodiments, M isIn embodiments, M is

[0125] In embodiments, the compound of Formula (I) is represented by Formula (la-10):wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene; and3741827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)M is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, - C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene.

[0126] In embodiments, Rdis selected from -CH3, -CH2CH3, and -CH2CH2CH3. In embodiments, Rdis -CH3. In embodiments, Rdis -CH2CH3. In embodiments, Rdis -CH2CH2CH3.

[0127] In embodiments, each Y is independently selected from F, Cl, Br, and I. In embodiments, each Y is F, In embodiments, each Y is Cl. In embodiments, each Y is Br. In embodiments, each Y is I.

[0128] In embodiments, L is selected from

[0129] In embodiments, L is. In embodiments, L is. In embodiments, L isembodiments, L is. In embodiments, L is. In embodiments, L is. In embodiments, L is. In embodiments, L isIn embodiments, Lisembodiments, L is. In embodiments, L is. In embodiments, L is. In embodiments, L is. In embodiments, L is3841827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)embodiments, L is, In embodiments, L is. In embodiments, L is. In embodiments, L is embodiments, L is

[0131] In embodiments, M is selected fromIn embodiments, M is. In embodiments, M is. In embodiments, M is. In embodiments, M is. In embodiments, M is3941827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO). In embodiments, M is O. In embodiments, M iss. In embodiments, M isembodiments, M is. In embodiments, M is -•r / \.■ N N~|x- — / , In embodiments, M is,N§. In embodiments, M is. In embodiments, M isIn embodiments, M isIn embodiments, M is

[0133] In embodiments, Mis orIn embodiments, M is

[0134] In embodiments, the compound of Formula (I) is represented by Formula (lb):(Z)wwherein:X is CH or N;R1is H or Ci-Cg alkyl;G is NH or N(CI-C6 alkyl);each Y is independently selected from C1-C2alkyl, F, Cl, Br, and I;L is a bond or a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, - NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, C3-C64041827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)cycloalkylene. C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene;M is a bond or a divalent group with a backbone of 1-6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, - NH-, -N(Rb1)-, -C(O)-, -C(O)-NH-, -C(O)N(Rb1)-, -NH-C(O)-, -N(Rb1)-C(O)-, C3-C6cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, 7- to 14- membered bicyclic heterocyclylene;Q is a bond or a divalent group of 1-6 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from C6-C10 monocyclic arylene, C8-C12 bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered bicyclic heteroarylene, and wherein each of C6-C10 monocyclic arylene, C8-C12 bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered bicyclic heteroarylene is independently substituted with 0, 1, 2, or 3 Rd; andRdis independently selected from hydrogen, halogen, C1-C3 alkyl, hydroxyl, -OC1-C4 alkyl, oxo, and -NH2

[0135] In embodiments, the compound of Formula (I) is represented by Formula (Ib-1):wherein:G is NH or N(C1-C6)alkyl;each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(RaI)-, - C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra’)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene; andM is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Rai)-, - C(O)-, -C(O)-NH-, -C(O)N(Ra’)-, -NH-C(O)-, -N(Ral)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene.

[0136] In embodiments, G is NH. In embodiments, G is N(C1-C6)alkyl.

[0137] In embodiments, X is CH. In embodiments, X is N.

[0138] In embodiments, Rdis selected from -CH3, -CH2CH3, and -CH2CH2CH3 In embodiments, Rd4141827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)is -CH3. In embodiments, Rdis -CH2CH3. In embodiments, R“ is -CH2CH2CH3.

[0139] In embodiments, each Y is independently selected from F, Ci, Br, and I. In embodiments, each Y is F. In embodiments, each Y is Cl. In embodiments, each Y is Br. In embodiments, each Y is I.

[0140] In embodiments, L is selected fromIn embodiments, L isIn embodiments, Lisembodiments, L isIn embodiments, L is. In embodiments, L isembodiments, L is, In embodiments, L is. In embodiments, L is‘. In embodiments, L is. In embodiments, L is4241827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)embodiments, L is

[0142] In embodiments, L isor 0 ' — '-4. In embodiments, L is. In embodiments,L is

[0143] In embodiments, M is selected fromO. In embodiments, M is. In embodiments, M is4341827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)embodiments, M isx— / . In embodiments, M isy. In embodiments, M is. In embodiments, M is,N§. In embodiments, M isIn embodiments, M is In embodiments, M is

[0145] In embodiments, M is' — ' or ’. In embodiments, M is' — ->. In embodiments, M is \-..7

[0146] In embodiments, the compound of Formula (I) is represented by Formula (Ib-2):wherein:G is NH orN(Ci-C6)alkyl;each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, - N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene; andM is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, - N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ral)-, -NH-C(O)-, -N(Ral)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene.

[0147] In embodiments, G is NH. In embodiments, G is N(C1-C6)alkyl.

[0148] In embodiments, X is CH. In embodiments, X is N.

[0149] In embodiments, Rdis selected from -CH3, -CH2CH3, and -CH2CH2CH3 In embodiments, Rd4441827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)is -CH3. In embodiments, Rdis -CH2CH3. In embodiments, R“ is -CH2CH2CH3.

[0150] In embodiments, each Y is independently selected from F, Ci, Br, and I. In embodiments, each Y is F. In embodiments, each Y is Cl. In embodiments, each Y is Br. In embodiments, each Y is I.

[0151] In embodiments, L is selected fromIn embodiments, L isIn embodiments, Lisembodiments, L isIn embodiments, L is. In embodiments, L isembodiments, L is, In embodiments, L is. In embodiments, L is‘. In embodiments, L is. In embodiments, L is4541827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)embodiments, L isIn embodiments, L is

[0154] In embodiments, M is selected fromIn embodiments, M is O. In embodiments, M is\N A O A. In embodiments, M is H. In embodiments, M is. In embodiments, M is. In embodiments, M is. In embodiments, Misembodiments, M is. In embodiments, M is 4641827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO). In embodiments, M is In embodiments, M is. In embodiments, M is". In embodiments, M is. In embodiments, Mis

[0156] In embodiments, M is

[0157]

[0158] In embodiments, Q is a divalent group of 1-4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected fromC6-C10 monocyclic arylene and 5- to 10-membered bicyclic heteroarylene, and wherein each of the C6- C10 monocyclic arylene and 5- to 10-membered bicyclic heteroarylene is independently substituted with 0, 1, 2, or 3 Rd; andeach Rdis independently selected from hydrogen, halogen, C1-C6 alkyl, hydroxyl, -OC1-C6 alkyl, oxo, and -NH2.

[0159] In embodiments, Q is selected fromRdis selected from hydrogen, C1-C6 alkyl, and -OC1-C6 alkyl, and wherein the C1-C6 alkyl is substituted with one or more of halogen, C1-C6 alkyl, hydroxyl, oxo, and -NH2;each X1is independently selected from hydrogen, halogen, C1-C6 alkyl, and -OC1-C3 alkyl; and n is 0, 1, 2, or 3.4741827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0160] In embodiments, Qis embodiments, Qis. In embodiments, Q is

[0161] In embodiments, Q is selected from4841827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0162] In embodiments, L is selected from

[0163] In embodiments, M is selected from

[0164] In embodiments, P is selected from

[0165] In embodiments, n is 2 and each Y is F.

[0166] In embodiments, X is CH.

[0167] In embodiments, X is N.4941827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0168] In embodiments, R1is selected from -CH3, -CH2CH3, and -CH2CH2CH3.

[0169] In embodiments, R1is -CH3.

[0170] In embodiments of any one of the above, X is CH or N. In embodiments, X is CH. In embodiments, X is N.

[0171] In embodiments of any one of the above, G is selected from CH2, O, NH, and N(C-;-C6 alkyl). In embodiments, G is CH2. In embodiments, G is O. In embodiments, G is NH. In embodiments, G is N(C1-C6 alkyl).

[0172] In embodiments of any one of the above, each Y is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, -OC1-C3 alkyl, -CN, and -NH2. In embodiments, Y is halogen. In embodiments, Y is C1-C6 alkyl. In embodiments, Y is C1-C6 haloalkyl. In embodiments, Y is hydroxyl. In embodiments, Y is -OC1-C3 alkyl. In embodiments, Y is -CN. In embodiments, Y is -NH2.

[0173] In embodiments of any one of the above, each Z is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, -OC1-C3 alkyl, -CN, and -NH2. In embodiments, Z is halogen. In embodiments, Z is C1-C6 alkyl. In embodiments, Z is C1-C6 haloalkyl. In embodiments, Z is hydroxyl. In embodiments, Z is -OC1-C3 alkyl. In embodiments, Z is -CN. In embodiments, Z is -NH2.

[0174] In embodiments of any one of the above, R1is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and -(CH2)C6-C14aryl. In embodiments, R1is hydrogen. In embodiments, R1is C1-C6 alkyl. In embodiments, R1is C1-C6 haloalkyl. In embodiments, R1is -(CH2)C6-C14aryl.

[0175] In embodiments of any one of the above, R2is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, -(CH2)1-6NH2, -(CH2)1-6N(Re1)(Re2), -C(O)C1-C6alkyl, -C(O)OH, and -C(O)OCi-C6alkyl. In embodiments, R2is hydrogen. In embodiments, R2is C1-C6 alkyl. In embodiments, R2is C1-C6 haloalkyl. In embodiments, R2is -(CH2)1-6NH2. In embodiments, R2is -(CH2)1-6N(Re1)(Re2). In embodiments, R2is -C(O)C1-C6 alkyl. In embodiments, R2is -C(O)OH. In embodiments, R2is - C(O)OC1-C6alkyl.

[0176] In embodiments of any one of the above, each Relis hydrogen or Ci-Ce alkyl. In embodiments, Re‘ is hydrogen. In embodiments, Relis Ci-Ce alkyl. In embodiments, Relis Ci alkyl. In embodiments, Relis C2 alkyl. In embodiments, Relis C3 alkyl. In embodiments, Relis C4 alkyl. In embodiments, Reiis C5 alkyl. In embodiments, Relis Ce alkyl.

[0177] In embodiments of any one of the above, each Re2is hydrogen or C1-C6 alkyl. In embodiments, Re2is hydrogen. In embodiments, Re2is C1-C6 alkyl. In embodiments, Re2is C1 alkyl. In embodiments, Re2is C2 alkyl. In embodiments, Re2is C3 alkyl. In embodiments, Re2is C4 alkyl. In embodiments, Re2is C5 alkyl. In embodiments, Re2is C6 alkyl.

[0178] In embodiments of any one of the above, L is a bond or a divalent group with a backbone of 1-6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(RaI)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-5041827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)C(0)-, -N(Ral)-C(O)-, C3-C6 cycloalkylene. C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene, wherein each of the Cs-Cs cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 Ra2.

[0179] In embodiments of any one of the above, L is a bond.

[0180] In embodiments of any one of the above, L is a divalent group with a backbone of 1-6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -Nil-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra’)-, -NH-C(O)-, - N(Ral)-C(O)-, C3-C6 cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene, wherein each of the Cs-Ce cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 Ra2.

[0181] In embodiments of any one of the above, L is a divalent group with a backbone of 1-6 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(RaI)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, C3-C, cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14- membered bicyclic heterocyclylene, wherein each of the Cs-Cs cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 Ra2.

[0182] In embodiments of the variable L, the divalent group is -O-. In embodiments, the divalent group is -NH-. In embodiments, the divalent group is -N(Ra1)-. In embodiments, the divalent group is -C(O)~. In embodiments, the divalent group is -C(O)-NH~. In embodiments, the divalent group is -C(O)N(Ra1)-, In embodiments, the divalent group is -NH-C(O)-. In embodiments, the divalent group is -N(Ra1)-C(O)-.

[0183] In embodiments of the variable L, the divalent group is C3-C6 cycloalkylene. In embodiments the divalent group is C3 cycloalkylene. In embodiments the divalent group is C4 cycloalkylene. In embodiments the divalent group is C5 cycloalkylene. In embodiments the divalent group is Ce cycloalkylene.

[0184] In embodiments of the variable L, the divalent group is C5-C12 bicyclic cycloalkylene. In embodiments, the divalent group is Cs bicyclic cycloalkylene. In embodiments, the divalent group is C6 bicyclic cycloalkylene. In embodiments, the divalent group is C? bicyclic cycloalkylene. In embodiments, the divalent group is Cs bicyclic cycloalkylene. In embodiments, the divalent group is C9 bicyclic cycloalkylene. In embodiments, the divalent group is Cio bicyclic cycloalkylene. In embodiments, the divalent group is Cn bicyclic cycloalkylene. In embodiments, the divalent group is Ci 2 bicyclic cycloalkylene.5141827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0185] In embodiments of the variable L, the divalent group is 3- to 9-membered heterocyclylene. In embodiments, the divalent group is a 3 -membered heterocyclylene. In embodiments, the divalent group is a 3-membered heterocyclylene. In embodiments, the divalent group is a 4-membered heterocyclylene. In embodiments, the divalent group is a 5-membered heterocyclylene. In embodiments, the divalent group is a 6-membered heterocyclylene. In embodiments, the divalent group is a 7-membered heterocyclylene. In embodiments, the divalent group is a 8-membered heterocyclylene. In embodiments, the divalent group is a 9-membered heterocyclylene.

[0186] In embodiments of the variable L, tire divalent group is 7- to 14-membered bicyclic heterocyclylene. In embodiments, the divalent group is a 7 -membered bicyclic heterocyclylene. In embodiments, the divalent group is a 8-membered bicyclic heterocyclylene. In embodiments, the divalent group is a 9-membered bicyclic heterocyclylene. In embodiments, the divalent group is a 10-membered bicyclic heterocyclylene. In embodiments, the divalent group is a 11-membered bicyclic heterocyclylene. In embodiments, the divalent group is a 12-membered bicyclic heterocyclylene. In embodiments, the divalent group is a 13 -membered bicyclic heterocyclylene. In embodiments, the divalent group is a 14-membered bicyclic heterocyclylene,

[0187] In embodiments of any one of the above, each Ralis independently selected from Cj-Cg alkyl, oxo, -(CH2)C6-Ci4aryl, -(CH^Cs-Cscycloalkyl,-C(O)OCi-Cg alkyl, -C(O)OCi-Cg haloalkyl, and - C(O)O-(CH2)Cg-Ci4 aryl. In embodiments, Ralis hydrogen. In embodiments, Ralis Ci-Cg alkyl. In embodiments, Raiis oxo. In embodiments, Ralis -(CH2)C6-C14aryl. In embodiments, Ralis -(CH2)C3-Cscycloalkyl, In embodiments, Ralis -C(O)OCi-Cg alkyl. In embodiments, Ralis -C(O)OCi-Cg haloalkyl. In embodiments, Ralis -C(O)O-(CH2)Cg-Ci4 aryl.

[0188] In embodiments of any one of the above, each Ra2is independently selected from hydrogen, halogen, C1-C6 alkyl, oxo, and C3-C6 cycloalkyl. In embodiments, Ra2is hydrogen. In embodiments, Ra2is halogen. In embodiments, Ra2is C1-C6 alkyl. In embodiments, Ra2is oxo. In embodiments, Ra2is C3-C6 cycloalkyl.

[0189] In embodiments of any one of the above, M is a bond or a divalent group with a backbone of 1-6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(Rb1)-, -C(O)-, -C(0)-NH-, -C(O)N(Rb1)-, -NH-C(O)-, -N(Rbl)-C(O)-, C3-C6 cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene, w herein each of the Cs-Cg cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14- membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 Rb2.

[0190] In embodiments of any one of the above, M is a bond.

[0191] In embodiments of any one of the above, M is a divalent group with a backbone of 1-6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(Rbl)-, -C(O)-, -C(O)-NH-, -C(O)N(Rbl)-, -NH-C(O)-, -5241827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)N(Rb1)-C(O)-, C3-C6 cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene, wherein each of the C3-C6 cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 Rb2.

[0192] In embodiments of any one of the above, M is a divalent group with a backbone of 1-6 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Rb1)-, -C(O)-, -C(O)-NH-, -C(O)N(Rb1)-, -NH-C(O)-, -N(Rbl)-C(O)-, C3-C6 cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14- membered bicyclic heterocyclylene, wherein each of the Cg-Cg cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 Rb2.

[0193] In embodiments of the variable M, the divalent group is -O-. In embodiments, the divalent group is -NH-. In embodiments, the divalent group is -N(Rb1)-. In embodiments, the divalent group is -C(O)-. In embodiments, the divalent group is -C(O)-NH-. In embodiments, the divalent group is -C(O)N(Rb1)-. In embodiments, the divalent group is -NH-C(O)-. In embodiments, the divalent group is -N(Rb1)-C(O)-.

[0194] In embodiments of the variable M, the divalent group is C3-C6 cycloalkylene. In embodiments the divalent group is C3 cycloalkylene. In embodiments the divalent group is C4 cycloalkylene. In embodiments the divalent group is C5 cycloalkylene. In embodiments the divalent group is C6 cycloalkylene.

[0195] In embodiments of the variable M, the divalent group is C5-C12 bicyclic cycloalkylene. In embodiments, the divalent group is C5 bicyclic cycloalkylene. In embodiments, the divalent group is C6 bicyclic cycloalkylene. In embodiments, the divalent group is C? bicyclic cycloalkylene. In embodiments, the divalent group is Cg bicyclic cycloalkylene. In embodiments, the divalent group is C9 bicyclic cycloalkylene. In embodiments, the divalent group is Cio bicyclic cycloalkylene. In embodiments, the divalent group is Cn bicyclic cycloalkylene. In embodiments, the divalent group is Ci 2 bicyclic cycloalkylene.

[0196] In embodiments of the variable M, the divalent group is 3- to 9-membered heterocyclylene. In embodiments, the divalent group is a 3 -membered heterocyclylene. In embodiments, the divalent group is a 3-membered heterocyclylene. In embodiments, the divalent group is a 4-membered heterocyclylene. In embodiments, the divalent group is a 5-membered heterocyclylene. In embodiments, the divalent group is a 6-membered heterocyclylene. In embodiments, the divalent group is a 7-membered heterocyclylene. In embodiments, the divalent group is a 8-membered heterocyclylene. In embodiments, the divalent group is a 9-membered heterocyclylene.

[0197] In embodiments of the variable M, the divalent group is 7- to 14-membered bicyclic heterocyclylene. In embodiments, the divalent group is a 7-membered bicyclic heterocyclylene. In5341827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)embodiments, the divalent group is a 8-membered bicyclic heterocyclylene. In embodiments, the divalent group is a 9-membered bicyclic heterocyclylene. In embodiments, the divalent group is a 10- membered bicyclic heterocyclylene. In embodiments, the divalent group is a 11-membered bicyclic heterocyclylene. In embodiments, the divalent group is a 12-membered bicyclic heterocyclylene. In embodiments, the divalent group is a 13 -membered bicyclic heterocyclylene. In embodiments, the divalent group is a 14-membered bicyclic heterocyclylene.

[0198] In embod im ents of any one of the above, each Rb1is independently selected from C1-C6 alkyl, -(CH2)C6-C14aryl, -(CH2)C3-C8cycloalkyl, -C(O)OC1-C6 alkyl, -C(O)OC1-C6 haloalkyl, and -C(O)O-(CH2)C6-C14 aryl. In embodiments, Rb1is C1-C6 alkyl. In embodiments, Rb1is -(CH2)C6-C14aryl. In embodiments, Rb1is -(CH2)C3-C8cycloalkyl. In embodiments, Rblis -C(O)OCi-Cg alkyl. In embodiments, Rb1is -C(O)OC1-C6 haloalkyl. In embodiments, Rb1is -C(O)O-(CH2)C6-C14 aryl.

[0199] In embodiments of any one of the above, each Rb2is independently selected from hydrogen, halogen, C1-C6 alkyl, oxo, and C3-C6 cycloalkyl. In embodiments, Rb2is hydrogen. In embodiments, Rb2is halogen. In embodiments, Rb2is Ci-Cg alkyl. In embodiments, Rb2is oxo. In embodiments, Rb2is Cs-Cg cycloalkyl.

[0200] In embodiments of any one of the above, P is a bond or a divalent group with a backbone of 1-6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(Rc1)-, -C(O)-, -C(O)-NH-, -C(O)N(Rc1)-, -NH-C(O)-, -N(Rcl)-C(O)-, Cs-Cg cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene, wherein each of C3-C6 cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 Rc2.

[0201] In embodiments of any one of the above, P is a bond.

[0202] In embodiments of any one of the above, P is a divalent group with a backbone of 1-6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(Rc1)-, -C(O)-, -C(O)-NH-, -C(O)N(Rc1)-, -NH-C(O)-, -N(Rc1)-C(O)-, C3-C6 cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene, wherein each of C3-C6 cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 Rc2.

[0203] In embodiments of any one of the above, each Rclis independently selected from Ci-Cg alkyl, -(CH2)C6-C14aryl, -(CH2)C3-C8cycloalkyl, -C(O)OCi-Cg alkyl, -C(O)OCi-Cg haloalkyl, and -C(O)O-(CH2)Cg-Cu aryl.

[0204] In embodiments of any one of the above, each Rc2is independently selected from hydrogen, halogen, Ci-Cg alkyl, oxo, and Cs-Cg cycloalkyl.5441827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0205] In embodiments of any one of the above, Q is a bond or a divalent group of 1-6 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from C6-C10 monocyclic arylene, C8-C12 bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered bicyclic heteroarylene, and wherein each of the Ce-Cio monocyclic arylene, C8-C12 bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered bicyclic heteroarylene is independently substituted with 0, 1, 2, or 3 Rd.

[0206] In embodiments of any one of the above, Q is a bond.

[0207] In embodiments of any one of the above, Q is a divalent group of 1-6 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from Ce-Cio monocyclic arylene, Cg-Ci2 bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5-to 10-membered bicyclic heteroarylene, and wherein each of the Ce-Cio monocyclic arylene, C8-C12 bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered bicyclic heteroarylene is independently substituted with 0, 1, 2, or 3 Re.

[0208] In embodiments of the variable Q, the divalent group is C6-C10 monocyclic arylene. In embodiments, the divalent group is C6 monocyclic arylene. In embodiments, the divalent group is C7 monocyclic arylene. In embodiments, the divalent group is C8 monocyclic arylene. In embodiments, the divalent group is C9 monocyclic arylene. In embodiments, the divalent group is C10 monocyclic arylene.

[0209] In embodiments of the variable Q, the divalent group is C8-C12 bicyclic arylene. In embodiments, the divalent group is Cg bicyclic arylene. In embodiments, the divalent group is C? bicyclic arylene. In embodiments, the divalent group is C10 bicyclic arylene. In embodiments, the divalent group is C11 bicyclic arylene. In embodiments, the divalent group is C12 bicyclic arylene.

[0210] In embodiments of the variable Q, the divalent group is 3- to 10-membered monocyclic heteroarylene. In embodiments, the divalent group is a 3-membered monocyclic heteroarylene. In embodiments, the divalent group is a 3-membered monocyclic heteroarylene. In embodiments, the divalent group is a 4-membered monocyclic heteroarylene. In embodiments, the divalent group is a 5- membered monocyclic heteroarylene. In embodiments, the divalent group is a 6-membered monocyclic heteroarylene. In embodiments, the divalent group is a 7-membered monocyclic heteroarylene In embodiments, the divalent group is a 8-membered monocyclic heteroarylene. In embodiments, the divalent group is a 9-membered monocyclic heteroarylene

[0211] In embodiments of the variable Q, the divalent group is 5- to 10-membered bicyclic heteroarylene. In embodiments, the divalent group is a 5-membered bicyclic heteroarylene. In embodiments, the divalent group is a 6-membered bicyclic heteroarylene. In embodiments, the divalent group is a 7-membered bicyclic heteroarylene. In embodiments, the divalent group is a 8-membered bicyclic heteroarylene. In embodiments, the divalent group is a 9-membered bicyclic heteroary lene. In embodiments, the divalent group is a 10-membered bicyclic heteroary lene.5541827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0212] In embodiments of any one of the above, each Rdis independently selected from hydrogen, halogen, Ci-Ce alkyl, hydroxyl, -OCi-Ce alkyl, oxo, -C(O)NH-, and -NH2. In embodiments, Rdis hydrogen. In embodiments, Rdis halogen. In embodiments, Rdis Ci-Cg alkyl. In embodiments, Rdis hydroxyl. In embodiments, Rdis -OCi-Ce alkyl. In embodiments, Rdis oxo. In embodiments, Rdis -C(O)NH-. In embodiments, Rdis -NH2.

[0213] In embodiments of any one of the above, n is 0, 1, 2, 3, or 4. In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4.

[0214] In embodiments of any one of the above, w is 0, 1, 2, 3, or 4. In embodiments, w is 0. In embodiments, w is 1. In embodiments, w is 2. In embodiments, w is 3. In embodiments, w is 4.

[0215] In some embodiments, provided herein is a compound chosen from the compounds listed in Table 1, Table 2, Table 3, and Table 4 or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt of any of the foregoing.Table 1. Compounds of the present disclosureCpd # Structure(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((I-((l-(2-(2,6-dioxopiperidin-3-yl)- l-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl- 1, 3,4-thiadiazole-3 (2H)-carboxamide(2J?)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((I-((I-(2-(2,6-dioxopiperidin-3-yl)- l-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H)-carboxamide5641827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)0 0 / T 7 / ~NHH2N--'X^ r^o JL JLyN-\ >=oS^N N" y J3Cr-~ / \ v / —F(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((7-(2-(2,6-dioxopiperidin-3-yl)- 1 -oxoisoindolin-5 -yl)-7-azaspiro [3.5]nonan-2-yl)methyl)piperidin -4-yl)oxy)-N- methyl -2 -phenyl - 1,3,4-thiadiazole-3(2H)-carboxamide_ 0 07 7 k~NHH2N-'"\ ^ JL JL / N\v A ox—& i N I" Y > i / r-4. Jy=N41V-F’ \ / (2R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((7-(2-(2,6-dioxopiperidin-3-yl)- l-oxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2-yl)methyl)piperidin-4-yl)oxy)-N- methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideoHN-AH; N-V-. OXo kj5(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(3-(2,6-dioxopiperidin-3-yI)- l-methy1-lH-indazol-6-yl)piperidin-4-yl)metbyl)piperidin-4-yl)oxy)-N-methyl-2- phenyl- 1,3,4-thiadiazole-3(2H)-carboxamide / 0 / HN"\ / AH2N~L &c iko^ <- i 1NXXNI i \> O6 kNANXA / (2S)-2-(3-aminopropy l)-5 -(2,5 -difluorophenyl)-N-(( 1 -(( 1 -( 1 -(2,6-dioxopiperidin-3 -yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo|d]imidazol-5-yl)piperidin-4-5741827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)yl)methyl)pipendin-4-yl)oxy)-N-methyl-2 -phenyl- 1, 3, 4-thiadiazole-3(2H)- carboxamide0HN-A^o °^J / -'N- N-°yy Z-'H^ Hr-O >=oAN!7FV(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(3-(2,6-dioxopiperidin-3-yl)~ 2-oxo-2,3-dihydrobenzo[d|oxazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N- methyl-2-phenyl-l,3,4-thiadiazole-3(2H)-carboxamideHH2N osV A / 'so l it'N''X'N'°y^A ■'T8(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideH— ^0H2N" X._ ( v^o r J Y ur^N'9(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(4-(2,6-dioxopiperidin-3-yl)~ 3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl- 1,3,4-thiadiazole-3(2H)-carboxamide5841827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO) / / 'AF 0A / O A AT HS^N N A < N r YpN 1 k'N'kA A^NH10F_ / AF°(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(4-((2,6-dioxopiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2- phenyl-l,3,4-thiadiazoIe-3(2H)-carboxamidei? PHzN-'V-. A o AYASP A xk / -'x A Jkm6‘ N N Y r N F11F"'\__yk''F(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-((1-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3,5-difluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamidep 0,A — N H| ji N < A®< NA / J12NrJ s-4 FY pF(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((r-(2-(2,6-dioxopiperidin-3-yl)-l- oxoi soindolin-5-yl)-[ 1.4'-bipiperidin] -4-yl)oxy)-N-methyl-2-phenyl- 1,3,4-thiadiazole- 3 (2H) -carboxamide / TA0\ J y— NHH2N'"\— - o f ifN\ AoZNAN'°Y^ V- / 13F / y-F(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(2-(2,6-dioxopiperidin-3-yl)- l-oxoisoindolin-5-yI)piperidin-4-yl)methyi)azetidin-3-yl)oxy)-N-methyI-2-phenyl-l,3,4-thiadiazoIe-3(2H)-carboxamide5941827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)0 0r~N.Hi r N--\ x-°' -z< N14 C —AF AYF(2tS)-2-(3-aminopropy1)-5-(2,5-difluorophenyl)-N-((l-(7-(2-(2,6-dioxopiperidin-3-yl)- l-oxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yi)oxy)-N-methyl-2- phenyl-l,3,4-thiadiazole-3(2H)-carboxamide0 0AA-X V~NHf jT N--( '>=0f'NX""715 A.>> Y Ns-0 JH2N / / F(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-(l-(2-(2,6-dioxopiperidin-3-yI)- l-oxoisoindolin-5-yi)piperidin-4-yl)azetidin-3-yl)oxy)-N-methyl-2-phenyl-l,3,4- thiadiazole-3(2H) -carboxamideN Y'A-'A ANH2oN N r N16 / / FFA-AZ(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(3-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methoxy)propoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H)-carboxamide6041827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO) / TA 92JT JLn\ W°SANAN'OXI 'V r N A o -X \zA xxJ'17cJ--—^ A. y / --F(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(2-(2-(4-(2-(2,6-dioxopiperidin-3- yl)- 1 -oxoisoindolin-5-yl)piperazin- 1 -yl)ethoxy)ethoxy)-N-methyl -2 -phenyl- 1,3.4- thiadiazole-3(2H) -carboxamide / TA 0 0H2N-X WO jf I IINA \ AS0ANANZ°> \ '> N 1 Lx\A )18 j00FWV-F °(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(2-(2-(4-(2-(2,6-dioxopiperidin-3- y 1 )- 1 -oxoisoindolin-5 -yl)piperazin- 1 -yl)-2-oxoethoxy)ethoxy)-N -methyl -2 -phenyl - l,3,4-thiadiazole-3(2H)-carboxamidef,?2 v-"-j? „ 1' r W >oX'N ''N,'0y o XX \ — / VN1< A. A. J19 / N / rAHF4AF(2tS)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(4-((l-(2-(2,6-dioxopiperidin-3-yl)- l-oxoisoindolin-5-yl)piperidin-4-yl)aniino)-4-oxobutoxy)-N-methyl-2-phenyl-l,3,4- thiadiazole-3(2H)-carboxamideAA o osAA r^A-X y~NH■ o d >. <0VN1A20 A Y ~F^VF0(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(3-(((l-(2-(2,6-dioxopiperidin-3-yl)- l-oxoisoindolin-5-yl)piperidin-4-yl)methyl)amino)-3-oxopropoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide6141827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)0 0KNHr ii N-< >=o7--MO'"-N JF\(M.4 / / T21AN'NJ s--4Fr Y2(JF z(2tS)-2-(3-aminopropy1)-5-(2,5-difluorophenyl)-N-(2-(7-(2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-2-yl)ethoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamidep oY YNH FAH2N'^\^ZV=: Jo )g / AK NA N'°X / N 'ZN'J22 \Yr 1(25)-2-(3-aminopropyl)-5 -(2,5 -difluorophenyl)-N-(3 -(7-(2-(2,6-dioxopiperidin-3 -yl)- 1 - oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-2-yl)propoxy)-N-methyl-2-phenyl-1,3,4- thiadiazole-3(2H) -carboxamideH, NFx\v==rx o o23 % t N-^Y0\ F i r V_ / O |; | N(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideH2N0 0\=x S-4-C / / YYX r~NH / Y-4 1 L / N~\24y> 7 N | | \ —F J F O '-'(25)-2-(3-aniinopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-3-yl)oxy)-N-methyl-2-phenyl-l,3,4-thiadiazole-3(2H)-carboxamide6241827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)FH2N\S, ~AF0 025AA i X £N\ A0X / ANAXX(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-3-yl)methoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide0 0'v V-NH / ^N | ] |TN— / V=0V-“ / 26w(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(2-(2,6-dioxopiperidin-3-yI)- l-oxoisoindolin-5-yl)piperidin-4-yl)niethyl)azetidm-3-yl)methoxy)-N-methyl-2- phenyl-l,3,4-thiadiazole-3(2H)-carboxamideo oxN--< X=0\ / F / "l I NA A N,N"°2FT7 N-4s- / oAri1 yyH2N^(2S)-2-(3-ammopropyl)-5-(2,5-dif]tJorophenyl)-N-((l-((l-(2-(2,6-dioxopiperidin-3-yl)- l-oxoisoindolin-5-yl)piperidin-4-yl)methyi)pyrroiidin-3-yi)methoxy)-N-methyl-2- phenyl- 1, 3,4-thiadiazole-3(2H)-carboxaniideF\i 0 0S'^'N / “MH" J: N ( > 028 A VK. / "r r N' '"7 X—70 0(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(2-(2,6-dioxopiperidin-3-yl)- 1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)pyrrolidin-3-yl)oxy)-N-methyl-2-phenyl-l,3,4-thiadiazole-3(2H)-carboxamide6341827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)o o\ y— NH H22N-"\ / V r r \ N.— < / k=O A AN XN,cx >TJ / x.. \X / ' \ i i H i29 VN1ANx zF__^ y— F0(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carboxamido)propoxy)-N-methyl-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamideO 0y-NHX AN\H |0H / AOA. 0o30,oV N_ / S-4,FH2N / A>F(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(2-(l-(2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-5-yl)piperidine-4-carboxamido)ethoxy)-N-methyl-2-phenyl-1,3,4- thiadiazole-3 (2H)-carboxamideAA o o\ _- / r-NH H2N-^\_--, F O r Ln A A / A Av \ / g / ^N N y A p Nx zAN1X / X^N\X31F(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(((lS,4R)-4-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclohexyl)oxy)-N-methyl-2-phenyl-l, 3, 4-thiadiazole-3(2H) -carboxamide6441827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO) / TX o o2£ X 9.e _x \X> JX / N-\ \ _ / )=o b XN; N | I r | N i ' 32 VN X / Nz^Xz7 \y_-pF~~\ / (25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(((lR,4S)-4-((4-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazin-l-yl)methyl)cyclohexyl)oxy)-N- methyl -2 -phenyl - 1,3,4-thiadiazole-3(2H)-carboxamide0 OV-NH[ |T N- / o*'X>33,>< V N7 S-A,FH2NF(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(((lS,4R)-4-(4-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-5-y])piperazin-l-yl)cyclohexyl)oxy)-N-methyl-2- phenyl- l,3,4-thiadiazole-3(2H)-carboxamide0 0<^.^7 y~NHL / x >oA'X) ° y34 / S. J / FH; NyjF(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(((1R,4S)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)cyclohexyl)oxy)-N-methyl-2-phenyl-l,3.4-thiadiazole-3(2H)-carboxamide6541827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)0 0X~NHX XN\ A°0. / N E35NH2(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(((1S,4R)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)cyclohexyl)methoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideP oy-NHL IL X \ X"°hk J / X°'N / 36O^NA / Aru- / M\FNH2(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(((1R,4S)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)cyclohexyl)methoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide / TA o 0 \^J y-NH 0 i XN\ X^0VN 137 / / % — FF\= / (2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((lS,3R)-3-((4-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindoiin-5-yl)piperazin-l-yI)methyl)cyclobutoxy)-N-methyl-2-pheny] - 1,3,4-thiadiazole-3(2H)-carboxamide6641827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1R,3S)-3-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclobutoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide39(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((lS,3R)-3-(4-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazin-l-yl)cyclobutoxy)-N-methyl-2- phenyl- l,3,4-thiadiazole-3(2H)-carboxamideO OF(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((lR,3S)-3-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)cyclobutoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideTable 2. Compounds of the present disclosure6741827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)Cpd # Structure0 OX JEn\C / J^T41 yL. Xb 1 I,0AN1P" L / (25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(((lS,3R)-3-(4-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazin-l-yl)cyclobutyl)methoxy)-N- methyl-2-phenyl-l,3,4-thiadiazole-3(2H)-carboxamide0 OA ' A JA A / "" N - e. N, >HO2N'^\^->ja42 'yL. o \A.,6S^N NAN(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(((1R,3S)-3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)cyclobutyl)methoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideH2NF\===\ >S 0043 VC V-Y frA yoF V- / A M(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(((lS,3R)-3-((4-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazin-l-yl)methyl)cyclobutyi)methoxy)-N-methyl -2 -phenyl - 1,3,4-thiadiazole-3(2H)-carboxamide6841827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)H2NE\==x / S 0 044 4\ny in~\ AY yL=oF v- / (2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(((1R,3S)-3-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclobutyl)methoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide0 0YyX y-NH\ / NH2 JL JL / N\ ' — / A0F / f 1 145\== / N y 0p 0(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-(2-(4-(2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl- 1,3,4-thiadiazole-3 (2H)-carboxami de0 0V-NH\ / JNH2 As. JA / N\ / A°F / / 1 J46 rV-4 T i JPJN\ _ / N Y 0^^p 0(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-(2-(l-(2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl- 1,3,4-thiadiazole-3 (2H)-carboxamideP o o, / -- / y"NHFKN,NN47 X Y °H2N--Y (Y'A(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-(2-(4-(2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ethyl)azetidin-3-yl)oxy)-N-methyl-2-phenyl-l,3,4-thiadiazole-3(2H)-carboxamide6941827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)F _ / \H2N \ X / / Fo n os- / / -~NH, N L II >=0 / | r N48x~ IN p ^-.N.zx'x. hL Xx X-"(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-(2-(4-(2-(2,6-dioxopiperidin-3- yl)-l-oxoisoindolin-5-yl)piperazin-l-yl)ethyl)azetidin-3-yl)methoxy)-N-methyl-2- phenyl-l,3,4-thiadiazole-3(2H)-carboxamide / XA 0 0H HoN \ n v if \. / x~N\H~f o N — ( >=ON Y A < N AVN 1 XxN^X\X490X % — FF\-= / (2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2- phenyl-1,3,4-thiadiazole-3(2H)-carboxamideoH2N'''\__Z)r OC / ^N N i f Y 7\x^^0y°50 / ] Nx_ _E N 0F\== / X4( NH0(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-(2-(2-((2-(2,6-dioxopiperidin-3- yI)-l-oxoisoindolin-5-yl)oxy)ethoxy)ethyl)piperidin-4-yl)oxy)-N-methyl-2-phenyi- 1,3,4-thiadiazole-3 (2H)-carboxami deoZ, 0A zA. A x^\ zOxg / ^N N j X ( X iVN 1 L zN. X-x J XxA XVJ H0z^051 AAx F0OF\ ) _ €NH0(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-(2-(2-((2-(2,6-dioxopiperidin-3- yl)-l-oxoisomdolin-5-yl)oxy)ethoxy)acetyl)piperidin-4-yl)oxy)-N-methyl-2 -phenyl-1,3,4-thiadiazole-3(2H)-carboxamide7041827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)0 0V-NHX JLN\ X°. N. J0 ~_ iO r. N„52 N<H2N / )>F(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-5-yl)-2,7-diazaspiro|3.5]nonan-7-yl)ethoxy)-N-methyl-2-phenyl-l,3,4- thi adi azole-3 (2H)-carboxam ide0 C>V-NHL l / A / =°< N53 M I,oy NJ s--4FH2N / ^J / F(2A')-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-(2-(2-(2,6-dioxopiperidin-3-yl)- l-oxoisoindolin-5-yl)-2-azaspiro[3.5]nonan-7-yl)piperidin-4-yl)oxy)-N-methyl-2- phenyl-1,3,4-thiadiazole-3(2H)-carboxamideoH2N^^''AN _S\<7N 'y t?vo54 / . / TVNVXFA^ / NH< / Xo(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-(7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide7141827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)0 0V--NHr |F Xoy— / rNZx / O, U'JQ V- 55V'NJ x OO z: -.1 1 TH2N r~\rF / (2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((2-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)-2-azaspiro[3.5]nonan-7-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide() O 0o y~NH£ J? o- 1 / --X / / / "oX I X J X56 LLX,-,> Y NJ S-X FA \=XH2N / >yjF(2tS)-2-(3-aminopropy1)-5-(2,5-difluorophenyl)-N-((2-(l-(2-(2,6-dioxopiperidin-3-yl)- l-oxoisoindolin-5-yl)piperidin-4-yl)-2-azaspiro[3.3]heptan-6-yl)oxy)-N-methyl-2- phenyl- 1,3,4-thiadiazole-3(2H)-carboxamide577241827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3- yl)-l-oxoisoindolin-5-yl)oxy)ethoxy)ethoxy)ethoxy)-N-methyl-2-phenyl-l,3,4- thiadiazole-3(2H)-carboxamideH2NX(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(2-((2-(2-((2-(2,6-dioxopiperidin-3- yl)-l-oxoisoindolin-5-yl)oxy)acetamido)ethyl)amino)-2-oxoethoxy)-N-methyl-2- phenyl-1,3,4-thiadiazole-3(2H)-carboxamideO(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(2-((3-(2-((2-(2,6-dioxopiperidin-3- yl)-l-oxoisoindolin-5-y!)oxy)acetamido)propyl)amino)-2-oxoethoxy)-N-methyl-2- phenyl- 1,3,4-thiadiazole-3(2H)-carboxamide41827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(2-((3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetamido)propyl)amino)-2-oxoethoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideO(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(2-((3-(2-((2-(2,6-dioxopiperidin-3- yl)-l-oxoisoindolin-4-yl)amino)acetamido)propyl)aniino)-2-oxoethoxy)-N-methyl-2- phenyl- 1,3,4-thiadiazole-3(2H)-carboxamide7441827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)0HN-A_ 1621 J T7 S-4 / FH2N OF(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1'-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-[1,4'-bipiperidin]-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide0HN-A01 L63 0., / N E0^ N "\ / ' FNH2(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1'-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-[1,4'-bipiperidin]-4-yl)methoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide41827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)0HN-A1 iL64 0. / N RNH2(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-(l-(3-(2,6-dioxopiperidin-3-yl)- l-methyl-lH-indazol-6-yl)piperidin-4-yl)azetidin-3-yl)methoxy)-N-methyl-2 -phenyl- l,3,4-thiadiazole-3(2H)-carboxamide0HN-A0^ / o f IT^N65F- / ” / F(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(3-(2,6-dioxopiperidin-3-yl)- l-metliyl-lH-indazol-6-yl)piperidin-4-yl)methyl)azetidin-3-yl)oxy)-N-methyl-2- phenyl-1,3,4-thiadiazole-3(2H)-carboxamide0HN-A66S. ' I VJ< N Jr \ / 7641827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1S,3R)-3-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)cyclobutoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide0HN-A67AN iF'O'F(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((lR,3S)-3-((4-(3-(2,6- dioxopiperidin-3-yl)- 1 -methyl- lH-indazol-6-yl)piperazin- 1 -yl)methyl)cyclobutoxy )-N- methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide0HN"'\oX. Jf / J\ f n 1 N68 b | 1 1 I \V^N1r \ / (25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(((lS,4R)-4-((4-(3-(2,6- dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)cyclohexyl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideHN-A69(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(((lR,4S)-4-((4-(3-(2,6- dioxopiperidin-3-yl)- 1 -methyl- lH-indazol-6-yl)piperazin- 1 -yl)methyl)cyclohexyl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide7741827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)0HN-Ar— -x oY JOH2N'A-—, O JiQzN N > < N ■’70U1VJjF__^ry~-F0(25)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((5-(4-(3-(2,6-dioxopiperidin-3-yl)- 1-methyl-1H-indazol-6-yl)piperazin-1-yl)-5-oxopentyl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide0HNY OA / H2N-X^-, V''' O AAZ A Jk-u'71C / ^N N > 0 < NNxS i I |l I \VN1k A A J / N# V-FF(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(4-((l-(3-(2,6-dioxopiperidin-3-yl)- 1 -methyl- lH-indazol-6-yl)piperidin-4-yl)amino)-4-oxobutoxy)-N -methyl -2 -phenyl- l,3,4-thiadiazole-3(2H)-carboxamide0HNY,f rUANZN72 8 i i i H Ik^N!ANAAy_F°(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(3-(((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)amino)-3-oxopropoxy)-N-methyl-2-phenyl-l,3,4-thiadiazole-3(2H)-carboxamide7841827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)ethyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)ethyl)azetidin-3-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide7941827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)0\ / CK'A A- A J76C / ^N N Y 1 r No! I 1 Iy=N1AA(S)-2-(3-aminopropyl)-N-((1-((1-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-5-(2,5-difluorophenyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideOHbT 7yAx O^NTH2N'AS^Zo 'X ll‘"'A X As. J77 i i 1 i1F"^\^y ”F(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methylphenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide0HN A >zrA CA'AH2N-^\_, y-" Q p-" |f78A1LLXjc / ArFN= / (S)-2-(3-aminopropyl)-N-((1-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-5-(2,5-difluorophenyl)-N-methyl-2 -phenyl- 1,3,4-thiadiazole-3 (2H)-carboxamide8041827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)(5)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(3-(2,4- dioxotetrahydropyrimidin- 1 (2H)-yl)-4-methoxyphenyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-l,3,4-thiadiazole-3(2H)- carboxamide80(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-(l-(2-(2,6-dioxopiperidin-3-yl)- l-oxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl- 1,3,4-thiadiazole-3(2H)-carboxamide(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(2-(2,6-dioxopiperidin-3-yl)- 1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)-N-methyl-2-phenyl- 1, 3,4-thiadiazole -3 (2H) -carboxamideTable 3. Compounds of the present disclosureCpd # Structure8141827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)P HN-\_ _ Ja SVO VTA82 / N N °JV]-N'IVN;1YNYY 0F / fA-vF Yr- / (S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-(((lr,4S)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4- c]pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4- thiadiazole-3(2H)-carboxamide0HNYV °V< 7 7H^XYA o _ rj >A v TV rv83 YV!ANV\Z 0(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-(((1r,4S)-4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide0HN-KOA JO - / HN" X.-, rr7o r^V "kS7Y Y f T YN\84j / — FF\___y(S)-5-(2,5-difluorophenyl)-N-((1-(((1r,4S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-N-methyl-2-(3-(methylamino)propyl)-2-phenyl-l,3.4-thiadiazole-3(2 / / )-carboxamide8241827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)0 HNX^r' — N. OX. / n. 7x n.,0^ x l>85 s?? f 7 r T' \1X'NxX''X OxX(2S)-5-(2,5-difluorophenyl)-N-((1-(((1r,4S)-4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-N-methyl-2-(3-(methylamino)propyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide0HNXoX / *\ _ / o r u %xs' 7 7 7 r 7 IfN\86F-X VF\=r- / (S)-5-(2,5-difluorophenyl)-N-((1-(((1r,4S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-2-(3-(ethylamino)propyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide0 HNX.p X rHN-XXX r VNxsz7: 7 T T 7 787XXxP\X05-XFX VF(2S)-5-(2,5-difluorophenyl)-N-((1-(((1r,4S)-4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-2-(3-(ethylamino)propyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide8341827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)H2N \ _ z 0y=N!AN\A\_ J / ^V-F °x88 FA / 7 1 V-HN A ArA00v > AJN~N / (S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-((1r,4S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideAr 0A A zOg / N NxV AN!]! A--F 0H89 F- \_J JJ i ANQ O' 'A'" A —J\ / ZN-N(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-((1r,4S)-4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide0HN-AH2N" A-—Z jA 0 1 II ' NA. A z-O^A^N N 1 I n \90 \^N1AN^AA 0F / V(5)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-(((lr,4S)-4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)azetidin-3-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2 / / )-carboxamide8441827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)O / / HN'\r o r H N91XX(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-(((1r,4S)-4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)azetidin-3-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideH2NJ F S / =\92 / o [ | K \(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-(((1r,4S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)azetidin-3-yl)methoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideH2N\ o / HN'A93 MN'VF0(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-(((1r,4S)-4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)azetidin-3-yl)methoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3 ( 2 / / )-carboxam ideTable 4. Compounds of the present disclosureCpd # I Structure8541827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)0 HNY^nH2N" V--Z r'o H f YAI / Jl N ~ M J-Yr < Y r 1 i TY Y94 V--N1Y / N-^ZYY 0YYF(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N'-(1-(((1r,4S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carbohydrazide0 HN YO'X JI ) 7NZ N- N' yy Y' -N95[l % — p(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(((1r,4S)-4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)piperidin-1-yl)methyl)cyclohexyl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideH2N) 0 / / / \ HNAF\ _ s 7 oY _yY4 N'NV° YY\ i 1 h N96? H n it "(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(2-((((1r,4S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)amino)ethoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideH2N-^SN0oY'f0V 1 ' N / N~O \ / / — N \H _ / i \ \ ' / / ==\ \ KI )97 I 1 / :! NFM.1O N1(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(3-((((1r,4S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-8641827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)c]pyridin-6-yl)cyclohexyl)methyl)amino)propoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide£ A HH2N \ V-"' o C ^1k X.0. J U,oHs7? ~ 1 V"V-S-N!A. < A ■ Vs098 7 °' T> VF__Z V-FZN N(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(3-(((1r,4S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)amino)propoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideH2N^F r 1N--4 PZQN N-Q. X'~'YZ99 "■"-A HN— ( >-'NFv \,-N0 Nu1(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(2-(((1r,4S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)amino)ethoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideH2N^•ZO A / ^N N-Q100 I A7 X\ \TFHNA -- / " A o y 0N 1 "w1(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(2-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)amino)ethoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide8741827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)O)HH2N o: r 1AIXM'OX 0Hs' ■ T V-NV'-N!XX ' V-'O101 J \ V"NvXX X— F N-NF\ '(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(3-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)amino)propoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide H2N0\ r.-s=\ HN-AXy / SXX0=V102F"N"° H pX'-X(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(2-(((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)amino)ethoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamidesX 0 LI / .o■ N~X103FYX / =\ X\ N>-Nt1(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(3-(((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)amino)propoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide 0HN-XH2N-\ 0\-AO H[ TX104 XXNXJ3N;(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N'-(1-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carbohydrazide8841827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)pHN"\kAH2N-\_ V'o 03105pFF" A= / (S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-(((1r,4S)-4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)cyclohexyl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide H22N X o / HN-k / S~T^O °" V106(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)azetidin-3-yl)methoxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamidepHN'X. / / kH2N-X^y-7o K jr >sANAN'°Yy107(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)azetidin-3-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide oHN-k-x O-"k. J108F / V / -F(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxam ide8941827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)0 HN' \H2N'A-rj? o I n109VN1 / / FF"^ / ((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideH.0 H2N— x \___ / N— ^7 / 00;=( \o N — - / S N N" V'"\ / — \ / 1 _ / VN!110Z7“< NF— C V-F 1(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideO / 'N VJ I N OHH2N" 7-N \ns' N lAj y 1 \ Vx""y111 / N“N(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)pyrrolidin-3-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamideH2N-\Xf~\---, >= / H O>-~N / \ \ N--v z"’ — -z x / / ) —112 F-Z wrN1(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((2-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.3]heptan-6-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3 (2H) -carboxam ide9041827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)H2N— A ( / \\ if V_ \— / HN--A / -N / Y"-\113F~- / \\CVNX / 'N'\_ Z-F vAy \(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((2-((l-(3-(2,4- dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-1H-indazol-6-yl)azetidin-3-yl)methyl)- 2-azaspiro[3.3]heptan-6-yl)oxy)-N-methyl-2-phenyl-l,3,4-thiadiazole-3(2H)- carboxamideH2N~^ x- V \ f oHN-A / I H °1 )114(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(3-(2,4- dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yi)azetidin-3- yl)methyl)pyrrolidin-3-yl)oxy)-N-methyl-2-phenyl-l,3,4-thiadiazole-3(2H)- carboxamideo H2N— x HN--yoS N N'UVA - / NAN! L-V-X lArl,115 ■ - < i 1 AN(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((7-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)azetidin-3-yl)methyl)- 7-azaspiro[3,5]nonan-2-yl)oxy)-N-methyl-2 -phenyl- 1,3,4-thiadiazoIe-3(2H)-carboxamide4.3. Methods of Treatment

[0216] In some embodiments, a compound of Formula (I), or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, is administered to treat a KIF11 - mediated disease or disorder in a subject in need thereof. In some embodiments, the KIF11 -mediated disease or disorder is cancer.

[0217] In an aspect, the present disclosure relates to a method for the treatment of a disease or disorder associated with abnormal kinesin-like protein activity.

[0218] In embodiments, the therapeutic treatment is for the treatment of diseases and conditions associated with abnormal kinesin-like protein activity, for example abnormal kinesin-like protein activity caused by a mutation in the KIF11 gene. Examples of disease or disorder associated with9141827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)abnormal kinesin-like protein activity include cancer. In embodiments, the cancer is adrenal glands: neuroblastoma; biliary7tract: gall bladder carcinoma, ampullary7carcinoma, cholangiocarcinoma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; breast: invasive ductal carcinoma, ductal carcinoma in situ (DCIS), invasive lobular carcinoma, lobular carcinoma in situ (LCIS), Paget disease, Phyllodes tumor, and inflammatory' breast cancer; cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; eye: intraocular melanoma, retinoblastoma, and lymphoma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary’ tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); gynecological: uterus (endometrial 'carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embry onal rhabdomyosarcoma), fallopian tubes (carcinoma), ovarian (epithelial ovarian cancer, stromal tumors, and germ cell tumors); hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, nonHodgkin's lymphoma (malignant lymphoma); liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; lung: non-small cell lung cancer, bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); oral and oropharyngeal: squamous cell carcinomas, verrucous carcinoma, minor salivary gland carcinomas, and lymphomas; thymus:9241827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)thymoma and thymic carcinoma; thyroid: papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, anaplastic thyroid cancer, and thyroid lymphoma; or skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis.

[0219] In another aspect, the present disclosure relates to a method for treating cancer in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I), a pharmaceutically acceptable salt of a compound of Formula (I); or pharmaceutical composition thereof disclosed herein. Tire present disclosure also relates to the use of a compound of Formula (I), a pharmaceutically acceptable salt of a compound of Formula (1); or pharmaceutical composition thereof disclosed herein for treating cancer, or for the manufacture of a medicament for treating cancer. The present disclosure also relates to a compound of Formula (I), a pharmaceutically acceptable salt of a compound of Formula (I); or pharmaceutical composition thereof disclosed herein for use in treating cancer.

[0220] In embodiments, the contemplated method, use and compounds of Formula (I) are for treating a subject with glioma. In embodiments, the use and compounds of Formula (I) are for treating a subject with glioblastoma. In embodiments, the use and compounds of Formula (I) are for treating a subject with astrocytoma. In embodiments, the use and compounds of Formula (I) are for treating a subject with adrenocortical carcinoma. In embodiments, the use and compounds of Formula (I) are for treating a subject with adrenocortical meningioma. In embodiments, the use and compounds of Formula (I) are for treating a subject with lung cancer. In embodiments, the use and compounds of Formula (I) are for treating a subject with lung adenocarcinoma. In embodiments, the use and compounds of Formula (I) are for treating a subject with laryngeal squamous cell carcinoma. In embodiments, the use and compounds of Formula (I) are for treating a subject with hepatocellular carcinoma. In embodiments, the use and compounds of Formula (I) are for treating a subject with colorectal cancer. In embodiments, the use and compounds of Formula (I) are for treating a subject with esophageal squamous cell carcinoma. In embodiments, the use and compounds of Formula (I) are for treating a subject with pancreatic ductal adenocarcinoma (PDAC). In embodiments, the use and compounds of Formula (I) are for treating a subject with bladder cancer. In embodiments, the use and compounds of Formula (I) are for treating a subject with clear cell renal cell carcinoma. In embodiments, the use and compounds of Formula (I) are for treating a subject with cervical cancer. In embodiments, the use and compounds of Formula (I) are for treating a subject with serous ovarian cancer. In embodiments, the use and compounds of Formula (I) are for treating a subject with ovarian cancer. In embodiments, the use and compounds of Formula (I) are for treating a subject wi th prostate cancer. In embodiments, the use and compounds of Formula (I) are for treating a subject with breast cancer.9341827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0221] In embodiments, provided is a method for inhibiting and / or degrading protein kinesin-like protein KIF 11 in a cell, comprising contacting the cell with a compound as contemplated herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0222] In embodiments, provided is a method of treating a KIF 11 -mediated disease or disorder in a subject in need thereof, comprising administering an effective amount of a compound as contemplated herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In embodiments, the KIF 11 -mediated disease is cancer. In embodiments, the cancer is selected from breast cancer, lung cancer, pancreatic cancer, small bowel cancer, colorectal cancer, gall bladder cancer, thyroid cancer, liver cancer, bile duct cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, esophageal cancer, and blood cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is papillary' adenocarcinoma. In embodiments, the cancer is adenocarcinoma. In embodiments, the cancer is ductal carcinoma. In embodiments, the cancer is a primary cancer or a metastatic cancer.

[0223] In embodiments, provided is a method of inhibiting the production of kinesin-like protein (KIF 11 ) in a subject, the method comprising administering an effective amount of a compound as contemplated herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0224] In embodiments, provided is use of a compound as contemplated herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of medicament for the treatment of a disease or disorder. In embodiments, the KIF 11 -mediated disease is cancer. In embodiments, the cancer is selected from breast cancer, lung cancer, pancreatic cancer, small bowel cancer, colorectal cancer, gall bladder cancer, thyroid cancer, liver cancer, bile duct cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, esophageal cancer, and blood cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is papillary' adenocarcinoma. In embodiments, the cancer is adenocarcinoma. In embodiments, the cancer is ductal carcinoma. In embodiments, the cancer is a primary cancer or a metastatic cancer.

[0225] In some embodim ents, upregulation of KIF 11 is associated with the enrichm ent of histone H3 27 acetylation (FI3K27ac) in the promoter region. In embodiments, the compounds of Formula (I) are used in a method of treating gallbladder cancer.

[0226] In some embodiments, non-coding RN As regulate the expression of KIF 11. MicroRNA (miRNA) influences protein synthesis via the post-transcriptional regulation of messenger RNA (mRNA). In embodiments, miR-186-5p binds to the 3UTR of KIF11, inhibiting the proliferation of neuroblastoma. In embodiments, KIF 11 is the target of miR-424 and miR-381, which is associated with ovarian cancer.4.4. Pharmaceutical Compositions9441827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0227] In some embodiments, pharmaceutical compositions comprise any one of the compounds disclosed herein and a pharmaceutically acceptable excipient.

[0228] The compounds disclosed herein can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. The compounds disclosed herein can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds described herein can be administered by inhalation, for example, intranasally.Additionally, the compounds disclosed herein can be administered transdermally. Accordingly, the present embodiments also provide pharmaceutical compositions including one or more pharmaceutically acceptable carriers and / or excipients and either a compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I).

[0229] For preparing pharmaceutical compositions from the compounds disclosed herein, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules, A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, surfactants, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co, Easton PA (“Remington's”).

[0230] Tire powders, capsules and tablets contain from 0.1% to 99% of the active compound and any integer therein, such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%. 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%. 59%, 60%, 61%. 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low' melting wax. cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or w ithout other excipients, is surrounded by a carrier, which is thus in association w ith it. Tablets, powders, capsules, and pills can be used as solid dosage forms suitable for oral administration.

[0231] Suitable solid excipients are carbohydrate or protein fillers including, but not limited to sugars, including lactose, sucrose, mannitol, or sorbitol; starch from com, wheat, rice, potato, or other9541827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

[0232] Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i.e., dosage). In soft capsules, the compounds disclosed herein may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers,

[0233] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0234] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from faty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame, or saccharin.Formulations can be adjusted for osmolarity.

[0235] Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0236] Oil suspensions can be formulated by suspending the compounds disclosed herein in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid9641827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol, or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. The pharmaceutical formulations can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. Hie emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.

[0237] The compounds disclosed herein can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously as biodegradable and injectable gel formulations; or, as microspheres for oral administration.

[0238] The pharmaceutical formulations of the compounds disclosed herein can be provided as a salt and can be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms. In other cases, the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0. l%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with buffer prior to use.

[0239] The pharmaceutical formulations of the compounds disclosed herein can be provided as a salt and can be formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl -ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts.

[0240] In some embodiments, the formulations of the compounds disclosed herein can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employ ing ligands atached to the liposome, or atached directly to the oligonucleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the GR modulator into the target cells in vivo.

[0241] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. Tire unit dosage form can be a packaged preparation, the package containing discrete quantities of9741827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, or tablet, or it can be the appropriate number of any of these in packaged form,

[0242] The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most typically 10 mg to 500 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

[0243] The dosage regimen also takes into consideration pharmacokinetics parameters well known in the art, i.e., the rate of absorption, bioavailability, metabolism, clearance, and the like.

[0244] Single or multiple administrations of the compounds disclosed herein formulations can be administered depending on the dosage and frequency as required and tolerated by the patient. The formulations should provide a sufficient quantity of active agent to effectively treat the disease state. Thus, in one embodiment, the pharmaceutical formulations for oral administration of the compounds disclosed herein is in a daily amount of between about 0.5 to about 30 mg per kilogram of body weight per day. In an alternative embodiment, dosages are from about 1 mg to about 20 mg per kg of body weight per patient per day are used. Lower dosages can be used, particularly when the drug is administered to an anatomically secluded site, such as the cerebral spinal fluid (CSF) space, in contrast to administration orally, into the blood stream, into a body cavity or into a lumen of an organ. Substantially higher dosages can be used in topical administration. Actual methods for preparing formulations including the compounds disclosed herein for parenteral administration are known or apparent to those skilled in the art and are described in more detail in such publications as Remington’s, supra.

[0245] The compounds described herein can be used in combination w ith one another, with other active agents known to be useful in inhibiting a Ras-mutant, or w'ith adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.

[0246] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co- administration can be accomplished by co -formulation, i.e., preparing a single pharmaceutical composition including both active agents. In some embodiments, the active agents can be formulated separately. In some embodiments, the active and / or adjunctive agents may be linked or conjugated to one another.

[0247] After a pharmaceutical composition including a compound disclosed herein has been formulated in one or more acceptable carriers, it can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of the compounds of Formula (I), such9841827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)labeling would include, e.g., instructions concerning the amount, frequency and method of administration.

[0248] In some embodiments, the compositions disclosed herein are useful for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ. The formulations for administration will commonly comprise a solution of the compositions disclosed herein dissolved in one or more pharmaceutically acceptable carriers. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectabies. These solutions are sterile and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, tonicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of the compositions in these formulations can vary' widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in anontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol.

[0249] In some embodiments, the formulations of the compositions disclosed herein can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing ligands attached to the liposome, or attached directly to the oligonucleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery' of tire compositions disclosed herein into the target cells in vivo.5. EXAMPLES

[0250] AbbreviationsACN acetonitrileAc2O acetyl acetateAcOH acetic acidBINAP (+ / −)-2,2′-bis(diphenylphosphino)-l,r-binaphthyl9941827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)BOC tert-butyloxycarbonylBoc2O di-tert-butyl dicarbonateBOP (benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate Cbz Benzyl chloroformateDABCO 1,4-diazabicyclo[2.2.2]octaneDBU 1,8-diazabicyclo[5.4.0]undec-7-eneDCE 1,2-dichloroethaneDCM di chloromethaneDIAD diisopropyl azodicarboxylateDIBAL-H diisobutylaluminium hydrideDIEA or DIPEA N, N-diisopropylethylamineDMA N. N-dimethylacetamideDMAc N, N -dimethylacetamideDMAP 4-dimethylaminopyridineDME dimethyl etherDMF N, N -dim ethylformamideDMP Dess-Martin periodinaneDMSO dimethyl sulfoxideDNP 2.4-Dinitrophenoldppf 1, 1 '-bis(diphenylphosphino)ferrocenedtbpy, dtbbpy 4,4'-di-tert-butyl-2,2'-bipyridineEA ethyl acetateee enantiomeric excessEtOAc ethyl acetateEtOH ethanolFA formic AcidHATU 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate HFIP hexafluoroisopropanolHOAc acetic acidiPrOAc isopropyl acetatei-PrOH isopropyl alcoholKF potassium fluorideKOAc potassium acetateLDA lithium di isopropylamideLiHMDS lithium bis(trimethylsilyl)amideLC / MS (LCMS) liquid chromatography / mass spectrometrymCPBA 3 -chloroperoxybenzoic acid10041827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)MeCN acetonitrileMel iodomethaneMe OH methanolMeONa sodium methoxide or sodium methanolateMOM methoxymethyl etherMTBE methyl tert-butyl etherMS molecular sievesn-Bu butan-l-ylNaBH(OAc)3sodium triacetoxyborohydrideNIS N -iodosuccinimideNMP N-methylpyrrolidoneNMR nuclear magnetic resonanceP(Cy)3or PCy3tricyclohexylphosphineP(t-Bu)3HBF4tri-tert-butylphosphonium tetrafluoroboratePd / C palladium on carbonPd2(dba)3tris(dibenzylideneacetone)dipalladium(0)Pd2(dba)3CHCl3tris(dibenzylidenacetone)dipalladium(0) chloroformPd(dppf)Cl2·CH2Cl2[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) or dichloro[1.1′-bis(diphenylphosphino)ferrocene]palladium(II), complexed with dichloromethanePd(PPh3)4tetrakis(triphenylphosphine)palladium(0)Pd(PPh3)2Cl2bis(triphenylphosphine)palladium(II) dichloridePE petroleum etherPMBCl 4-methoxybenzylchloridepTsA / ?-toluenesulfonic acidppy phenylpyridineprep-HPLC preparative high-performance liquid chromatographyprep-TLC preparative thin layer chromatographyr.t. room temperature[Rh(COD)Cl]2chloro(l,5-cyclooctadiene)rhodium(I) dimerRF retention factorsSEM 2-(trimethylsilyl)ethoxymethylSFC supercritical fluid chromatographySn2(n-Bu)6hexabutylditinTBAB tetrabutylammonium bromideTBAF tetrabutylammonium fluorideTBS tert-butyldimethylsilyl10141827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)TBSC1 tert-butyldimethylsilyl chloride or ter / -butyldimethylchlorosilanet-Bu tert-butylTEA triethylamineTFA trifluoroacetic acid or 2, 2, 2 -trifluoroacetic acidTFAA trifluoroacetic anhydrideTHF tetrahydrofuranTHP tetrahydropyranTLC thin layer chromatographyTMS tetramethylsilaneTos toluenesulfonyl groupTsOH p-toluenesulfonic acidTTMSS tris(trimethylsilyl)silaneXantPhos (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)5.1. Synthetic Procedures

[0251] The compounds contemplated herein may be prepared from commercially available reagents using the synthetic methods and reaction schemes herein, or using other reagents and conventional methods well known to those skilled in the art. For instance, compounds of the present invention may be prepared according to the general reaction schemes set forth below,5.1.1. Preparation of IntermediatesPreparation of tert-butyl (S)-(3-(5-(2,5-difluorophenyl)-3-(methyl(piperidin-4-yloxy)carbamoyl)-2-phenyl-2,3-dihydro-l,3,4-thiadiazol-2-yl)propyl)carbamate, Int 1 and tert¬ butyl (l?)-(3-(5-(2,5-difluorophenyl)-3-(methyl(piperidin-4-yloxy)carbamoyl)-2-phenyl-2,3-dihydro-l,3,4-thiadiazol-2-yl)propyl)carbamate, Int 210241827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)Int 2Step 1: Preparation of preparation of 2-trimethylsilylethyl 4-bromopiperidine-l -carboxylate

[0252] To a solution of 4-bromopiperidine (4 g, 16.3 mmol, 1 eq., HBr) in THF (20 mL) wasadded NaHCOs (4.12 g, 48.9 mmol, 1.91 mL, 3 eq.) in H2O (20 mL) and (2,5-dioxopyrrolidin-l-yl) 2-trimethylsilylethyl 4-[[(25)-2-[3-(ten‘-butoxycarbonylamino)propylJ-5-(2,5-difluorophenyl)-2 -phenyl 2-trimethylsilylethyl carbonate (4.45 g, 17.1 mmol, 1.05 eq.). The mixture was stirred at 20 °C for 3 hours. LCMS indicated the complete consumption of reactant and the formation of desired product (79.8% peak area). The mixture was poured into H2O (100 mL), extracted with EA (50 mL * 3), washed with brine (60 mL), dried over anhydrous b^SCL, and filtered. Hie filtrate was concentrated under reduced pressure to give a crude residue. The residue was then purified by column chromatography (SiO2, PE: EA = 1: 0 to 5: 1, Rf=0.31, 1 ) to afford 2-trimethylsilylethyl 4- bromopiperidine- 1 -carboxylate (6.1 g, 19.7 mmol, 96.9% yield) as a yellow oil. ‘H NMR (400 MHz,10341827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)CDCl3-d) δ = 4.43 - 4.30 (m, 1H), 4.24 - 4.12 (m, 2H), 3.79 - 3.67 (m, 2H), 3.45 - 3.31 (m, 2H), 2.16 - 1.87 (m, 4H), 1.06 - 0.94 (m, 2H), 0.05 (s, 9H).Step 2: Preparation of 2-trimethylsilylethyl 4-[tert~butoxycarbonyl-(methyl)amino]oxypiperidine-l-carboxylate

[0253] To a solution of 2-trimethylsilylethyl 4-bromopiperidine-l -carboxylate (4.52 g, 14.6 mmol, 1.2 eq.) and tert-butyl A-hydroxy-A'-methyl-carbamate (1.8 g, 12.2 mmol, 1 eq.) in DMF (20 mb) was added Cs2CO3, (5.98 g, 18.3 mmol, 1.5 eq.) at 20 °C under nitrogen. Tire mixture was stirred for 12 hours at 20 °C under nitrogen. LCMS indicated the complete consumption of reactant and the formation of desired product (26.5% peak area). The mixture was poured into H2O (60 mL), extracted with EA (50 mL * 3), washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a crude residue. The residue was then purified by column chromatography (SiO2, PE: EA = 100: 1 to 10: 1, Rf=0.20, I2) to afford 2-trimethylsilylethyl 4-[tert-butoxycarbonyl(methyl)amino]-oxypiperidine-1-carboxylate (2 g, 2.67 mmol, 21.8% yield, 50% purity) as a colorless oil. LCMS: m / z [M+H] + = 360.0. 'H NMR (400 MHz, CDCl3-d) δ = 4.21 - 4.14 (m, 2H), 4.04 - 3.95 (m, 1H), 3.91 - 3.80 (m, 2H), 3.22 - 3.17 (m, 2H), 3.10 (s, 3H), 1.94 - 1.82 (m, 2H), 1.67 - 1.61 (m, 2H), 1.50 (s, 9H), 1.04 - 0.95 (m, 2H), 0.05 (s, 9H). Step 3: Preparation of 2-trimethylsilylethyl 4-(methylaminooxy)piperidine-l-carboxylate

[0254] To a solution of 2-trimethylsilylethyl 4-[tert-butoxycarbonyl(methyl)amino] -oxypiperidine- 1-carboxylate (2.1 g, 5.61 mmol, 1 eq.) in EtOH (20 mL) was added TsOH (1.93 g, 11.2 mmol, 2 eq.) at 20 °C and stirred for 12 hours at 60 °C. LCMS indicated the complete consumption of reactant and the formation of desired product (61.6% peak area). The mixture was poured into H2O (100 mL), extracted with EA (50 mL * 3), washed with saturated NaHCOs solution (60 mL) and brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 2-trimethylsilylethyl 4-(methylaminooxy)-piperidine-l -carboxylate (260 mg, 947 pmol, 16.9% yield) as a yellow oil without purification, ’ll NMR (400 MHz, CDClj-ri) 6 = 4.23 - 4.11 (m, 2H), 3.86 - 3.72 (m, 3H), 3.19 - 3.08 (m, 2H), 2.72 (s, 3H), 1.92 - 1.81 (m, 2H), 1.58 - 1.50 (m, 2H), 1.04 - 0.96 (m, 2H), 0.07 - 0.01 (m, 9H).Step 4: Preparation of 2,5-difluorobenzodithioic acid

[0255] To a solution of 1,4-difluorobenzene (1 g, 8.76 mmol, 1 eq.) in THF (20 mL) was added sec-butyllithium (1.3 M, 6.74 mL, 1 eq.) at -78 °C dropwise under nitrogen. The mixture was stirred for 0.5 hours at -78 °C under nitrogen. Then, CS2(633 mg, 8.33 mmol, 501 μL, 0.95 eq.) was added the above mixture at -78 °C dropwise under nitrogen. The mixture was stirred for 2 hours at 25 °C under nitrogen. LCMS indicated the complete consumption of reactant and the formation of desired product. The mixture was poured into H2O (3 mL) dropwise at 25 °C, the mixture was concentrated under reduced pressure to afford 2,5-difluorobenzenecarbodithioic acid (1.67 g, 8.78 mmol, 100% yield) as brown semi -solid without purification.10441827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)Step 5: Preparation of 2, 5-difluorobenzothiohydrazide hydrochloride

[0256] To a solution of 2,5-difluorobenzenecarbodithioic acid (1.67 g, 8.78 mmol, 1 eq.) in H2O (10 mL) was added a solution of NaHCO3(737 mg, 8.78 mmol, 341 μL, 1 eq.) in H2O (3 mL) and 2-bromoacetic acid (1.59 g, 11.4 mmol, 819 jiL, 1.3 eq.) at 20 °C and stirred for 12 hours at 20 °C. LCMS indicated the complete consumption of reactant and the formation of desired product (29.7% peak area). Hie mixture was acidified to pH = 4 with 50% H2SO4, then extracted with DCM (100 mL * 3), washed with brine (60 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 2-(2,5-difluoro-benzenecarbothioyl)sulfanylacetic acid (2 g, 8.06 mmol, 91.7% yield) as a red-brown syrup without purification. To a solution of 2-(2,5-difluorobenzenecarbothioyl)sulfanylacetic acid (2 g, 8.06 mmol, 1 eq.) in NaOH (0.5 M, 16.1 mL, 1 eq.) at 0 °C dropwise and then hydrazine monohydrate (1.9 g, 37.2 mmol, 1.84 mL, 4,62 eq.) was added to the above mixture at 0 °C dropwise. The mixture was stirred for 12 hours at 20 °C. LCMS indicated the complete consumption of reactant and the formation of desired product (33.7% peak area). The mixture was diluted with H2O (50 mL) and acidified to pH = 4 with 1 M HC1, then extracted with EA (30 mL * 3), washed with brine (50 mL), dried over anhydrous Na2SC>4, and filtered. The filtrate was concentrated under reduced pressure to afford the crude product. To the crude product was added HC1 solution (2 M in dioxane, 15 mL) and stirred for 0.5 hours at 0 °C and then filtered. The filtrate was concentrated under reduced pressure to afford 2,5 -difluorobenzene¬ carbothiohydrazide (450 mg, 1.71 mmol, 21.2% yield, 85.3% purity, HC1) as a yellow solid. LCMS: m / z [M+H] + = 189.0. ’H NMR (400 MHz, DMSO-de) 5 = 7.43 - 7.14 (m, 3H).Step 6: Preparation of tert-butyl (3-(5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-l,3,4-thiadiazol-2- yl)propyl)carbamate

[0257] To a solution of 2,5 -difluorobenzenecarbothiohydrazide (428 mg, 1.63 mmol, 1 eq., HC1) and tert-butyl N-(4-oxo-4-phenyl-butyl)carbamate (427 mg, 1.63 mmol, 1 eq.) in EtOH (18 mL) was added TEA (246 mg, 2.44 mmol, 339 pL, 1.5 eq.) at 20 °C and stirred for 12 hours at 20 °C. LCMS indicated the complete consumption of reactant and the formation of desired product (69.6% peak area). Hie mixture was concentrated under reduced pressure to give a crude residue. The mixture was poured into H2O (50 ml,), extracted with EA (30 mL * 3), washed with brine (30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate w as concentrated under reduced pressure to afford a residue. The residue was purified by column chromatography (SiO2, PE: EA = 1: 0 to 2: 1, Rf= 0.35, I2) to afford tert-butyl N-[3-[5-(2,5-difluorophenyl)-2-phenyl-3H-1,3,4-thiadiazol-2-yl]propyl]carbamate (550 mg, 1.16 mmol, 71.1% yield, 91.1%purity) as brown oil. LCMS: m / z [M+H] + = 434.2. ’HNMR (400 MHz, DMSO-i / g) 5 = 8.91 (br s, 1H), 7.48 (br d, J = 7.6 Hz, 2H), 7.37 (br t, J === 7.6 Hz, 3H), 7.33 - 7.24 (m, 3H), 6.88 - 6.71 (m, 1H), 2.89 (br d, J === 5.4 Hz, 2H), 2.27 - 2.03 (m, 3H), 1.61 - 1.44 (m, 3H), 1.33 (s, 9H)Step 7: Preparation of tert-butyl (3-(5-(2,5-difluorophenyl)-3-(lH-imidazole-l-carbonyl)-2-phenyl-2, 3-dihydro-l, 3, 4-thiadiazol-2-yl)propyl)carbamate10541827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0258] To a solution of te / 7-butyl A-[3-[5-(2,5-difluorophenyl)-2-phenyl-3 / -l,3,4-thiadiazol-2-yl] propyl] carbamate (440 mg, 924 pmol, 1 eq.) and CDI (197 mg, 1.22 mmol, 1.32 eq.) in THF (9 mL) was stirred for 3 hours at 70 °C. LCMS indicated the complete consumption of reactant and the formation of desired product (93.2% peak area). The mixture was poured into 0.2 M HCl (25 mL) and DCM (35 mL), extracted with DCM (30 mL * 2), washed with brine (30 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl A-[3-[5- (2,5-difluorophenyl)-3-(imidazole-l-carbonyl)-2-phenyl-l,3,4-thiadiazol-2-yl]propyl]carbamate (487 mg, 923 pmol, 99.8% yield) as a brown oil without purification.Step 8: Preparation of l-(2-(3-((tert-butoxycarbonyl)ammo)propyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-l,3,4-thiadiazole-3-carbonyl)-3-methyl-lH-imidazol-3-ium

[0259] To a solution of tert-butyl V-[3-[5-(2,5-difluorophenyl)-3-(imidazole-l-carbonyl)-2-phenyl- l,3,4-thiadiazol-2-yl]propyl]carbamate (450 mg, 852 pmol, 1 eq.) in ACN (6 mL) was added Mel (1.21 g, 8.53 mmol, 530 pL, 10 eq.) at 20 °C and stirred for 12 hours at 50 °C. LCMS indicated the complete consumption of reactant and the formation of desired product (82.8% peak area). The reaction solution was concentrated under reduced pressure to afford l-(2-(3-((tert-butoxycarbonyl)amino)propyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-l,3,4-thiadiazole-3- carbonyl)-3-methyl-l / 7-imidazol-3-ium iodide (520 mg, 733 pmol, 85.9% yield, 94.4% purity) as a brown oil without purification. LCMS: m / z [M+HJ + = 542.3.Step 9: Preparation of 2-trimethylsilylethyl 4-[[(2S)-2-[3-(tert-butoxycarbonylamino)propyl]-5-(2,5- difluorophenyl)-2-phenyl-l,3, 4-thiadiazole-3-carbonyl]-methyl-amino]oxypiperidine-l ' -carboxylate and (2-trimethylsilylethyl 4-[[(2R)-2-[3-(tert-butoxycarbonylamino)propyl]-5-(2,5-difluorophenyl)-2-phenyl-l,3,4-thiadiazole-3-carbonyl]-methyl-amino oxypiperidine-l-carboxylate)

[0260] To a solution of tert-butyl A’-[3-[5-(2,5-difluorophenyl)-3-(3-methylimidazol-3-ium-l- carbonyl)-2-phenyl-l,3,4-thiadiazol-2-yl]propyl]carbamate;iodide (300 mg, 422 pmol, 1 eq.) and 2-trimethylsilylethyl 4-(methylaminooxy)piperidine-l -carboxylate (225 mg, 819 pmol, 1.94 eq.) in DCM (5 mL) was stirred for 1.5 hours at 20 °C. LCMS indicated the complete consumption of reactant and the formation of desired product (61.5% peak area). The mixture was poured into H2O (30 mL), extracted with DCM (20 mL * 3), washed with brine (30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a crude residue. The residue was purified by column chromatography (SiO2, PE: EA = 1: 0 to 1: 2, Rf= 0.42, UV) to afford 300 mg as a yellow oil, which was then further purified by Prep-SFC (column: (s,s) WHELK-O®1 (250 mm * 30 mm, 10 pm); mobile phase: [CO2-i-PrOH(0.1%NH3H2O)]; B%:28%, isocratic elution mode) to afford 2-trimethylsilylethyl 4-[[(25)-2-[3-(tert-butoxycarbonylamino)propyl]-5-(2,5- difluorophenyl)-2 -phenyl- 1,3,4-thiadiazole-3 -carbonyl] -methyl -amino] oxypiperidine- 1 -carboxylate as yellow oil and 2-trimethylsilylethyl 4-[[(2R)-2-[3-(tert-butoxycarbonylamino)propyl]-5-(2,5-difluorophenyl )-2 -phenyl- 1,3,4-thiadiazole-3 -carbonyl] -methyl -am ino] oxypiperidine- 1 -carboxylate as10641827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)a yellow oil. LCMS: m / z [M+H] -f- = 734.4. ’H NMR (400 MHz, CDCl3-d) 8 - 7.50 - 7.43 (m, 3H), 7.40 - 7.29 (m, 3H), 7.12 (brt, J = 5.8 Hz, 3H), 4.21 - 4.11 (m, 2H), 4.10 - 3.97 (m, 1H), 3.89 - 3.71 (m, 2H), 3.37 - 3.32 (m, 3H), 3.31 - 3.23 (m, 2H), 3.22 - 3.09 (m, 3H), 2.36 (s, 1H), 2.08 - 1.83 (m, 4H), 1.70 - 1.61 (m, 3H), 1.45 (s, 9H), 1.04 - 0.95 (m, 2H), 0.04 (s, 9H).Step 10: Preparation of tert-butyl (S)-(3-(5-(2,5-difluorophenyl)-3-(methyl(piperidin-4-yloxy)carbamoyl)-2-phenyl-2,3-dihydro-l,3, 4-thiadiazol-2-yl)propyl)carbamate

[0261] To a solution of 2-trimethylsilylethyl 4-[[(2S)-2-[3-(tert-butoxycarbonylamino)propyl]-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3-carbonyl]-methyl-amino]oxypiperidine-1-carboxylate (80 mg, 108 μmol, 1 eq.) in DMF (2 mL) was added CsF (164 mg, 1.08 mmol, 10 eq.) at 20 °C and stirred for 3 hours at 50 °C. LCMS indicated the complete consumption of reactant and the formation of desired product (93,9% peak area). The mixture was poured into H2O (20 mL), extracted with EA (20 mL * 2), washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl N-[3-[(2S)-5-(2,5-difluorophenyl)-3-[methyl(4-piperidyloxy)carbamoyl]-2-phenyl-1,3,4-thiadiazol-2-yl]propyl]carbamate (63.8 mg, 108.1 μmol, 99.9% yield) as a yellow oil without purification.Step 11: Preparation of tert-butyl (R)-(3-(5-(2,5-difluorophenyl)-3-(methyl(piperidin-4-yloxy)carbamoyl)-2-phenyl-2,3-dihydro-l,3,4-thiadiazol-2-yl)propyl)carbamate

[0262] To a solution of 2-trimethylsilylethyl 4-[[(2R)-2-[3-(tert-butoxycarbonylamino)propyl]-5- (2,5-difluorophenyl)-2-phenyl-l,3,4-thiadiazole-3-carbonyl]-methyl-amino]oxypiperidine-l-carboxylate (120 mg, 158 ul, 1 eq.) in DMF (3 mL) was added CsF (240 mg, 1.59 mmol, 10 eq.) at 20 °C and stirred for 3 hours at 50 °C. LCMS indicated the complete consumption of reactant and the formation of desired product (95.1% peak area). The mixture was poured into H2O (20 mL), extracted with EA (20 mL * 2), washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl N-[3-[(2R)-5-(2,5-difluorophenyl)-3-[methyl(4-piperidyloxy)carbamoyl]-2-phenyl-1,3,4-thiadiazol-2-yl]propyl]carbamate (93.5 mg, 158 μmol, 99.9% yield) as a yellow oil without purification.5.1.2. Preparation of exemplary compoundsExample 1. Preparation of (2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperidin-4-yI)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-l,3,4-thiadiazole-3(2H)-carboxamide, Compound 110741827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)TFA. Jg&n DCM, 20 °C, 0.5 hoursStep 1: Preparation of tert-butyl (3-((2S)-5-(2,5-difluorophenyl)-3-(((l-((l-(2-(2,6-dioxopiperidm-3-yl)-l-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)(methyl)carbamoyl)-2-phenyl-2,3-dihydro-1, 3, 4-thiadiazol-2-yl)propyl)carbamate

[0263] To a mixture of tert-butyl N-[3-[(2S)-5-(2,5-difluorophenyl)-3-[methyl(4-piperidyloxy)carbamoyl]-2-phenyl-l,3,4-thiadiazol-2-yl]propyl]carbamate (32 mg, 54.2 pmol, 1 eq.), l-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]piperidine-4-carbaldehyde (17.4 mg, 48.8 pmol, 0.9 eq.) in THF (0.5 mL), DMSO (0.5 mL) was added AcOH (3.26 mg, 54,2 pmol, 3,11 pL, 1 eq.) and stirred at 20 °C for 0.5 hours. Then NaBH(OAc)3(23.0 mg, 108 pmol, 2 eq.) was added to tire mixture and stirred at 20 °C for 12 hours. LCMS indicated the complete consumption of reactant and the formation of desired product (62.7% peak area). The mixture was poured into H2O (20 mL), extracted with EA (10 mL * 3), washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl (3-((25)-5-(2,5-difluoropheny l)-3 -((( 1 -(( 1 -(2 -(2,6-dioxopiperidin-3 -yl)- 1 -oxoisoindolin-5 -yl)piperidin-4-yl)niethyl)piperidin-4-yl)oxy)(niethyl)carbamoyl)-2-phenyl-2,3-dihydro-l,3,4-thiadiazol-2-yl)propyl)carbamate (50 mg, 53,8 pmol, 99.1%yield) as a yellow oil without purification.Step 2: Preparation of (2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(2-(2, 6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-l,3,4-thiadiazole-3(2H)-carboxamide

[0264] To a solution of tert-butyl N-[3-[(2S)-5-(2,5-difluorophenyl)-3-[[l-[[l-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-4-piperidyl]methyl]-4-piperidyl]oxy-methyl-carbamoyl]-2 -phenyl- l,3,4-thiadiazol-2-yl]propyl]carbamate (45 mg, 48.4 pmol, 1 eq.) in DCM (1 mL) was added TFA (153 mg, 1.35 mmol, 0.1 mL, 27.7 eq.) at 20 °C and stirred for 0.5 hours at 20 °C. LCMS indicated the complete consumption of reactant and the formation of desired product (66.0% peak area). The reaction solution was concentrated under reduced pressure to afford a residue. Tire residue was purified by Prep-HPLC (FA column: PHENOMENEX™ Luna C18 150 * 25 mm * 10 pm; mobile phase: [water (FA) - ACN]; gradient: 11%-41 % B over 10 min) and lyophilized to afford (2, S)-2-(3- aminopropyl)-5-(2,5-difluorophenyl)-j'V-((l-((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-A-methyl-2-phenyl-l,3,4-thiadiazole-3(2H)-carboxamide (10.7 mg, 12.0 pmol, 24.8% yield, 97,6% purity, FA). LCMS: m / z [M+H] + = 829.5. HPLC: 97.6% purity (220 nm), RT = 2.089 min. ’H NMR (400 MHz, CD3OD-a'4) 5 === 8.54 - 8.44 (m, 1H), 7.64 - 7.55 (m, 2H), 7.52 (br d, J = 7.8 Hz, 2H), 7.44 - 7.37 (m, 2H), 7.36 - 7.25 (m, 3H), 7.10 -10841827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)7.04 (m, 2H), 5.13 - 5.06 (m, 1H), 4.65 - 4.55 (m, 1H), 4.43 - 4.33 (m, 2H), 4.11 - 4.01 (m, 1H), 3.96 - 3.86 (m, 2H), 3.41 - 3.36 (m, 3H), 3.10 (br t, J = 7.6 Hz, 3H), 3.04 - 2.84 (m, 5H), 2.82 - 2.72 (m, 1H), 2.67 - 2.40 (m, 6H), 2.28 - 2.11 (m, 2H), 2.09 - 1.96 (m, 2H), 1.93 - 1.74 (m, 6H), 1.42 - 1.24 (m, 2H).Example 2: Preparation of (2R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide, Compound 2Step 1: Preparation of tert-butyl (3-((2R)-5-(2,5-difluorophenyl)-3-(((l-((l-(2-(2,6-dioxopiperidin-3- yl)-l-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)(methyl)carbamoyl)-2-phenyl-2, 3-dihydro-l,3,4-thiadiazol-2-yl)propyl)carbamate

[0265] To a mixture of tert-butyl N-[3-[(2A)-5-(2,5-difluorophenyl)-3-[methyl(4-piperidyloxy)carbamoyl]-2-phenyl-l,3,4-thiadiazol-2-yl]propyl]carbamate (44 mg, 74.6 pmol, 1 eq.),l-[2-(2,6-dioxo-3-piperidyI)-l-oxo-isoindolin-5-yl]piperidine-4-carbaidehyde (23.9 mg, 67.1 pmol, 0.9 eq.) in THF (0.5 mL), DMSO (0.5 mL) was added AcOH (4.48 mg, 74.6 pmol, 4.27 pL, 1 eq.) and stirred at 20 °C for 0.5 hours. Then NaBH(OAc)3 (31.6 mg, 149 pmol, 2 eq.) was added to the mixture and stirred at 20 °C for 12 hours. LCMS indicated the complete consumption of reactant and the formation of desired product (65.4% peak area). The mixture was poured into H2O (20 mL), extracted with EA (10 mL * 3), washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl (3-((2A)-5-(2,5- difluorophenyl)-3-(((l-((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)(methyl)carbamoyl)-2-phenyl-2,3-dihydro-l,3,4-thiadiazol-2-yl)propyl)carbamate (60 mg, 64.5 pmol, 86.5% yield) as a yellow oil without purification.Step 2: Preparation of (2R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide10941827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0266] To a solution of tert-butyl A-[3-[(2R)-5-(2,5-difluorophenyl)-3-||l-[[l-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-4-piperidyl]methyl]-4-piperidyl]oxy-methyl-carbamoyl]-2 -phenyl- l,3,4-thiadiazol-2-yl]propyl]carbamate (60 mg, 64,5 pmol, 1 eq.) in DCM (1 mb) was added TFA (153 mg, 1.35 mmol, 0.1 mL, 20.8 eq.) at 20 °C and stirred for 0.5 hours at 20 °C. LCMS indicated the complete consumption of reactant and the formation of desired product (65.2% peak area). The reaction solution was concentrated under reduced pressure to afford a residue. The residue was purified by prep-HPLC (FA column: PHENOMENEX™ Luna C18 150 * 25 mm * 10 pm; mobile phase: [water (FA) - ACN]; gradient: 11% - 41% B over 10 min) and lyophilized to afford (2R)-2-(3-aminopropyl)-5 -(2,5 -difluorophenyl)-N-(( 1 -(( 1 -(2-(2,6-dioxopiperidin-3 -y 1)- 1 -oxoisoindolin-5 - yl)piperidin -4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2 -phenyl- 1, 3, 4-thiadiazole-3(2 / / )-carboxamide (18,8 mg, 21.3 pmol, 33,0% yield, 99.3% purity, FA). LCMS: m / z [M+H] + = 829.4.HPLC: 99.3% purity (220 nm), RT = 1.873 min.1H NMR (400 MHz, CD3OD-d4) δ = 8.55 - 8.45 (m, 1H), 7.66 - 7.60 (m, 1H), 7.60 - 7.49 (m, 3H), 7.45 - 7.38 (m, 2H), 7.36 - 7.27 (m, 3H), 7.11 - 7.02 (m, 2H), 5.13 - 5.05 (m, 1H), 4.64 - 4.53 (m, 1H), 4.44 - 4.31 (m, 2H), 4.10 - 4.02 (m, 1H), 3.97 - 3.85 (m, 2H), 3.39 (s, 3H), 3.18 - 3.08 (m, 3H), 3.06 - 2.95 (m, 2H), 2.81 - 2.73 (m, 1H), 2.66 - 2.43 (m, 6H), 2.25 - 2.09 (m, 2H), 2.07 - 1.95 (m, 2H), 1.91 - 1.80 (m, 5H), 1.41 - 1.25 (m, 2H).Example 3: Preparation of (2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-((7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide, Compound 3Step 1: Preparation of tert-butyl N-[3-[(2S)-5-(2, 5-difluorophenyl)-3-[[l-[[7-[2-(2, 6-dioxo-3- piperidyl)-l-oxo-isoindolin-5-yl]-7-azaspiro[3.5]nonan-2-yl]methyl]-4-piperidylJoxy-methyl-carbamoyl]-2-phenyl-l,3,4-thiadiazol~2-yl]propyl]carbamate

[0267] To a mixture of tert-butyl N-[3-[(2S)-5-(2,5-difluorophenyl)-3-[methyl(4-piperidyloxy)carbamoyl|-2-phenyl-l,3,4-thiadiazol-2-yl]propyl|carbamate (32.00 mg, 54.27 pmol, 1 eq.), 7-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-ylJ-7-azaspiro[3.5]nonane-2-carbaldehyde (25.211041827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)mg, 54.2 pmol, 1 eq.) in THF (0.5 mL), DMSO (0.5 mL) was added AcOH (3.26 mg, 54.2 pmol, 3.11 pL, 1 eq.) and stirred at 20 °C for 0.5 hours. Then NaBH(OAc)3 (23.0 mg, 108 pmol, 2 eq.) was added to the mixture and stirred at 20 °C for 1.5 hours. LCMS indicated the complete consumption of reactant and the formation of desired product (67.0% peak area). The mixture was poured into H₂O (20 mL), extracted with EA (10 mL * 3), washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl N-[3-[(25)-5- (2,5-dif]uorophenyl)-3-[[l-[[7-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-7-azaspiro[3.5]nonan-2-yl]methyl]-4-piperidyl]oxy-methyl-carbamoyl]-2-phenyl-l,3,4-thiadiazol-2- yl]propyl]carbamate (50 mg, 51.5 pmol, 95.0% yield) as a yellow' oil without purification.Step 2: Preparation of (2S)-2-(3-aminoprop’l)-5-(2,5-difluorophenyl)-N-((l-((7-(2-(2,6-dioxopiperidin-3-yl)-l~oxoisomdolin~5-yl)-7-azaspiro[3.5]nonan~2-yl)methyl)piperidin~4-yl)oxy)-N- methyl-2-phenyl-l,3, 4-thiadiazole-3(2H)-carboxamide

[0268] To a solution of tert-butyl N-[3-| (2S)-5-(2,5-difluorophenyl)-3-[| l-[ [7-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-7-azaspiro[3.5]nonan-2-yl]methyl]-4-piperidyl]oxy-methyl-carbamoyl]-2-phenyl-l,3,4-thiadiazol-2-yl]propyl]carbamate (50 mg, 51.5 umol, 1 eq.) in DCM (1 mL) was added TFA (153 mg, 1.35 mmol, 0.1 mL, 26.0 eq.) at 20 °C and stirred for 0.5 hours at 20 °C. LCMS indicated the complete consumption of reactant and the formation of desired product (74.4% peak area). The reaction solution was concentrated under reduced pressure to afford a residue. Hie residue was purified by Prep-HPLC (FA column: PHENOMENEX™ Luna C18 150 * 25 mm * 10 pm; mobile phase: [w'ater (FA)-ACNJ; gradient: 13%-43% B over 10 min) and lyophilized to afford (2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((7-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-7-azaspiro|3.5]nonan-2-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-l,3,4-thiadiazole-3(2H)-carboxamide (7.25 mg, 7.4 pmol, 14.3% yield, 93.5% purity, FA salt). LCMS: m / z [M+H] + = 869.5. HPLC: 93.5% purity (220 nm), RT = 2.134 min. ’H NMR (400 MHz, CD₃OD-d₄) 8 = 8.50 - 8.46 (m, 2H), 7.64 - 7.54 (m, 2H), 7.50 (d, J = 7.6 Hz, 2H), 7.44 - 7.38 (m, 2H), 7.36 - 7.28 (m, 3H), 7.10 - 7.04 (m, 2H), 5.13 - 5.05 (m, 1H), 4.69 - 4.53 (m, 2H), 4.44 - 4.30 (m, 2H), 4.21 - 4.07 (m, 1H), 3.42 (s, 3H), 3.37 - 3.33 (m, 3H), 3.28 - 3.23 (m, 2H), 3.21 - 3.07 (m, 5H), 3.03 - 2.97 (m, 2H), 2.95 - 2.84 (m, 2H), 2.81 - 2.73 (m, 1H), 2.71 - 2.59 (m, 2H), 2.52 - 2.40 (m, 1H), 2.25 - 2.07 (m, 5H), 2.03 - 1.89 (m, 3H), 1.82 - 1.75 (m, 3H), 1.68 - 1.54 (m, 4H).Example 4: Preparation of (2R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((7-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-l,3,4-thiadiazole-3(2H)-carboxamide, Compound 411141827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)Step 1: Preparation of tert-butyl (3-((2R)-5-(2,5-difluorophenyl)-3-(((l-((7-(2-(2,6-dioxopiperidm-3- yl)-l-oxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2-yl)methyl)piperidin-4-yl)oxy)(methyl)carbamoyl)-2-phenyl-2, 3-dihydro-l, 3, 4-thiadiazol-2-yl)propyl)carbamate

[0269] To a mixture of tert-butyl N-[3-[(2R)-5-(2,5-difluorophenyl)-3-[methyl(4- piperidyloxy)carbamoyl]-2-phenyl-l,3,4-thiadiazol-2-yl]propyl]carbamate (44 mg, 74.61 umol, 1 eq.), 7-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-7-azaspiro[3.5]nonane-2-carbaldehyde (34.7 mg, 74.6 pmol, 1 eq.) in THF (1 mL), DMSO (1 mL) was added AcOH (4.48 mg, 74.6 pmol, 4.27 pL, 1 eq.) and stirred at 20 °C for 0.5 hour. Then NaBH(OAc)3 (31.6 mg, 149 pmol, 2 eq.) was added to the mixture and stirred at 20 °C for 1.5 hours. LCMS indicated the complete consumption of reactant and the formation of desired product (69.4% peak area). The mixture was poured into H₂O (20 mL), extracted with EA (10 mL * 3), washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl N-[3-[(2R)-5- (2,5-difluorophenyl)-3-[[l-[[7-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]-7- azaspiro[3.5]nonan-2-yl]methyl]-4-piperidyl]oxy-methyl-carbamoyl]-2-phenyl-l,3,4-thiadiazol-2- yl]propyl]carbamate (70 mg, 72.2 pmol, 96.8% yield) as yellow oil without purification.Step 2: Preparation of (2R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-((7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide

[0270] To a solution of tert-butyl N-[3-[(2R)-5-(2,5-difluorophenyl)-3-[[1-[[7-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-7-azaspiro[3.5]nonan-2-yl]methyl]-4-piperidyl]oxy-methyl-carbamoyl]-2-phenyl-1,3,4-thiadiazol-2-yl]propyl]carbamate (70 mg, 72.2 pmol, 1 eq.) in DCM (1 mL) was added TFA (153 mg, 1.35 mmol, 0.1 mL, 18.6 eq.) at 20 °C and stirred for 0.5 hour at 20 °C. LCMS indicated the complete consumption of reactant and the formation of desired product (64,2% peak area). The reaction solution was concentrated under reduced pressure to afford a residue. Tire residue was purified by Prep-HPLC (FA column: PHENOMENEXTMLuna C18 150 * 25 mm * 1011241827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)pm; mobile phase: [water (FA) - ACN]; gradient: 13% - 43% B over 10 min) and lyophilized to afford (2?)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-[[l-[[7-[2-(2,6-dioxo-3-piperidyl)-l-oxo- isoindolin-5-yl]-7-azaspiro[3.5]nonan-2-yl]methyl]-4-piperidyl]oxy]-N-methyl-2-phenyl-l,3,4-thiadiazole-3-carboxamide (17,5 mg, 17.1 pmol, 23.8% yield, 94.4% purity, FA salt). LCMS: m / z [M+H] + = 869.5. HPLC: 94.4% purity (220 nm), RT = 2.135 min. ’H NMR (400 MHz, CD3OD-d4) 8 = 8.55 - 8.49 (m, 1H), 7.63 - 7.53 (m, 2H), 7.50 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.35 - 7.27 (m, 3H), 7.08 - 7.03 (m, 2H), 5.12 - 5.05 (m, 2H), 4.60 - 4.54 (m, 1H), 4.44 - 4.30 (m, 2H), 4.13 - 4.01 (m, 1H), 3.39 (s, 3H), 3.36 - 3.32 (m, 2H), 3.27 - 3.22 (m, 2H), 3.17 - 3.05 (m, 4H), 2.95 - 2.87 (m, 1H), 2.87 - 2.81 (m, 2H), 2.80 - 2.70 (m, 2H), 2.66 - 2.58 (m, 2H), 2.50 - 2.35 (m, 1H), 2.23 - 2.07 (m, 4H), 2.01 - 1.85 (m, 3H), 1.80 - 1.75 (m, 3H), 1.66 - 1.54 (m, 4H).Example 5: Preparation of (2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-HI-indazoI-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-l,3,4-thiadiazole-3(2H)-carboxamide, Compound 5Xphos Pd G2, Cs2CO3dioxane, 100 °C, 3 hoursFA25 °C, 10 minutesNaBH(OAc)3, AcOH, DMSO / THF, 20 °C, 13 h11341827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)HCI / dioxane.... H2N DOM, 20 °C, 0.5 h S,(s) jStep 1: Preparation of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-l-methyl-lH-indazole

[0271] To a solution of 6-bromo-3-iodo-l-methyl-lH-indazole (10.0 g, 29.7 mmol, 1 eq) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) pyridine (12,4 g, 29.7 mmol, 1 eq) in dioxane (200 mL) and H2O (20 mL) was added Cs2CO3(29.0 g, 89.0 mmol, 3 eq) and Pd(dppf)Cl2»CH2Cl2(2.42 g, 2.97 mmol, 0.1 eq) at 20 °C under N2atmosphere. The mixture was stirred at 100 °C under N2atmosphere for 6 hours. LCMS indicated complete consumption of the starting material and formation of the product with desired mass (59,2% peak area). The reaction solution was poured into water (200 mL), then extracted by EA (200 mL * 3). The organic layers were combined and washed by brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO₂, PE:EA = 1:0 to 5:1, Rf = 0.43) to afford 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-l-methyl- IH-indazole (10.3 g, 16.0 mmol, 54.0% yield, 77.7% purity) as a yellow solid, LCMS: m / z [M+H]+= 502.0; ’HNMR (400 MHz, DMSO-6) 5 = 7.96 (d, J = 1.0 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.62 (d, J === 8.6 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.43 - 7.26 (m, 8H), 7.15 - 7.08 (m, 1H), 6.59 (d, J = 8.1 Hz, 1H), 5.44 (d, J = 8.1 Hz, 4H), 4.05 (s, 3H).Step 2: Preparation of 3-(2,6-bis(benzyloxy)pyridin~3-yl)-6-(4~(dimethoxymethyl)piperidin-l-yl)-l- methyl-1 H -indazole

[0272] To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-l-methyl-lH-indazole (3.00 g, 6.00 mmol, 1 eq) and 4-(dimethoxymethyl)piperidine (1.91 g, 12.0 mmol, 2 eq) in dioxane (60 mL) was added Cs2CO3(5.86 g, 18,0 mmol, 3 eq) and Xphos Pd G2(472 mg, 600 pmol, 0,1 eq). The resulting mixture was stirred at 100 °C for 3 hours under N? atmosphere. The reaction solution was poured into water (50 mL) and then extracted by EA (50 mL * 3). The combined organic layers were washed by brine (50 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. Tire residue was purified by silica column (PE: EA = 10: 1 to 1:1, Rf = 0,2) and concentrated under reduced pressure to afford 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(4-(dimethoxymethyl)piperidin-l-yl)-l -methyl- IH-indazoIe (2.50 g, 4.26 mmol, 71.1% yield, 98.6% purity) as a light yellow solid. LCMS: m / z [M+H] ’ === 579.3.Step 3: Preparation of 3-(6-(4-(dimethoxymethyl)piperidin-l-yl)-l-methyl-lH-indazol-3- yl)piperidine-2, 6-dione11441827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0273] To a mixture of dry Pd / C (500 mg, 10% purity) and Pd(OH)z (500 mg, 20% purity) in THF (20 mL) was added 3-(2,6-dibenzyloxy-3-pyridyl)-6-[4-(dimethoxymethyl)-l-piperidyl]-l-methyl-indazole (1,30 g, 2.25 mmol, 1 eq) under Nz atmosphere. The mixture was stirred at 40 °C for 12 hours under H₂ (50 Psi). LCMS indicated full consumption of the starting material and formation of the product with desired mass (82.6% peak area). The reaction mixture was filtered and concentrated under reduced pressure to afford 3-(6-(4-(dimethoxymethyl)piperidin-l-yl)-l-methyl-lH-indazol-3-yl)piperidine-2, 6-dione (890 mg, 2.22 mmol, 98.9% yield) as a white solid. LCMS: m / z [M+H]+= 401.2.Step 4: Preparation of 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carbaldehyde

[0274] A solution of 3-(6-(4-(dimethoxymethyl)piperidin - 1 -yl)- 1 -methyl- 1 H-indazol-3-yl)piperidine-2, 6-dione (105 mg, 262 jimol, 1 eq) in HCOOH (1 mL) was stirred at 20 °C for 10 minutes. LCMS indicated full consumption of the starting material and formation of the product with desired mass (93.0% peak area). The reaction solution was concentrated under reduced pressure to afford 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carbaldehyde (93,0 mg, crude) as a colorless oil. LCMS: m / z [M+H] = 355.2.Step 5: Preparation of tert-butyl (3-((2S)-5-(2,5-difluorophenyl)-3-(((l-((l-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)(methyl)carbamoyl)-2-phenyl-2, 3-dihydro-l, 3, 4-thiadiazol-2-yl)propyl)carbamate

[0275] To a solution of l-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yI)piperidine-4-carbaldehyde (93.0 mg, 262 pmol, 1 eq) and tert-butyl (S)-(3-(5-(2,5-difluorophenyl)-3-(methyl(piperidin-4-yloxy)carbamoyl)-2-phenyl-2, 3-dihydro-l, 3, 4-thiadiazol-2-yl)propyl)carbamate (155 mg, 262 pmol, 1 eq) in DMSO (1 mL) and THF (1 mL) was added AcOH (15.8 mg, 262 pmol, 1 eq), and the mixture was stirred at 20 °C for 1 hour. Then NaBH(OAc)₃, (139 mg, 656, pmol, 2.5 eq) was added and the reaction mixture was stirred at 20 °C for another 12 hours. LCMS indicated full consumption of the starting material and formation of the product with desired mass (75.6% peak area). The reaction solution was poured into water (20 mL) and then extracted by EA (20 mL * 4). Then combined organic layers was washed by brine (50 mL) and dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford tert-butyl (3-((2S)-5-(2,5-difluorophenyl)- 3 -((( 1 -(( 1 -(3 -(2,6-dioxopiperidin-3 -yl)- 1 -methy 1- lH-indazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)(methyl)carbamoyl)-2-phenyl-2, 3-dihydro-l, 3, 4-thiadiazol-2-yl)propyl)carbamate (240 mg, 259 pmol, 98.5% yield) as a yellow solid, LCMS: m / z [M+H]+= 928.5.Step 6: Preparation of (2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(3-(2, 6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide11541827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0276] To a solution of tert-butyl (3-((2S)-5-(2,5-difluorophenyl)-3-(((l-((l-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)(methyl)carbamoyl)-2- phenyl-2,3-dihydro-l,3,4-thiadiazol-2-yl)propyl)carbamate (220 mg, 237 pmol, 1 eq) in DCM (4 mL) was added HC1 solution (2 M in dioxane, 2 mL, 16.9 eq), and the resulting mixture was stirred at 20 °C for 0.5 hours. LCMS indicated full consumption of the starting material and formation of the product with desired mass (80.6% peak area). The reaction solution was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (FA): column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [H₂O (0.225% FA)-ACN]; gradient: 11%-41%B over 10.0 min and lyophilized to afford (2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(3-(2,6-dioxopiperidin-3 -yl)- 1 -methyl- lH-indazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N -methyl-2-phenyl- 1,3,4- thiadiazole-3(2H)-carboxamide (43.8 mg, 52,4 pmol, 22.1% yield, 99.0% purity) as a white solid.LCMS: m / z [M+H]+= 828.4; HPLC: 99.0% purity (220 nm), RT = 1.68 minutes; ‘HNMR (400 MHz, DMSO-6 / e) 6 11.51 - 10.17 (m, 1H), 8.36 (br s, 2H), 7.58 (brt, J == 7.1 Hz, 1H), 7.50 - 7.43 (m, 5H), 7.43 - 7.38 (m, 2H), 7.33 (br d, J = 7.0 Hz, 1H), 6.89 (br d, J = 9.0 Hz, 1H), 6.81 (s, 1H), 4.32 - 4.17 (m, 1H), 3.98 - 3.90 (m, 1H), 3.88 (s, 3H), 3.76 (br d, J = 11.8 Hz, 2H), 3.22 (s, 3H), 2.98 -2.82 (m, 3H), 2.77 - 2.52 (m, 7H), 2.33 - 2.25 (m, 1H), 2.20 - 2.09 (m, 3H), 2.02 (br d, J = 8.6 Hz, 3H), 1.91 - 1.89 (m, 1H), 1.78 (br d, J = 13.9 Hz, 4H), 1.52 (brd, J = 8.1 Hz, 5H), 1.29 - 1.14 (m, 2H). Example 6: Preparation of (S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((1-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methylphenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide, Compound 7711641827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)HOAc, NaBH(OAc)3, THF, DMSO, 0-20 °C, 1.5 hStep 1: Preparation of 3,3'-((3-bromo-2-methylphenyl)azanediyl)dipropionic acid— methane (1 / 1)

[0277] A mixture of 3 -bromo-2 -methyl -aniline (5 g, 26.9 mmol, 3.31 mL, 1 eq) and acrylic acid (5.26 g, 72.9 mmol, 5 mL, 2.71 eq) was heated to 110 °C and then stirred at this temperature for an hour. LCMS indicated complete consumption of 3 -bromo-2 -methyl-aniline and formation of the desired product (98.2% peak area). The crude reaction mixture was used in the next step directly.LCMS: m / z [M+H]+= 331.9.Step 2: Preparation of 1 ~(3-bromo-2-methylphenyl)dihydropyrimidme-2, 4(1H,3H) -dione

[0278] To a solution of 3-[3-bromo-N-(2-carboxyethyl)-2-methyl-anilino]propanoic acid (8.87 g, 26.9 mmol, 1 eq) in HOAc (45 mL) was added urea (2.42 g, 40.3 mmol, 2.17 mL, 1.5 eq). The mixture was stirred at 120 °C for 12 hours. LCMS indicated complete consumption of 3-[3-bromo-N-(2-carboxyethyl)-2-methyl-anilino]propanoic acid and formation of the desired product (74% peak area). The reaction was quenched with water (120 mL) and the resulting suspension was filtered. The filter cake was recrystallized with ACN (30 mL) and dried under reduced pressure to afford l-(3- bromo-2-methyl-phenyl)hexahydropyrimidine-2, 4-dione (4 g, 13.5 mmol, 50.3% yield, 95.6% purity) as a brown solid. LCMS: m / z [M+H]+= 284.9;!H NMR (400 MHz, DMSO-6) 5 = 10.42 (s, 1H), 7.59 (dd, J = 0.8, 8.0 Hz, 1H), 7.39 - 7.29 (m, 1H), 7.26 - 7.16 (m, 1H), 3.79 (ddd, J = 5.2, 10.0, 12.4 Hz, 1H), 3.52 (td, J = 6.0, 12.0 Hz, 1H), 2.87 - 2.74 (m, 1H), 2.73 - 2.62 (m, 1H), 2.24 (s, 3H).Step 3: Preparation of l-(3-(4-(dimethoxymethyl)piperidin-l-yl)-2-methylphenyl)dihydropyrimidine- 2,4(lH,3H)-dione11741827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0279] A mixture of l-(3-bromo-2-methyl-phenyl)hexahydropyrimidine-2, 4-dione (500 mg, 1.77 mmol, 1 eq), 4-(dimetlioxyniethyl)piperidine (562 mg, 3.53 mmol, 2 eq), [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(2-methylpyridin-1-ium-1-yl)palladium (148 mg, 177 pmol, 0.1 eq) and CS2CO3 (1.73 g, 5.30 mmol, 3 eq) in dioxane (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 3 hours under N2 atmosphere. LCMS indicated complete consumption of l-(3-bromo-2-methyl-phenyl)hexahydropyrimidine-2, 4-dione and formation of the desired product (59% peak area). Tire reaction mixture was quenched with 10% IIOAc (2 mL) at 0 °C, and then diluted with water (20 mL) and extracted with EtOAc (20 mL * 2). The combined organic layers were washed with brine (20 mL * 2) and dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The erode product was purified by reversed-phase HPLC (0.1% FA condition) and lyophilized to afford 1 -[3-[4-(dimethoxymethyl)-l-piperidyI]-2-methyI-phenyI]hexahydropyrimidine- 2, 4-dione (330 mg, 876 pmol, 49.6% yield, 96% purity) as a white solid. LCMS: m / z [M+H]+= 362.2; ’H NMR (400 MHz, DMSO- «) 5 = 10.31 (s, 1H), 7.24 - 7.12 (m, 1H), 6.96 (dd, J = 7.6, 14.0 Hz, 2H), 4.13 (d, J = 6.4 Hz, 1H), 3.73 (ddd, J = 5.6, 9.6, 12.4 Hz, 1H), 3.49 (dd, J = 6.0, 12.4 Hz, 2H), 3.28 (s, 6H), 3.03 (d, J = 11.2 Hz, 2H), 2.80 - 2.58 (m, 3H), 2.08 (s, 3H), 1.81 - 1.62 (m, 3H), 1.48 - 1.33 (m, 2H).Step 4: Preparation of l-(3-(2, 4-dioxotetrahydropyrimidin-l (2H)-yl)-2-methylphenyl)piperidine-4-carbaldehyde

[0280] A solution of l-[3-[4-(dimethoxymethyl)-l-piperidyl]-2-methyl-phenyl]hexahydropyrimidine-2,4-dione (100 mg, 277 pmol, 1 eq) in HCOOH (2 mL) was stirred at 25 °C for 2 hours. LCMS indicated complete consumption of l-[3-[4-(dimethoxymethyl)-l-piperidyl]-2-methyl-phenyl]hexahydropyrimidine-2, 4-dione and formation of the desired product (94.8% peak area). The reaction mixture was concentrated under reduced pressure to afford 1 -[3-(2,4-dioxohexahydropyrimidin-l-yl)-2 -methyl -phenyl]piperidine-4-carbaIdehyde (99 mg, crude, FA) as a brown solid. LCMS: m / z [M+H]+= 316.2.Step 5: Preparation of tert-butyl (S)-(3-(5-(2,5-difluorophenyl)-3-(((l-((l-(3-(2,4- dioxotetrahydropyrimidin-1 (2H)-yl)-2~methylphenyl)piperidin-4-yl)methyl)piperidin-4- yl)oxy)(methyl)carbamoyl)-2-phenyl-2,3-dihydro-l,3,4-thiadiazol-2-yl)propyl)carbamate

[0281] To a solution of l-|3-(2,4-dioxohexahydropyrimidin-l-yl)-2-methyl-phenyl]piperidine-4-carbaldehyde (99 mg, 258 pmol, 1 eq) and tert-butyl N-[3-[(2S)-5-(2,5-difluorophenyl)-3-[methyl(4-piperidyloxy)carbamoyl]-2-phenyl-l,3,4-thiadiazol-2-yl]propyl]carbamate (152 mg, 258 pmol, 1 eq) in THF (1 mL) and DMSO (1 mL) was added HOAc (15.5 mg, 258 pmol, 14.7 pL, 1 eq), and the mixture was stirred at 20 °C for 30 minutes. The reaction mixture was added with NaBH(OAc)s (136 mg, 644 pmol, 2.5 eq) at 0 °C, and then stirred at 20 °C for 1 hour. LCMS indicated complete consumption of l-[3-(2,4-dioxohexahydropyrimidin-l-yl)-2-methyl-phenyl]piperidine-4-carbaldehyde11841827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)arid formation of the desired product (78.4% peak area). The reaction mixture was quenched by the addition of H2O (2 mL) at 0 °C, and then diluted w ith water (10 mL) and extracted with EtOAc (10 mL * 2), The combined organic layers were washed with brine (10 mL * 2) and dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford tert-butyl N-[3-[(2S)-5-(2,5-difluorophenyl)-3-[[ l-[[l-|3-(2,4-dioxohexahydropyrimidin-l-yl)-2-methyl-phenyl]-4-piperidyl jmethyl] -4-piperidyl]oxy-methyl -carbamoyl] -2 -phenyl- 1,3,4-thiadiazol-2- yl] propyl] carbamate (200 mg, 202 gmol, 78,6% yield, 90% purity) as a brown solid, LCMS: m / z [M+H] ’ = 889.4.Step 6: Preparation of (S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2-methylphenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N- methyl-2-phenyl~l,3,4-thiadiazole-3(2H)-carboxamide

[0282] To a solution of tert-butyl N-[3-[(2S)-5-(2,5-difluorophenyl)-3-[[l-[[l-[3-(2,4-dioxohexahydropyrimidin- 1 -yl)-2 -methyl -phenyl]-4-piperidyl]methyl] -4-piperidyl]oxy-methyl-carbanioyl]-2-phenyl-l,3,4-thiadiazol-2-yl]propyl]carbamate (100 mg, 101 pmol, 1 eq) in DCM (l mL) was added HC1 solution (2 M in dioxane, 900 gL, 17,8 eq). The mixture was stirred at 25 °C for 30 minutes. LCMS indicated complete consumption of tert-butyl N-[3-[(2S)-5-(2,5-difluorophenyl)-3-[[!-[[ 1 -[3-(2,4-dioxohexahydropyrimidin- 1 -yl)-2-methyl-phenyl] -4-piperidyl]methyl] -4-piperidyl] oxy-methyl -carbamoyl] -2 -phenyl- 1, 3, 4-thiadiazol-2-yl]propyl]carbamate and formation of the desired product (89.6% peak area). Hie reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna Cl 8 150 * 25 mm * 10 um; mobile phase: [H₂O (0.225% FA) - ACN]; gradient: 15% - 35% B over 10.0 min) and lyophilized to afford (2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-[| l-[ [ l-[3-(2,4-dioxohexahydropyrimidin- 1 -yl)-2 -methyl -phenyl] -4-piperidyl]methyl] -4-piperidyl]oxy] -N -methyl -2- phenyl-1, 3, 4-thiadiazole-3 -carboxamide (37,93 mg, 43.29 gmol, 42.77% yield, 95,3% purity, FA) as an off-white solid. LCMS: m / z [M+H]+= 789.4; HPLC: 95.3% purity (220 nm), RT = 1.817 minutes;1H NMR (400 MHz, DMSO-d6) 8 - 10.50 - 10.14 (m, 1H), 8.34 (s, 1H), 7.62 - 7.54 (m, 1H), 7.50 - 7.37 (m, 6H), 7.35 - 7.29 (m, 1H), 7.21 - 7.14 (m, 1H), 6.96 (dd, J = 8.0, 15.2 Hz, 2H), 3.99 - 3.86 (m, 2H), 3.73 (ddd, J = 5.6, 9.6, 12.4 Hz, 2H), 3.49 (td, J = 6.0, 12.4 Hz, 1H), 3.24 - 3.18 (m, 3H), 3.01 (d, J = 11.2 Hz, 2H), 2.89 (t, J = 7.2 Hz, 3H), 2.80 - 2.56 (m, 7H), 2.16 (d, J = 6.8 Hz, 2H), 2.08 (s, 3H), 2.02 (d, J = 11.2 Hz, 3H), 1.78 (d, J = 13.6 Hz, 4H), 1.63 - 1.47 (m, 4H), 1.30 - 1.16 (m, 2H).Example 7: Preparation of (S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-(((lr,4S)-4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-7-oxo-l,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yI)oxy)-N-methyl-2-phenyl-l,3,4-thiadiazoIe-3(2H)-carboxamide, Compound 8211941827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)oStep 1: Preparation of l-(6-((lr,4r)-4-(hydroxymethyl)cyclohexyl)-l-methyl-7-oxo-6, 7-dihydro-IH- pyrazolo[3, 4-c]pyridin-3-yl)-3-( 4-methoxybenzyl)dihydropyrimidine-2, 4(1H, 3H)-dione

[0283] To a solution of 6-((lr,4r)-4-(hydroxymethyl)cyclohexyl)-3-iodo-l-methyl-l,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (1.5 g, 3.87 mmol, 1 eq) and 6-((lr,4r)-4-(hydroxymethyl)cyclohexyl)- 3-iodo-l-methyl-l,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (998 mg, 4.26 mmol, 1.1 eq) in12041827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)DMSO (16 mL) was added Cui (738 mg, 3.87 mmol, 1 eq), 1,10-phenanthroline (698 mg, 3.87 mmol, 1 eq) and K3PO4(2.47 g, 11.6 mmol, 3 eq) at 20 °C under N2 atmosphere. Hie resulting mixture was stirred at 100 °C for 3 hours. LCMS indicated complete consumption of reactant and formation of the desired product (33.1% peak area). Tire mixture was quenched with ice H2O (200 mL) and extracted with ethyl acetate / ACN / THF===5 / l / l (200 mL * 3). The combined organic phase was washed with brine (50 mL * 3) and dried over anhydrous sodium sulfate, filtered and concentrated to afford l-(6-((lr,4r)-4-(hydroxymethyl)cyclohexyl)-l-methyl-7-oxo-6,7-dihydro-lH-pyrazolo[3,4-c]pyridin-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (1.95 g, 3.16 mmol, 81.6% yield, 80% purity) as a yellow' solid. LCMS: m / z [M+H]+= 494.3;;H NMR (400 MHz, DMSO, 298 K) 8 (ppm) = 7.24 (dd, J= 8.0, 17.2 Hz, 3H), 6.86 (d, J= 8.8 Hz, 2H), 6.44 - 6.37 (m, 1H), 4.82 (s, 2H), 4.77 - 4.70 (m, 1H), 4.52 (t, J= 5.2 Hz, 1H), 4.21 (s, 3H), 3.87 (br t, J= 6.8 Hz, 2H), 3.73 - 3.71 (m, 3H), 3.48 (br dd, J= 0.8, 4.0 Hz, 2H), 3.29 - 3.23 (m, 1H), 2.95 - 2.87 (m, 1H), 1.92 - 1.82 (m, 2H), 1.76 - 1.66 (m, 4H), 1.50 - 1.39 (m, 1H), 1.13 - 1.04 (m, 2H).Step 2: Preparation of l-(6-((lr,4r)-4-(hydroxymethyl)cy’clohexyl)-l-methyl-7-oxo-6, 7-dihydro-lH- pyrazolo[3, 4-c]pyridin-3-yl)dihydropyrimidine-2, 4(1H, 3H)-dione

[0284] A solution of l-(6-((lr,4r)-4-(hydroxymethyl)cyclohexyl)-l-methyl-7-oxo-6,7-dihydro-lH-pyrazolo[3,4-c]pyridin-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (1.85 g, 3.75 mmol, 1 eq) in TfOH (31.4 g, 209 mmol, 18.5 mL, 55.8 eq) was stirred at 40 °C for 3 hours. LCMS indicated complete consumption of reactant and formation of the desired product (55.7% peak area). Tire reaction mixture was diluted with DCM (100 mL) and quenched with ice H2O (300 mL) at 0 °C. Then the pH of the mixture as adjusted to 6-7 with saturated aqueous NaHCOs solution. Then the mixture was extracted with DCM (300 mL * 3). The combined organic phase was washed with brine (50 mL *3) and dried over anhydrous sodium sulfate, filtered and concentrated to give a residue, which was further triturated with MTBE (10 mL), Then the suspension was filtered and the filter cake was dried under reduced pressure to afford l-(6-((lr,4r)-4-(hydroxymethyl)cyclohexyl)-l-methyl-7-oxo-6, 7-dihydro-lH-pyrazolo[3,4-c]pyridin-3-yl)dihydropyrimidine-2,4( lH,3H)-dione (850 mg, 1.87 mmol, 49.8% yield, 82% purity) as a brown solid. LCMS: m / z [M+H]+= 374.1.Step 3: Preparation of (lr,4r)-4-(3-(2,4-dioxotetrahydropyrimidin-l (2H)-yl)-l-methyl-7-oxo-l, 7- dihydro-6H-pyrazolo[3, 4-c]pyridin-6-yl)cyclohexane-l-carbaldehyde

[0285] To a solution of l-(6-((lr,4r)-4-(hydroxymethyl)cyclohexyl)-l-methyl-7-oxo-6,7-dihydro-lH-pyrazolo[3,4-c]pyridin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (400 mg, 878 pmol, 1 eq) in DCM (4 mL) was added DMP (559 mg, 1,32 mmol, 408 pL, 1.5 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 1 hour. LCMS indicated complete consumption of the reactant and formation of the desired product (75.7% peak area). The reaction mixture was quenched with saturated aqueous Na2SO3solution (8 mL) and extracted with EA / ACN=10:1 (2 mL*3). The organic phase was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by reverse-phase flash [0.1% NH4HCO3] and lyophilized to afford ( lr,4r)-4-(3-(2,4- 12141827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl-7 -oxo- 1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexane-l-carbaldehyde (80 mg, 202 pmol, 23.0% yield, 93.9% purity) as a white solid. LCMS: m / z [M+H]+= 372.2.Step 4: Preparation of tert-butyl (3-((S)-5-(2,5-difluorophenyl)-3-(((1-(((1r,4S)-4-(3-(2,4- dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-7-oxo-l, 7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)(methyl)carbamoyl)-2-phenyl-2,3-dihydro-l,3, 4-thiadiazol-2- yl)propyl)carbamate

[0286] To a solution of (lr,4r)-4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-7-oxo-l,7- dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexane-l-carbaldehyde (20.5 mg, 55.3 pmol, 1.5 eq) and tert-butyl (S)-(3 -(5 -(2,5 -difluorophenyl)-3 -(methyl(piperidin-4-yloxy)carbamoyl)-2-phenyl-2,3 - dihydro-1, 3, 4-thiadiazol-2-yl)propyl)carbamate (34 mg, 36.8 pmol, 1 eq) in DMSO (1 ml.) was added HO Ac (2.21 mg, 36.8 pmol, 2.11 pL, 1 eq). Tire mixture was stirred at 20 °C for 0.5 hours. Then NaBH(OAc)3 (19.5 mg, 92.1 pmol, 2.5 eq) was added to the reaction mixture at 0 °C and the resulting mixture was stirred at 20 °C for another 10 hours. LCMS indicated partial consumption of the starting material (9.8% peak area) and formation of the desired product (49,5% peak area). Tire reaction mixture was quenched by water (0.1 mL) and directly purified by Prep-HPLC [column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 27%-57% B over 10.0 min] and lyophilized to afford tert-butyl (3-((S)-5-(2,5-difluorophenyl)-3-(((1-(((1r,4S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)(methyl)carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)carbamate (30 mg, 30.6 pmol, 83.1% yield, 96.4% purity) as a white solid. LCMS: m / z [M+H]+= 945.6.Step 5: Preparation of (S)-2-(3-aminopropyl)-5-(2, 5-difluorophenyl)-N-( (l-(( (1 r, 4S)-4-(3-(2, 4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-7-oxo-1, 7-dihydro-6H-pyrazolo[3,4-c]pyridin-6- yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3, 4-thiadiazole-3(2H)-carboxamide

[0287] A solution of tert-butyl (3-((S)-5-(2,5-difluorophenyl)-3-(((l-(((lr,4S)-4-(3-(2,4-dioxotetrahydropyrimidin- 1 (2H) -yl) - 1 -methyl-7 -oxo- 1, 7 -dihydro-6H-pyrazolo [3,4 -c Jpyridin-6- yl)cyclohexyl)methyl)piperidin-4-yl)oxy)(methyl)carbamoyl)-2-phenyl-2,3-dihydro-l,3,4-thiadiazol-2-yl)propyl)carbamate (26 mg, 27.5 pmol, 1 eq) in DCM (0.5 mL) was added HC1 solution (2 M in dioxane, 1 mL, 72.7 eq) at 30 °C. The mixture was stirred at 30 °C for 1 hour. LCMS indicated complete consumption of the reactant and formation of the desired product (96.1% peak area). The mixture was concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC [column: Phenomenex Luna C18 150*25mm* lOum; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 12%-42% B over 10.0 min] and lyophilized to afford (S)-2-(3-aminopropyl)-5-(2,5-difluoropheny l)-N-(( 1 -((( 1 r,4S)-4-(3 -(2,4-dioxotetrahydropyrimidin- 1 (2H)-y 1)- 1 -methyl-7 -oxo- 1,7- dihydro-6H-pyrazolo[3,4-cJpyridin-6-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-ty-methyl-2 -phenyl- l,3,4-thiadiazole-3(2H)-carboxamide (5.31 mg, 6,11 pmol, 22.2% yield, 97.2% purity) as a white 12241827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)solid. LCMS: m / z [M+H]+= 845.4; HPLC: 97.2% purity (220 nm), RT = 1.838 minutes; ’HNMR (400 MHz, DMSO-6) 8 (ppm) = 8.38 (s, 1H), 7.62 - 7.53 (m, 1H), 7.46 (br d, J = 7.2 Hz, 6H), 7.36 - 7.28 (m, 1H), 7.27 - 7.21 (m, 1H), 6.46 (d, J= 7.6 Hz, 1H), 4.84 - 4.69 (m, 1H), 4.22 (s, 3H), 3.98 - 3.90 (m, 1H), 3.90 - 3.84 (m, 2H), 3.21 (s, 3H), 2.95 - 2.79 (m, 4H), 2.73 (s, 2H), 2.67 (br s, 3H), 2.10 (br d, J = 6.0 Hz, 2H), 2.04 - 1.97 (m, 2H), 1.90 (br s, 5H), 1.72 (br d, J = 1.2 Hz, 4H), 1.62 - 1.39 (m, 5H), 1.11 -0.97 (m, 2H).Example 8: Preparation of (2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-(((lr,4S)-4-(3- (2,6-dioxopiperidin-3-yl)-l-methyl-7-oxo-l,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-l,3»4-thiadiazole-3(2H)- carboxamide, Compound 83Step 1: Preparation of tert-butyl (3-((2S)-5-(2,5-difluorophenyl)-3-(((l-(((lr,4S)-4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-7-oxo-l, 7-dihydro-6H-pyrazolo[3,4-c]pyridin-6- yl)cyclohexyl)methyl)piperidin-4-yl)oxy)(methyl)carbamoyl)-2-phenyl-2,3-dihydro-l,3,4-thiadiazol-2-yl) propyl) carbamate

[0288] To a solution of (lr,4r)-4-(3-(2,6-dioxopiperidin-3-yl)-l-metliyl-7-oxo-l,7-dihydro-6H- pyrazolo[3,4-c]pyridin-6-yl)cyclohexane-l-carbaldehyde (20.3 mg, 54.8 pmol, 1.1 eq) and tert-butyl (S)-(3-(5-(2,5-difluorophenyl)-3-(methyl(piperidin-4-yloxy)carbamoyl)-2-phenyl-2,3-dihydro-l,3,4- thiadiazol-2-yl)propyl)carbamate (46 mg, 49.9 pmol, 1 eq) in DMSO (0.5 mL) and THF (0.5 mL) was added HOAc (2.99 mg, 49.9 pmol, 2.85 pL, 1 eq). The mixture was stirred at 20 °C for 0.5 hours. NaBH(OAc)3(26.4 mg, 125 pmol, 2.5 eq) was added at 0 °C and the reaction mixture was stirred at 20 °C for another 0.5 hours. LCMS indicated partial consumption of the reactant (6.6% peak area) and formation of the desired product (60.9% peak area). Tire reaction mixture was quenched by water (0,2 mL) and then purified by reverse-phase flash [0.1% FA] and lyophilized to afford tert-butyl (3-((2S)- 5-(2,5-difluorophenyl)-3-(((l-(((lr,4S)-4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-7-oxo-l,7-dihydro-12341827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)metliyl)piperidin-4-yl)oxy)(metliyl)carbamoyl)-2-phenyl-2,3-dihydro-l,3,4-thiadiazol-2-yl)propyl)carbamate (35 mg, 30.1 pmol, 60.3% yield, 81.1% purity) as a white solid. LCMS: m / z [M+H]+= 944.4.Step 2: Preparation of ( 2S)-2-( 3-aminopropyl)-5-(2, 5-difluorophenyl)-N-( ( 1 -(( (1 r, 4S)-4-( 3-(2, 6-dioxopiperidin-3-yl)-l-methyl-7-oxo-l, 7-dihydro-6H-pyrazolo[3, 4-c]pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide

[0289] To a solution of tert-butyl (3-((2S)-5-(2,5-difhiorophenyl)-3-(((l-(((lr,4S)-4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-7-oxo-l,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6- yl)cyclohexyl)methyl)piperidin-4-yl)oxy)(methyl)carbamoyl)-2-phenyl-2,3-dihydro-l,3,4-thiadiazol-2-yl)propyl)carbamate (26 mg, 27.5 pmol, 1 eq) in DCM (0.5 mL) was added HC1 solution (2 M in dioxane, 1 mL, 72,7 eq) at 20 °C. Tire mixture was stirred at 20 °C for 1 hour. LCMS indicated complete consumption of the reactant and formation of the desired product (96.1% peak area). The mixture was concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC [column: Phenomenex Luna C18 150*25mm* lOum; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 12%-42% B over 10.0 min] and lyophilized to afford (2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-(((lr,4S)-4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-7-oxo-l,7-dihydro-6H- py razolo [3,4-c ]pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yI)oxy)-N-methyl-2-pheny 1- 1,3,4-thiadiazole-3(2H)-carboxamide (5.31 mg, 6.11 pmol, 22.2% yield, 97.2% purity) as a white solid. LCMS: m / z [M+H]+= 844.6; HPLC: 99.4% purity (220 nm), RT = 1.898 minutes;1H NMR (400 MHz, DMSO-6) δ (ppm) = 11.22 - 10.54 (m, 1H), 8.36 (s, 1H), 7.61 - 7.55 (m, 1H), 7.52 - 7.35 (m, 7H), 7.35 - 7.30 (m, 1 H), 7.28 - 7.22 (m, 1H), 6.54 (d, J= 7.2 Hz, 1H), 4.85 - 4.71 (m, 1H), 4.22 (s, 3H), 3.96 - 3.91 (m, 1H), 3.21 (s, 3H), 2.87 (br d, J = 5.6 Hz, 3H), 2.71 -2.58 (m, 5H), 2.31 -2.25 (m, 1H), 2.16 - 2.07 (m, 3H), 2.06 - 1.95 (m, 3H), 1.92 - 1.78 (m, 5H), 1.71 (br s, 4H), 1.52 (br d, J = 9.6 Hz, 5H), 1.12 - 0.94 (m, 2H).Example 9: Preparation of (S)-5-(2,5-difluorophenyI)-N-((l-(((lr,4S)-4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-7-oxo-l,7-dihydro-6H-pyrazolo[3,4-c|pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-N-methyl-2-(3-(methylamino)propyl)-2-phenyl-l,3,4-thiadiazole-3(2H)-carboxamide, Compound 8412441827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)HCHO, pyrrolidineHFIP, 20 °C, 12 hStep 1: Preparation of (S)-5-(2,5-difluorophenyl)-N-((1-(((1r,4S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-N-methyl-2-(3-(methylamino)propyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide

[0290] To a solution of (S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-(((lr,4S)-4-(3-(2,4-dioxotetrahydropy rimidin- 1 (2H)-yl)- 1 -methyl-7 -oxo- 1, 7 -dihydro-6H-py razolo [3,4-c]pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide (30 mg, 35.5 pmol, 1 eq) in HFIP (1 mL) was added pyrrolidine (10.1 mg, 142 pmol, 11.9 pL, 4 eq) and HCHO (8,64 mg, 107 pmol, 7.93 pL, 37% purity, 3 eq). The mixture was stirred at 20 °C for 12 hours. LCMS indicated complete consumption of the reactant and formation of the desired product (60.4% peak area). The mixture was directly purified by Prep-HPLC [column: Phenomenex Luna C18 150*25mm* lOum; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 19%-29% B over 10.0 min] and lyophilized to afford (S)-5-(2,5-difluorophenyl)-N-((l-(((lr,4S)-4-(3-(2,4-dioxotetrahydropy rimidin- 1 (2H)-yl)- 1 -methyl-7 -oxo- 1, 7 -dihydro-6H-py razolo [3,4-c]pyridin-6- yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-N-methyl-2-(3-(methylamino)propyl)-2-phenyl-l,3,4-thiadiazole-3(2H)-carboxamide (8.81 mg, 10.1 pmol, 28.4% yield, 98.2% purity) as a white solid. LCMS: m / z [M+H]+= 859.4; HPLC: 98.2% purity (220 nm), RT = 1.882 minutes;1H NMR (400 MHz, DMSO-d6) 5 (ppm) = 11.16 - 10.02 (m, 1H), 8.37 (s, 1H), 7.58 (br s, 1H), 7.49 - 7.43 (m, 4H), 7.39 (t, J= 7.6 Hz, 2H), 7.32 (br d, 7= 7.2 Hz, 1H), 7.24 (d, J= 7.6 Hz, 1H), 6.46 (d, J= 7.2 Hz, 1H), 4.76 (br d, J = 7.6 Hz, 1H), 4.22 (s, 3H), 3.99 - 3.90 (m, 1H), 3.87 (t, J = 6.8 Hz, 2H), 3.21 (s, 3H), 2.86 (br d,.7= 10.0 Hz, 1H), 2.77 - 2.60 (m, 6H), 2.33 (s, 3H), 2.09 (br d, J = 7.6 Hz, 2H), 2.04 - 1.96 (m, 2H), 1.96 - 1.76 (m, 6H), 1.72 (br s, 4H), 1.51 (br d, J= 7.6 Hz, 5H), 1.10 - 0.97 (m, 2H).12541827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)Example 10: Preparation of (S)-5-(2,5-difluorophenyl)-N-((l-(((lr,4S)-4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-7-oxo-l,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)m ethyl)piperidin-4-yl)oxy)- 2-(3-(ethylam in o)propyl)-N-methyl-2-phenyl-l,3,4- thiadiazole-3(2H)-carboxamide, Compound 86CH3CHO (5 M in THF)HOAc, NaBH(OAc)3,DMSO / THF, 0-20 °C, 24.5 hStep 1: Preparation of (S)-5-(2,5-difluorophenyl)-N-((1-(((1r,4S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-2-(3-(ethylamino)propyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide

[0291] To a solution of (S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-(((lr,4S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-l-methyl-7-oxo-l,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-l, 3, 4-thiadiazole-3(2H) -carboxamide (22 mg, 26.0 pmol, 1 eq) in DMSO (0.5 mL) and THF (0.5 mL) was added acetaldehyde (5 M in THF, 10.4 pL, 2 eq) and HOAc (1.56 mg, 26.0 pmol, 1.49 pL, 1 eq) and the mixture was stirred at 20 °C for 0.5 hours. NaBH(OAc)s (16.6 mg, 78.1 pmol, 3 eq) was added at 0 °C and the mixture was stirred at 20 °C for another 12 hours. LCMS showed partial consumption of the start material, and additional acetaldehyde (5 M, 10.4 pL, 2 eq) and NaBH(OAc)3 (8.28 mg, 39.1 pmol, 1.5 eq) were added to the reaction mixture and the resulting mixture was stirred at 20 °C for 6 hours. LCMS indicated partial consumption of the starting material (15.4% peak area) and formation of the desired product (33.7% peak area). The reaction mixture was quenched with water (0.3 mL) and purified by Prep-HPLC [column: Phenomenex Luna Cl 8 150*25mm* lOum; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 15%-45% B over 15.0 min] and lyophilized to afford (S)-5-(2,5-difluorophenyl)-N-(( 1 -((( 1 r,4S)-4-(3 -(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl-7 -oxo- 1,7-dihydro-6H- pyrazolo[3,4-c]pyridin-6-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-2-(3-(ethylamino)propyl)-N-methyl-2-phenyl-l,3,4-thiadiazole-3(2H)-carboxamide (4.8 mg, 4.73 pmol, 18.2% yield, 86.1%12641827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)purity) as an off-white solid. LCMS: m / z |M+H]+===873.5; HPLC: 86.1% purity (220 nm), RT === 1.924 minutes; ’H NMR (400 MHz, CDCL) 5 (ppm) = 9.62 - 9.49 (m, 1H), 7.46 (br d, J = 7.6 Hz, 2H), 7.40 - 7.29 (m, 4H), 7.16 - 7.09 (m, 2H), 6.89 (s, 1H), 6.55 - 6.47 (m, 1H), 4.98 - 4.75 (m, 1H), 4.33 (s, 3H), 4.13 - 3.98 (m, 3H), 3.40 (s, 3H), 3.35 (s, 1H), 3.28 - 2.96 (m, 7H), 2.91 - 2.81 (m, 4H), 2.31 -2.13 (m, 4H), 2.08 - 1.97 (m, 3H), 1.97 - 1.84 (m, 5H), 1.70 - 1.57 (m, 3H), 1.37 - 1.19 (m, 6H). Example 11: Preparation of (2S)-2-(3-aminopropyl)-5-(2,5-difIuorophenyl)-N-[[l-[[l-[3-(2,4- dioxohexahydropyrimidin-l-yl)-l-methyl-pyrazolo[3,4-b]pyridin-6-yl]-4-piperidyl]methyl]-4-piperidyl]oxy]-N-methyl-2-phenyl-l,3,4-thiadiazole-3-carboxamide, Compound 108Step 1: Preparation of tert-butyl N-[3-[(2S)-5-(2,5-difluorophenyl)-3-[[l-[[l-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-pyrazolo[3, 4-b]pyridin-6-yl]-4-piperidyl]methyl]-4-piperidyl]oxy-methyl-carbamoyl]-2-phenyl-l,3,4-thiadiazol-2-yl]propyl]carbamate

[0292] To a solution of tert-butyl N-[3-[(2S)-5-(2,5-difluorophenyl)-3-[methyl(4-piperidyloxy)carbamoyl|-2-phenyl-l,3,4-thiadiazol-2-yl]propyl|carbamate (100 mg, 108 umol, 1 eq) and l-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-pyrazolo[3,4-b]pyridin-6-yl]piperidine-4- carbaldehyde (42.5 mg, 119 pmol, 1.1 eq) in DMSO (1 mL) and THF ( 1 mL) was added AcOH (6. 1 mg, 108 pmol, 6.20 pL, 1 eq) and the mixture was stirred at 25 °C for 30 minutes. Then the mixture was cooled to 0 °C and NaBH(OAc)3(57.4 mg, 271 μmol, 2.5 eq) was added. The resulting mixture was stirred at 25 °C for 12 hours. LCMS indicated complete consumption of the starting material and formation of the product with desired mass (63.8% peak area). Tire mixture was quenched with ice H2O (1 mL) and directly purified by reversed-phase HPLC (ACN / 0.1 % HC1 = 50%) and lyophilized to afford tert-butyl N-[3-[(2S)-5-(2,5-difluorophenyl)-3-[[l-[[l-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-pyrazolo[3,4-b]pyridin-6-yl]-4-piperidyl]methyl]-4-piperidyl]oxy-methyl-carbamoyl]-2-phenyl-1,3,4-thiadiazol-2-yl]propyl]carbamate (60 mg, 64.5 pmol, 59.5% yield) as a yellow solid. LCMS: m / z [M+H]+= 930.5.12741827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)Step 2: Preparation of (2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-[[1-[[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-pyrazolo[3,4-b]pyridin-6-yl]-4-piperidyl]methyl]-4-piperidyl]oxy]-N-methyl-2-phenyl-1,3,4-thiadiazole-3-carboxamide

[0293] To a solution of tert-butyl N-[3-[(2S)-5-(2,5-difluorophenyl)-3-[[l-[[l-[3-(2,4-dioxohexahydropyrimidin- 1-yl)-1-methyl-pyrazolo[3,4-b]pyridin-6-yl]-4-piperidyl]methyl]-4-piperidyl]oxy-methyl-carbamoyl]-2-phenyl-1,3,4-thiadiazol-2-yl]propyl]carbamate (30 mg, 32.3 pmol, 1 eq) in DCM (0.2 mL) was added HC1 solution (2 M in dioxane, 0.5 mL, 31.0 eq). The mixture was stirred at 25 °C for 1 hour. LCMS indicated complete consumption of the starting material and formation of the product with desired mass (88.2% peak area). The mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC (column:Phenomenex Luna C18 150*25mm* 10um;mobile phase: [H2O(0.225% FA)-ACN];gradient:25%-46% B over 10.0 min) and lyophilized to afford (2S)-2-(3-aminopropyI)-5-(2,5-difluorophenyl)-N- [[!-[[ 1 -[ 3 -(2,4-dioxohexahy dropyrimidin- 1 -y 1)- 1 -methyl-pyrazolo [3,4-b ] py ridin-6 -yl| -4-piperidyl]methyl]-4-piperidyl]oxy]-N-methyl-2-phenyl-l,3,4-thiadiazole-3-carboxamide (8.73 mg, 9.72 pmol, 30.1% yield, 97.5% purity, FA salt) as a white solid, LCMS: m / z [M+H]+= 830,4; HPLC: 97.5% purity (220 nm), RT = 1.850 minutes; ’HNMR (400 MHz, DMSO-tL) 8 = 10.52 (s, 1H), 8.14 (s, 1H), 7.82 (br d, J = 9.2 Hz, 3H), 7.61 - 7.55 (m, 1H), 7.49 - 7.39 (m, 6H), 7.36 - 7.30 (m, 1H), 6.75 (d, J = 9.2 Hz, 1H), 4.44 (br d, J = 12.8 Hz, 2H), 3.95 (t, J = 6.8 Hz, 3H), 3.79 (s, 3H), 3.23 (s, 3H), 2.97 - 2.86 (m, 5H), 2.72 (brt, J = 6.8 Hz, 4H), 2.61 (br d, J = 11.6 Hz, 1H), 2.26 - 1.95 (m, 5H), 1.89 - 1.73 (m, 5H), 1.66 - 1.48 (m, 3H), 1.16 - 1.00 (m, 2H).Example 12: Preparation of (S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-((l-((l-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-l,3,4-thiadiazole-3(2H)-carboxamide, Compound 10912841827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)HCI / dioxaneDCM, rt, 0.5 hStep 1: Preparation of l-[6-[4-(dimethoxymethyl)-l-piperidyl]-l-methyl-indazol-3-yl ]hex.ahydropyrimidine-2, 4-dione

[0294] To a mixture of 1 -(6-bromo-l-methyl-indazoI-3-yl)hexahydropyrimidine-2, 4-dione (500 mg, 1.55 mmol, 1 eq), 4-(dimethoxymethyl)piperidine (370 mg, 2.32 mmol, 1.5 eq) and CS2CO3 (1.51 g, 4.64 mmol, 3 eq) in dioxane (9 mL) was added [l,3-bis[2,6-bis(l-ethylpropyl)phenyl]-4,5-dichloro- imidazol-2-ylidene]-dichloro-(2-methylpyridin-l-ium-l-yl)palladium (130 mg, 155 pmol, 0.1 eq) under Nj atmosphere. Tire mixture was stirred at 100 °C for 1 hour. LCMS indicated complete consumption of the starting material and formation of the product with desired mass (69.6% peak area), The mixture was quenched with ice cooled aqueous AcOH solution (11 mL, AcOH / H2O = 1 / 10). The pH of the mixture was adjusted to 6~7 by saturated aqueous NaHCCL solution and extracted with ethyl acetate (15 ml, * 3). Tire combined organic phase was washed with brine (3 ml, * 5) and dried over anhydrous sodium sulfate, filtered and concentrated to afford 1 -[6-[4-(dimethoxymethyl)-l-piperidyl]-l-methyl-indazol-3-yl]hexahydropyrimidine-2, 4-dione (640 mg, 1.43 mmol, 92.7% yield, 90% purity) as a yellow solid. LCMS: m / z [M+H]+= 402.2;1H NMR (400 MHz, CDCl3) δ = 7.59 - 7.48 (m, 2H), 6.97 - 6.89 (m, 1H), 6.58 (s, 1H), 4.13 - 4.07 (m, 3H), 3.92 (s, 3H), 3.79 (br d, J = 12.4 Hz, 2H), 3.39 (s, 6H), 2.88 (t, J = 6.7 Hz, 2H), 2.75 (br t, J = 11.7 Hz, 2H), 1.89 (br d, J - 13.5 Hz, 2H), 1.83 - 1.78 (m, 1H), 1.57 - 1.47 (m, 2H).Step 2: Preparation of l-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]piperidine-4- carbaldehyde

[0295] A solution of l-[6-[4-(dimethoxymethyl)-l-piperidyl]-l-methyl-indazol-3-yl]hexahydropyrimidine-2, 4-dione (320 mg, 717 umol, 1 eq) in HCOOH (4 mL) was stirred at 20 °C for 1 hour. LCMS indicated complete consumption of the starting material and formation of the product with desired mass (84.2% peak area). The mixture was concentrated to give l-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]piperidine-4-carbaldehyde (260 mg, crude) as a brown oil. LCMS: m / z [M+H]+= 356.1.Step 3: Preparation of tert-butyl (S)-(3-(5-(2,5-difluorophenyl)-3-(((l-((l-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)(methyl)carbamoyl)-2-phenyl-2,3-dihydro-l,3, 4-thiadiazol-2-yl)propyl)carbamate12941827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)

[0296] To a solution of l-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]piperidine-4-carbaldehyde (60.3 mg, 170 nmol, 1 eq) and tert-butyl N-[3-[(2S)-5-(2,5-difluorophenyl)-3- [methyl(4-piperidyloxy)carbamoyl] -2 -phenyl -1,3,4-thiadiazol-2-yl]propyl]carbamate ( 100 mg, 170 pmol, 1 eq) in DMSO (1 mL) and THF (1 mL) was added AcOH (10.2 mg, 170 pmol, 9.71 pL, 1 eq) and stirred at 15 °C for 15 minutes. Then the mixture was cooled to 0 °C and NaBH(OAc)s (89.9 mg, 424 pmol, 2.5 eq) was added. The resulting mixture was stirred at 15 °C for 12 hours. LCMS indicated complete consumption of the starting material and formation of the product with desired mass (-93.4% peak area). The mixture was quenched with ice H2O (3 mL) and the pH was adjusted to 6-7 by saturated NaHCOs aqueous solution. The mixture was extracted with ethyl acetate (5 mL * 3). The combined organic phase was washed with brine (2 mL * 5) and dried over anhydrous sodium sulfate, filtered and concentrated to afford tert-butyl (S)-(3-(5-(2,5-difluorophenyl)-3-(((l-((l-(3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)(methyl)carbamoyl)-2-phenyl-2,3-dihydro-l,3,4-thiadiazol-2-yl)propyl)carbamate (150 mg, crude) as a yellow solid. LCMS: m / z [M+H]+= 929.4; ’H NMR (400 MHz, CDC13) 5 = 7.52 (d, J = 9.2 Hz, 2H), 7.51 - 7.47 (m, 1H), 7.44 (br d, J = 7.6 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.32 - 7.27 (m, 2H), 7.15 - 7.11 (m, 2H), 6.91 (br d, J = 8.8 Hz, 1H), 6.57 (d, J = 1.6 Hz, 1H), 4.69 - 4.56 (m, 1H), 4.10 (d, J - 6.8 Hz, 2H), 3.92 (s, 3H), 3.75 (br d, J = 12.4 Hz, 2H), 3.43 - 3.36 (m, 3H), 3.32 - 3.19 (m, 3H), 3.18 - 3.06 (m, 2H), 2.88 (t, J = 6.8 Hz, 2H), 2.84 - 2.74 (m, 3H), 2.46 - 2.38 (m, 2H), 2.05 - 1.79 (m, 9H), 1.64 - 1.54 (m, 2H), 1.45 (s, 11H).Step 4: Preparation of (S)-2-(3-aminopropyl)-5~(2,5~difluorophenyl)-N-((l~((l-(3-(2,4- dioxotetrahydropyrimidin-1 ' (2H)-yl)-l-methyl-lH-indazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide

[0297] To a solution of tert-butyl (S)-(3-(5-(2,5-difhiorophenyl)-3-(((l-((l-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)(methyl)carbamoyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)carbamate (150 mg, 161 μmol, 1 eq) in DCM (3 mL) was added HCl solution (2 M in dioxane, 1.5 mL, 18.6 eq). The mixture was stirred at 15 °C for 0.5 hours. LCMS indicated complete consumption of tire starting material and formation of the product with desired mass (-92.2% peak area). Tire reaction mixture was concentrated to give a residue. Tire residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm* 10um;mobile phase: [H2O(0.225% FA)-ACN| gradient: 15%-35% B over 10.0 min) and lyophilized to afford (S)-2-(3-aminopropyl)-5-(2,5-difhiorophenyl)-N-((l-((l-(3-(2,4-dioxotetrahydropynmidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-6-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-N-methyl-2-phenyl-l,3,4-thiadiazole-3(2H)-carboxamide (14.0 mg, 16.7 mol, 10.3% yield, 98.8% purity) as a white solid. LCMS: m / z [M+H]+= 829.4; HPLC: 98.8% purity (220 nm), RT = 1.697 minutes;1H NMR (400 MHz, DMSO-6) δ = 8.42 (s, 1H), 7.61 - 7.55 (m, 1H), 7.50 - 7.36 (m, 8H), 7.34 - 7.29 (m, 1H), 6.89 (dd, J = 1.6, 9.2 Hz, 1H), 6.79 (s, 1H), 3.99 - 3.91 (m, 1H), 3.91 - 3.86 (m, 5H), 3.78 (br d, J = 12.4 Hz, 2H), 3.56 - 3.27 (m, 2H), 3.22 (s, 3H), 2.94 - 2.80 (m, 3H), 2.76 - 13041827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)2.65 (m, 6H), 2.63 - 2.56 (m, 1H), 2.13 (br d, J = 6.8 Hz, 2H), 2.02 (br s, 2H), 1.95 - 1.87 (m, 1H), 1.85 - 1.75 (m, 4H), 1.66 (br dd, J = 1.6, 3.6 Hz, 1H), 1.52 (br d, J = 7.6 Hz, 3H), 1.27 - 1.16 (m, 2H).5.2. Biological CharacterizationsKIF 11 degradation in various cell lines

[0298] MCF7, HCC1954, NCI-H441 and Panc 04.03 cells were obtained from American Type Culture Collection (ATCC). Cells were plated in 24-well plates in the RPMI1640 growth medium containing 10% FBS and 1% Penicillin- Streptomycin at the density of 1.5 - 10E5 cells / well, and then incubated at 37 °C overnight. The following day, the test compound was administered to the cells by using 1000x compound stock solution prepared in DMSO at various concentrations. After administration of the compound, the cells were then incubated at 37 °C for 6 hours. Upon completion, the cells were washed with PBS and protein was collected in Laemmli sample buffer (lx; VWR International). Proteins in cell lysate were separated by SDS-PAGE and transferred to ODYSSEY® nitrocellulose membranes (Licor) with IBLOT® dry blotting transfer system (ThermoFisher).Nonspecific binding was blocked by incubating membranes with INTERCEPT® Blocking Buffer (Licor) for 1 hour at room temperature with gentle shaking. The membranes were then incubated overnight at 4 °C with primary antibodies rabbit anti-KIF11 (1: 1000, Cell Signaling Technologies, 7625s) and mouse anti-GAPDH (1:5,000, Santa Cruz Biotechnology, sc-47724) diluted in INTERCEPT® Blocking Buffer containing 0.1% TWEEN® 20. After washing 3 times with TBS-T, die membranes were incubated with IRDYE® 800CW goat anti-rabbit IgG (1:20,000, Licor, #926-32211) and IRDYE® 680RD goat anti-mouse IgG (Licor, #926-68070) for 1 hour. After TBS-T washes, membranes were rinsed in TBS and Western blot images were acquired by ODYSSEY® CLx (LI-COR Biosciences).

[0299] The results are shown in FIGs. 1-4, which illustrate the KIF11 degradation activity of exemplary Compound 1 of the present disclosure in cell lines 6 hours after administration.

[0300] The signal intensity of target proteins was calculated using IMAGESTUDIO™ software. KIF 11 fluorescent intensity (FLU) from DMSO (vehicle) treatment was set as 100%. Relative KIF 11 expression level was determined by the following formula:KIF11 expression (%) = "FLUcompound" / "FLUDMSO" ×100 (1)

[0301] The percentage of KIF 11 expression was calculated using Microsoft Excel. The half-maximal degradation concentration (DC50) values were generated by GraphPad Prism (Version 9) using the dose-response equation of variable slope (four parameters).

[0302] The results in MCF7 cells are shown in Table 5, which summarizes KIF11 degradation DC50 of exemplary compounds.13141827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)Table 5. KIF11 degradation DCso of exemplary compoundsCompound MCF7 KIF11 DC50(nM)1 A2 A3 A4 B5 A77 A82 A83 A84 A86 A108 A109 AA <1 nM; 1 nM < B <10 nM; 10 nM < C < 100 nM; 100 nM < D.Growth inhibition of MCF7 breast cancer cells

[0303] To set up the growth assay, MCF7 cells were seeded in white flat-bottom 96-well plates at 1,000 cells / well in 90 pL of RPMI1640 growth medium containing 10% FBS and 1% Penicillin Streptomycin, and then incubated at 37 °C overnight. The following day, the test compound was administered to the cells by using 1000x compound stock solution prepared in DMSO at various concentrations. 1000x compound stock solution was first diluted in culturing medium to lOx, and then 10 pL compound medium was added to each well in the cell plates. After administration of the compound, the cells were then incubated at 37 °C for 5 days. Upon completion, the plates were equilibrated at room temperature for approximately 10 minutes. 100 pL of CELLTITER-GLO® Reagent (Promega) was added to each well. The plates were then incubated at room temperature for 10 minutes and luminescence was recorded by ENSPIRE® plate reader (PerkinElmer).

[0304] Luminescence readout from DMSO treatment was set as 100%, The average of relative light unit (RLU) values from the duplicate samples were used to calculate relative cell growth. Relative cell growth after compound treatment was determined using the following formula:Cell Growth (%) - “RLUcompound” / “RLUDMSO” < 100 (2)

[0305] The percentage of cell growth was calculated using Microsoft Excel. Graphs of the percentage cell growth vs. log of compound concentrations, and half-maximal growth inhibition13241827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)(Giso) determinations were generated by GraphPad Prism using the dose-response equation of variable slope (four parameters).

[0306] The results shown in Table 6, summarizes the growth inhibition (GI50) in MCF7 cells with exemplary- compounds of the present disclosure.Table 6. KIF11 degradation GI50of exemplary compoundsCompound MCF7 Cell Growth GI50(nM)1 A2 A3 A4 A5 A77 A82 A83 A84 A86 A108 B109 AA <1 nM; 1 nM < B < 10 nM; 10 nM < C < 100 nM; 100 nM < D6. ADDITIONAL EMBODIMENTSEmbodiment 1. A compound, wherein the compound is represented by Formula (I) or is a pharmaceutically acceptable salt thereof:wherein:X is C orN;G is CH2 or O;each Y is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, -13341827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)OC1-C3 alkyl, -CN, and -NH2;R1is selected from hydrogen, C1-C6 alkyl, -(CH2)C6-C14aryl, -C(O)OC1-C6 alkyl, -C(O)OC1-C6 haloalkyl, and -C(O)O-(CH2)C6-C14 aryl;R2is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -NH2, -(CH2)1-6NH2, -C(O)C1-C6 alkyl, -C(O)OH, and -C(O)OC1-C6 alkyl;L is a bond or a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, - NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, C3-C6cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 8- to 14-membered bicyclic heterocyclylene, wherein each of the C3-Cg cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 8- to 14-membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 Ra2;each Ra1is independently selected from C1-C6 alkyl, oxo, -(CH2)C6-C14aryl, -(CH2)C3-C8cycloalkyl, -C(O)OC1-C6 alkyl, -C(O)OC1-C6 haloalkyl, and -C(O)O-(CH2)C6-C14 aryl;each Ra2is independently selected from hydrogen, halogen, Ci-Cg alkyl, oxo, and C3-Cg cycloalkyl; M is a bond or a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, - NH-, -N(Rb1)-, -C(O)-, -C(O)-NH-, -C(O)N(Rb1)-, -NH-C(O)-, -N(Rbi)-C(O)-, C3-Cg cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 8- to 14-membered bicyclic heterocyclylene, wherein each of the C3-Cg cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 8- to 14-membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 Rb2;each Rb1is independently selected from C1-C6 alkyl, -(CH2)C6-C14aryl, -(CH2)C3-C8cycloalkyl, -C(O)OC1-C6 alkyl, -C(O)OC1-C6 haloalkyl, and -C(O)O-(CH2)C6-C14 aryl;each Rb2is independently selected from hydrogen, halogen, Ci-Cg alkyl, oxo, and C3-Cg cycloalkyl; P is a bond or a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, - NH-, -N(Rci)-, -C(O)-, -C(O)-NH-, -C(O)N(Rc1)-, -NH-C(O)-, -N(Rcl)-C(O)-, C3-C6cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 8- to 14-membered bicyclic heterocyclylene, wherein each of C3-Cg cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 8- to 14-membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 Rc2;each Rc1is independently selected from C1-C6 alkyl, -(CH2)C6-C14aryl, -(CH2)C3-C8cycloalkyl, -C(O)OC1-C6 alkyl, -C(O)OC1-C6 haloalkyl, and -C(O)O-(CH2)C6-C14 aryl;each Rc2is independently selected from hydrogen, halogen, Ci-Cg alkyl, oxo, and C3-Cg cycloalkyl; Q is a bond or a divalent group of 1-6 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from C6-C10 monocyclic arylene, C8-C1241827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered bicyclic heteroarylene, and wherein each of the C6-C10 monocyclic arylene, C8-C12 bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered bicyclic heteroarylene is independently substituted with 0, 1, 2, or 3 Rd;each Rdis independently selected from hydrogen, halogen, C1-C6 alkyl, hydroxyl, -OC1-C6 alkyl, oxo, -C(O)NH-, and -NH2; andn is 0, 1, 2, 3, or 4.Embodiment 2. The compound of embodiment 1, wherein the compound of Formula (I) is represented by Formula (la):wherein:X is C or N;R1is II or Ci-Cg alkyl;each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a bond or a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, - NH-, -N(RaI)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, C3-C6cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 8- to 14-membered bicyclic heterocyclylene;M is a bond or a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, - NH-, -N(Rb1)-, -C(O)-, -C(O)-NH-, -C(O)N(Rb1)-, -NH-C(O)-, -N(Rbi)-C(O)-, C3-C6cycloalkylene, C5-C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, 8- to 14-membered bicyclic heterocyclylene;Q is a bond or a divalent group of 1-6 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from C6-C10 monocyclic arylene, C8-C12 bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered heteroarylene, and wherein each of C6-C10 monocyclic arylene, C8-C12 bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered bicyclic heteroary lene is independently substituted with 0, 1, 2, or 3 Rd; and13541827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)Rdis independently selected from hydrogen, halogen, C1-C3 alkyl, hydroxyl, -OC1-C4 alkyl, oxo, and -NH2.Embodiment 3. The compound of embodiment 1 or 2, wherein the compound of Formula (1) is represented by Formula (la- 1):wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, - N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, C3-C6cycloalkylene, 3- to 9-membered heterocyclylene and 8- to 14-membered bicyclic heterocyclylene; and M is a divalent group with a backbone of 1-6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, - N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, C3-C6cycloalkylene, 3- to 9-membered heterocyclylene and 8- to 14-membered bicyclic heterocyclylene.Embodiment 4. The compound of embodiment 3, wherein each Y is selected from F, Cl, Br, and I.Embodiment 5. The compound of embodiment 3, wherein L is selected from13641827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)Embodiment 6. The compound of embodiment 3, wherein M is selected fromoEmbodiment 7. The compound of embodiment 1 or 2, wherein the compound of Formula (I) is represented by Formula (la-2):wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, C3-C6cycloalkylene, C3-C6cycloalkylene, 3- to 9-membered heterocyclylene, and 8- to 14-membered bicyclic heterocyclylene;M is a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon 13741827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)atoms are optionally replaced by a divalent group independently selected -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, C3-C6cycloalkylene, 3- to 9- membered heterocyclylene and 8- to 14-membered bicyclic heterocyclylene; andRdis selected from hydrogen, -CH3, -CH2CH3, and -CH2CH2CH3.Embodiment 8. The compound of embodiment 7, wherein each Y is independently selected from F, Cl, Br, and I.Embodiment 9. The compound of embodiment 7, wherein L is selected fromEmbodiment 10. The compound of embodiment 7, wherein M is selected fromEmbodiment 11. The compound of embodiment 1 or 2, wherein the compound of Formula (I) is represented by Formula (la-3):(la-3). wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, - C(O)-, -C(O)-NH~, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, 4-membered heterocyclylene, 5-membered heterocyclylene, and 6-membered heterocyclylene;M is a divalent group with a backbone of 1-4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, - C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, 4-membered heterocyclylene, 5-membered heterocyclylene, and 6-membered heterocyclylene; and13841827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)Rdis hydrogen or C1-C5 alkyl.Embodiment 12. The compound of embodiment 11, wherein each Y is independently selected from F, Cl, Br, and I.Embodiment 13. The compound of embodiment 11, wherein L isEmbodiment 14. The compound of embodiment 11, wherein M isEmbodiment 15. The compound of embodiment 1 or 2, wherein the compound of Formula (I) is represented by Formula (la-4):l2Ns N\1 / =Nwherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, - C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, 4-membered heterocyclylene, 5-membered heterocyclylene, and 6-membered heterocyclylene; andM is a divalent group with a backbone of 1-4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, - C(O)-NH-, -C(O)N(R31)-, -NH-C(O)-, -N(Ra1)-C(O)-, 4-membered heterocyclylene, 5-membered heterocyclylene, and 6-membered heterocyclylene.Embodiment 16. The compound of embodiment 15, wherein each Y is independently selected from F, Cl, Br, and I.Embodiment 17. The compound of embodiment 15, wherein L is13941827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)Embodiment 18. The compound of embodiment 15, wherein M isEmbodiment 19. The compound of embodiment 1 or 2, wherein the compound of Formula (1) is represented by Formula (la-5):l2Ns' N,0)=N r ON... JIwherein:each Y is independently selected from C1-C2alkyl, F, Cl, Br, and I;L is a divalent group w ith a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, - C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, 4-membered heterocyclylene, 5-membered heterocyclylene, and 6-membered heterocyclylene; andM is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, - C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, 4-membered heterocyclylene, 5-membered heterocyclylene, and 6-membered heterocyclyleneEmbodiment 20. The compound of embodiment 19, wherein each Y is independently selected from F, Cl, Br, and I.Embodiment 21. The compound of embodiment 19, wherein L isEmbodiment 22. The compound of embodiment 19, wherein M isEmbodiment 23. The compound of embodiment 1 or 2, wherein the compound of Formula (I) is14041827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)represented by Formula (la-6):wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1-4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ral)-, - C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, 4-membered heterocyclylene, 5-membered heterocyclylene, and 6-membered heterocyclylene;M is a divalent group with a backbone of 1-4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, - C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, 4-membered heterocyclylene, 5-membered heterocyclylene, and 6-membered heterocyclylene;each X1is independently selected from hydrogen, halogen, C₁-C₆ alkyl, and -OC₁-C₃ alkyl; and p is 0, 1, or 2.Embodiment 24. The compound of embodiment 23, wherein each Y is independently selected from F, Cl, Br, and I.Embodiment 25. The compound of embodiment 23, wherein L isEmbodiment 26. The compound of embodiment 23, wherein M isEmbodiment 27. The compound of embodiment 1 or 2, wherein the compound of Formula (I) is represented by Formula (la-7):14141827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, - C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, 4-membered heterocyclylene, 5-membered heterocyclylene, and 6-membered heterocyclylene;M is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, - C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, 4-membered heterocyclylene, 5-membered heterocyclylene, and 6-membered heterocyclylene;each X1is independently selected from hydrogen, halogen, Ci-Cf, alkyl, and -OC1-C3 alkyl;Rdis hydrogen or Ci-Cg alkyl; andp is 0, 1, 2, 3, or 4.Embodiment 28. The compound of embodiment 27, wherein each Y is independently selected from F, Cl, Br, and I.Embodiment 29. The compound of embodiment 27, wherein L isEmbodiment 30. The compound of embodiment 27, wherein M isEmbodiment 31. The compound of embodiment 1, wherein Q is a divalent group of 1-4 carbon atoms in length,wherein one or more carbon atoms are replaced by a divalent group independently selected fromC10 monocyclic arylene and 5- to 10-membered bicyclic heteroarylene, and wherein each of the Cg-Cio monocyclic arylene and 5- to 10-membered bicyclic heteroarylene is independently substituted with 0, 1, 2, or 3 Rd; andeach Rdis independently selected from hydrogen, halogen, Ci-Ce alkyl, hydroxyl, -OCi-Ce alkyl, oxo,14241827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)and -NH2.Embodiment 32. The compound according to embodiment 1 or 31, wherein Q is selected from:Rdis selected from hydrogen, Ci-Ce alkyl, and -OCi-Cs alkyl, and wherein the Ci-Cs alkyl is substituted with one or more of halogen, Ci-Ce alkyl, hydroxyl, oxo, and -NH2;each X1is independently selected from hydrogen, halogen, C1-C6alkyl, and -OC1-C3alkyl; andn is 0, 1, 2, or 3.Embodiment 33. The compound according to embodiment 1 or 32, wherein Q is selected from:Embodiment 34. Tire compound according to embodiment 1, wherein L is selected from14341827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)Embodiment 35. Tire compound according to embodiment 1, wherein M is selected from5?? 5 andoEmbodiment 36. Tire compound of embodiment 1, wherein P is selected fromEmbodiment 37. The compound of embodiment 1, wherein n is 2 and each Y is F.Embodiment 38. The compound of embodiment 1, wherein X is C.Embodiment 39. The compound of embodiment 1, wherein X is X.Embodiment 40. The compound of embodiment 1, wherein R1is selected from -CH3, -CH2CH3, and - CH2CH2CH3Embodiment 41. The compound of embodiment 1 or 40, wherein R1is -CH3.Embodiment 42. Tire compound of embodiment 1, wherein the compound is selected from Table 1 or a pharmaceutically acceptable salt of any one.Embodiment 43. Tire compound of embodiment 1, wherein the compound is selected from Table 2 or a pharmaceutically acceptable salt of any one. Embodiment 44. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 1 to 43 and one or more pharmaceutically acceptable earners, pharmaceutically acceptable vehicles, pharmaceutically acceptable excipients, or combinations thereof.Embodiment 45. A method for inhibiting and / or degrading protein kinesin-like protein KIF11 in a14441827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)cell, comprising contacting the cell with a compound according to any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 44.Embodiment 46. A method of treating a KIF11 -mediated disease or disorder in a subject in need thereof, comprising administering an effective amount of a compound according to any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 44.Embodiment 47. Tire method of embodiment 46, wherein the KIF11 -mediated disease is cancer.Embodiment 48. The method of embodiment 47, wherein the cancer is selected from breast cancer, lung cancer, pancreatic cancer, small bowel cancer, colorectal cancer, gall bladder cancer, thyroid cancer, liver cancer, bile duct cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, esophageal cancer, and blood cancer.Embodiment 49. The method of embodiment 47 or 48, wherein the cancer is breast cancer.Embodiment 50. Tire method of embodiment 47, wherein the cancer is papillary adenocarcinoma.Embodiment 1. The method of embodiment 47, wherein the cancer is adenocarcinoma.Embodiment 52. The method of embodiment 47, wherein the cancer is ductal carcinoma.Embodiment 53. The method of embodiment 47 or 48, wherein the cancer is a primary cancer or a metastatic cancer.Embodiment 54. A method of inhibiting the production of kine sin-like protein (KIF11) in a subject, the method comprising administering an effective amount of a compound according to any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 44.Embodiment 55. Use of a compound of any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 44, in the manufacture of a medicament for the treatment of a disease or disorder.Embodiment 56. The use of embodiment 55, wherein the KIF 11 -mediated disease is cancer.Embodiment 57. The use of embodiment 56, wherein the cancer is selected from breast cancer, lung cancer, pancreatic cancer, small bowel cancer, colorectal cancer, gall bladder cancer, thyroid cancer, liver cancer, bile duct cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer.14541827 / 65012 / FW / 25498027.2Attorney Docket No.: 41827-65012 (045WO)prostate cancer, esophageal cancer, and blood cancer.Embodiment 58. The use of embodiment 56 or 57, wherein the cancer is breast cancer.Embodiment 59. The use of embodiment 56, wherein the cancer is papillary adenocarcinoma.Embodiment 60. The use of embodiment 56, wherein the cancer is adenocarcinoma.Embodiment 61. The use of embodiment 56, wherein the cancer is ductal carcinoma.Embodiment 62. Tire use of embodiment 56 or 57, wherein the cancer is a primary' cancer or a metastatic cancer.7. EQUIVALENTS AND INCORPORATION BY REFERENCE

[0307] While aspects of this disclosure have been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the scope of the disclosure.

[0308] All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes. In particular, U. S. Provisional Patent Application Nos. 63 / 745,652 (filed January 15, 2025) and 63 / 888,986 (filed September 26, 2025) are hereby incorporated by reference in their entirety.14641827 / 65012 / FW / 25498027.2

Claims

Attorney Docket No.: 41827-65012 (045WO)WHAT IS CLAIMED IS:

1. A compound, wherein the compound is represented by Formula (I) or is a pharmaceutically acceptable salt thereof:(Z)wwherein:X is CH or N;G is selected from CH₂, O, NH, and N(C₁-C₆ alkyl);each Y is independently selected from halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, hydroxyl, -OC₁-C₃ alkyl, -CN, and -NH₂;each Z is independently selected from halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, hydroxyl, -OC₁-C₃ alkyl, -CN, and -NH₂;R¹ is selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and -(CH₂)C₆-C₁₄aryl;R² is selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, -(CH₂)₁₋₆NH₂, -(CH₂)₁₋₆N(Rᵉ¹)(Rᵉ²), -C(O)C₁-C₆ alkyl, -C(O)OH, and -C(O)OC₁-C₆ alkyl;Rᵉ¹ is hydrogen or C₁-C₆ alkyl;Rᵉ² is hydrogen or C₁-C₆ alkyl;L is a bond or a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Rᵃˡ)-C(O)-, C₃-C₆ cycloalkylene, C₅-C₁₂ bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene, wherein each of the C₃-C₆ cycloalkylene, C₅-C₁₂ bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 Rᵃ²;each Rᵃˡ is independently selected from C₁-C₆ alkyl, oxo, -(CH₂)C₆-C₁₄aryl, -(CH₂)C₃-C₈cycloalkyl, -C(O)OC₁-C₆ alkyl, -C(O)OC₁-C₆ haloalkyl, and -C(O)O-(CH₂)C₆-C₁₄ aryl;each Rᵃ² is independently selected from hydrogen, halogen, C₁-C₆ alkyl, oxo, and C₃-C₆ cycloalkyl; M is a bond or a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-,Attorney Docket No.: 41827-65012 (045WO)-N(Rb1)-, -C(0)-, -C(O)-NH-, -C(O)N(Rb1)-, -NH-C(O)-, -N(Rᵇˡ)-C(O)-, C₃-C₆ cycloalkylene, C₅-C₁₂ bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene, wherein each of the C₃-C₆ cycloalkylene, C₅-C₁₂ bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 Rᵇ²;each Rᵇˡ is independently selected from C₁-C₆ alkyl, -(CH₂)C₆-C₁₄aryl, -(CH₂)C₃-C₈cycloalkyl, -C(O)OC₁-C₆ alkyl, -C(O)OC₁-C₆ haloalkyl, and -C(O)O-(CH₂)C₆-C₁₄ aryl;each Rᵇ² is independently selected from hydrogen, halogen, C₁-C₆ alkyl, oxo, and C₃-C₆ cycloalkyl;P is a bond or a divalent group with a backbone of 1-6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(Rc1)-, -C(O)-, -C(0)-NH-, -C(O)N(RC1)-, -NH-C(O)-, -N(Rᶜ¹)-C(O)-, C₃-C₆ cycloalkylene, C₅-C₁₂ bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene, wherein each of C₃-C₆ cycloalkylene, C₅-C₁₂ bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene are substituted with 0, 1, 2, 3, or 4 Rᶜ²;each Rᶜˡ is independently selected from C₁-C₆ alkyl, -(CH₂)C₆-C₁₄aryl, -(CH₂)C₃-C₈cycloalkyl, -C(O)OC₁-C₆ alkyl, -C(O)OC₁-C₆ haloalkyl, and -C(O)O-(CH₂)C₆-C₁₄ aryl;each Rᶜ² is independently selected from hydrogen, halogen, C₁-C₆ alkyl, oxo, and C₃-C₆ cycloalkyl;Q is a bond or a divalent group of 1-6 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from C₆-C₁₀ monocyclic arylene, C₈-C₁₂ bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered bicyclic heteroarylene, and wherein each of the C₆-C₁₀ monocyclic arylene, C₈-C₁₂ bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered bicyclic heteroarylene is independently substituted with 0, 1, 2, or 3 Rᵈ;each Rᵈ is independently selected from hydrogen, halogen, C₁-C₆ alkyl, hydroxyl, -OC₁-C₆ alkyl, oxo, -C(O)NH-, and -NH₂; andn is 0, 1, 2, 3, or 4; andw is 0, 1, 2, 3, or 4,2. The compound of claim 1, wherein the compound of Formula (I) is represented by Formula (la):Attorney Docket No.: 41827-65012 (045WO)(Z)wwherein:X is CH orN;R¹ is H or C₁-C₆ alkyl;each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a bond or a divalent group with a backbone of 1-6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(Rᵃ¹)-, -C(O)-, -C(O)-NH-, -C(O)N(Rᵃ¹)-, -NH-C(O)-, -N(Rᵃˡ)-C(O)-, C₃-C₆ cycloalkylene, C₅-C₁₂ bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene;M is a bond or a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(Rb1)-, -C(O)-, -C(O)-NH-, -C(O)N(Rb1)-, -NH-C(O)-, -N(Rb1)-C(O)-, C3-C6cycloalkylene, C5- C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, 7- to 14-membered bicyclic heterocyclylene;Q is a bond or a divalent group of 1-6 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from Cs-Cio monocyclic arylene, Cs-C’12bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered heteroarylene, and wherein each of Cg-Cio monocyclic arylene, Cs-Cn bicyclic ary lene, 3- to 10- membered monocyclic heteroarylene, and 5- to 10-membered bicyclic heteroarylene is independently substituted with 0, 1, 2, or 3 Ra; andRdis independently selected from hydrogen, halogen, C1-C3 alkyl, hydroxyl, -OC1-C4 alkyl, oxo, and -NH2.

3. The compound of claim 1 or 2, wherein the compound of Formula (I) is represented by Formula (la-1):Attorney Docket No.: 41827-65012 (045WO)wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, - C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, C3-C6cycloalkylene, 3- to 9- membered heterocyclylene and 7- to 14-membered bicyclic heterocyclylene; andM is a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -Nil-, -N(Ra!)~, - C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, C3-C6cycloalkylene, 3- to 9- membered heterocyclylene and 7- to 14-membered bicyclic heterocyclylene.

4. The compound of claim 3, wherein each Y is independently selected from F, Cl, Br, and I.

5. The compound of claim 3, wherein L is selected fromAttorney Docket No.: 41827-65012 (045WO)6. The compound of claim 3, wherein M is selected from7. The compound of claim 1 or 2, wherein the compound of Formula (I) is represented by Formula (la-2):wherein:each Y is independently selected from C₁-C₂ alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -NH-, -N(Ra1)-, -C(O)-, - C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, C₃-C₆ cycloalkylene, C₃-C₆ cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene;M is a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, C₃-C₆ cycloalkylene, 3- to 9-membered heterocyclylene and 7- to 14-membered bicyclic heterocyclylene; andAttomey Docket No.: 41827-65012 (045WO)Rdis selected from hydrogen, -CH3, -CH2CH3, and -CH2CH2CH3.

8. The compound of claim 7, wherein each Y is independently selected from F, Cl, Br, and I.

9. The compound of claim 7, wherein L is selected from10. The compound of claim 7, wherein M is selected from11. The compound of claim 1 or 2, wherein the compound of Formula (I) is represented by Formula (la-wherein:each Y is independently selected from C₁-C₂ alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)- NH-, -C(O)N(Rai)-, -NH-C(O)-, -N(Ra1)-C(O)-, 3- to 9-membered heterocyclylene and 7- to 14- membered bicyclic heterocyclylene;M is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, 3- to 9-membered heterocyclylene and 7- to 14- membered bicyclic heterocyclylene; andRdis hydrogen or C₁-C₆ alkyl.Attorney Docket No.: 41827-65012 (045WO)12. The compound of claim 11, wherein each Y is independently selected from F, Cl, Br, and I.13, The compound of claim 11, wherein L is14. The compound of claim 11, wherein M is15. The compound of claim 1 or 2, wherein the compound of Formula (I) is represented by Formula (la-S N)=N'wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, 3- to 9-membered heterocyclylene and 7- to 14- membered bicyclic heterocyclylene; andM is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ral)-, -NH-C(O)-, -N(Ra’)-C(O)-, 3- to 9-membered heterocyclylene and 7- to 14- membered bicyclic heterocyclylene.

16. The compound of claim 15, wherein each Y is independently selected from F, Cl, Br, and I.

17. The compound of claim 15, wherein L isAttorney Docket No.: 41827-65012 (045WO)18. The compound of claim 15, wherein M is19, The compound of claim 1 or 2, wherein the compound of Formula (I) is represented by Formula (la- 5):wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ral)-, -NH-C(O)-, -N(Ra1)-C(O)-, 3- to 9-membered heterocyclylene and 7- to 14- membered bicyclic heterocyclylene; andM is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, 3- to 9-membered heterocyclylene and 7- to 14- membered bicyclic heterocyclylene20. The compound of claim 19, wherein each Y is independently selected from F, Cl, Br, and I.

21. The compound of claim 19, wherein L is22. The compound of claim 19, wherein M is23. The compound of claim 1 or 2, wherein the compound of Formula (I) is represented by Formula (la- 6):Attorney Docket No.: 41827-65012 (045WO)H2NS N)=N(X1)pwherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)- NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, 3- to 9-membered heterocyclylene and 7- to 14- membered bicyclic heterocyclylene;M is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)- NH-, -C(O)N(Rai)-, -NH-C(O)-, -N(Ra1)-C(O)-, 3- to 9-membered heterocyclylene and 7- to 14- membered bicyclic heterocyclylene;each X1is independently selected from hydrogen, halogen, C₁-C₆ alkyl, and -OC₁-C₃ alkyl; and p is 0, 1, or 2.

24. The compound of claim 23, wherein each Y is independently selected from F, Cl, Br, and I.

25. The compound of claim 23, wherein L is26. The compound of claim 23, wherein M is27. The compound of claim 1 or 2, wherein the compound of Formula (I) is represented by Formula (la- 7):Attorney Docket No.: 41827-65012 (045WO)wherein:each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)- NH-, -C(O)N(Rai)-, -NH-C(O)-, -N(Ra1)-C(O)-, 3- to 9-membered heterocyclylene and 7- to 14- membered bicyclic heterocyclylene;M is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ral)~, -C(O)-, -C(O)~ NH-, -C(O)N(Rai)-, -NH-C(O)-, -N(Ra‘)-C(O)-, 3- to 9-membered heterocyclylene and 7- to 14- membered bicyclic heterocyclylene;each X1is independently selected from hydrogen, halogen, C₁-C₆ alkyl, and -OC₁-C₃ alkyl;Rdis hydrogen or C₁-C₆ alkyl; andp is 0, 1, 2, 3, or4.

28. The compound of claim 27, wherein each Y is independently selected from F, Cl, Br, and I.

29. The compound of claim 27, wherein L is30. The compound of claim 27, wherein M is31, The compound of claim 1 or 2, wherein the compound of Formula (I) is represented by Formula (la-8):Attorney Docket No.: 41827-65012 (045WO)wherein:each Y is independently selected from C₁-C₂ alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1-6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, - C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, C3-C6cycloalkylene, 3- to 9- membered heterocyclylene and 7- to 14-membered bicyclic heterocyclylene;M is a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, - C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, C3-C6cvcloalkylene, 3- to 9- membered heterocyclylene and 7- to 14-membered bicyclic heterocyclylene; andRdis hydrogen or C₁-C₆ alkyl.32, The compound of claim 31, wherein X is CH.

33. lire compound of claim 31, wherein X is N.

34. The compound of claim 31, wherein Rdis selected from -CH₃, -CH₂CH₃, and -CH₂CH₂CH₃.

35. The compound of claim 31, wherein each Y is independently selected from F, Cl, Br, and I.

36. The compound of claim 31, wherein L is selected fromAttorney Docket No.: 41827-65012 (045WO)a H X / nd ' — ’N~i 37. The compound of claim 36, wherein L is selected from38. The compound of claim 31, wherein M is selected from39. The compound of claim 38, wherein M is selected from40. The compound of claim 31, wherein ReIand Re2are hydrogen.

41. The compound of claim 31, wherein Relis hydrogen and R” is Ci-Cs alkyl.Attorney Docket No.: 41827-65012 (045WO)42. The compound of claim 31, wherein Reland Re2are Ci-Ce alkyl.

43. The compound of claim 41 or 42, wherein the C₁-C₆ alkyl is selected from -CH₃, -CH₂CH₃, and -CH₂CH₂CH₃.

44. The compound of claim 1 or 2, wherein the compound of Formula (I) is represented by Formula (la- 9):wherein:each Y is independently selected from C₁-C₂ alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ra1)-C(O)-, C₃-C₆ cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene; andM is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14- membered bicyclic heterocyclylene.

45. The compound of claim 44, wherein Rdis selected from -CH₃, -CH₂CH₃, and -CH₂CH₂CH₃.

46. The compound of claim 44, wherein each Y is independently selected from F, Cl, Br, and I.

47. The compound of claim 44, wherein L is selected fromAttorney Docket No.: 41827-65012 (045WO)48. The compound of claim 47. wherein L is selected from49. The compound of claim 44, w herein M is selected from50. The compound of claim 49, wherein M is selected fromAttorney Docket No.: 41827-65012 (045WO)51. The compound of claim 1 or 2, wherein the compound of Formula (1) is represented by Formula (la-(la- 10),wherein:each Y is independently selected from C1-C2alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1-4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14- membered bicyclic heterocyclylene; andM is a divalent group with a backbone of 1-4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene.

52. The compound of claim 51, wherein Rdis selected from -CH3, -CH2CH3, and -CH2CH2CH3.53, The compound of claim 51, wherein each Y is independently selected from F, Cl, Br, and I.

54. The compound of claim 1, wherein L is selected fromAttorney Docket No.: 41827-65012 (045WO)55. The compound of claim 51, wherein L is56. The compound of claim 51, wherein M is selected from57. The compound of claim 51, wherein M is58. The compound of claim 1, wherein the compound of Formula (I) is represented by Formula (Ib):(Z)wwherein:Attorney Docket No.: 41827-65012 (045WO)X is CH or N;R1is H or C1-C6alkyl;G is NH or N(Ci-Ce alkyl);each Y is independently selected from C₁-C₂ alkyl, F, Cl, Br, and I;L is bond or a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, C3-C6cycloalkylene, C5- C12 bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, and 7- to 14-membered bicyclic heterocyclylene;M is a bond or a divalent group with a backbone of 1 -6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by a divalent group independently selected from -O-, -NH-, -N(Rb1)-, -C(O)-, -C(O)-NH-, -C(O)N(Rb1)-, -NH-C(O)-, -N(Rbi)-C(O)-, C3-C6cycloalkylene, C5-C12bicyclic cycloalkylene, 3- to 9-membered heterocyclylene, 7- to 14-membered bicyclic heterocyclylene;Q is a bond or a divalent group of 1-6 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from C6-C10monocyclic arylene, C8-C12bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered bicyclic heteroarylene, and wherein each of C6-C10monocyclic arylene, C8-C12bicyclic arylene, 3- to 10-membered monocyclic heteroarylene, and 5- to 10-membered bicyclic heteroarylene is independently substituted with 0, 1, 2, or 3 Rd; andRdis independently selected from hydrogen, halogen, C1-C3 alkyl, hydroxyl, -OC1-C4 alkyl, oxo, and -NH259. The compound of claim 1 or 58, wherein the compound of Formula (I) is represented by Formula (Ib-1):wherein:G is NH or N(C1-C6)alkyl;each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;Attorney Docket No.: 41827-65012 (045WO)L is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ral)-, -NH-C(O)-, -N(Ral)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14- membered bicyclic heterocyclylene; andM is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14- membered bicyclic heterocyclylene.

60. The compound of claim 59, wherein G is NH.

61. The compound of claim 59, wherein G is N(C1-C6)alkyl.

62. The compound of claim 59, wherein X is CH.

63. The compound of claim 59, wherein X is N,64. The compound of claim 59, wherein Rdis selected from -CH3, -CH2CH3, and -CH2CH2CH3.

65. The compound of claim 59, wherein each Y is independently selected from F, Cl, Br, and I.

66. The compound of claim 59, wherein L is selected from67, The compound of claim 66, wherein L isAttorney Docket No.: 41827-65012 (045WO)K ' —D / H ” or \ '68, The compound of claim 59, wherein M is selected from69. The compound of claim 68, wherein M is70. The compound of claim 1 or 58, wherein the compound of Formula (I) is represented by Formula (Ib-2):wherein:G is NH or N(C1-C6)alkyl;each Y is independently selected from C1-C2 alkyl, F, Cl, Br, and I;L is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ral)-, -C(O)-, -C(O)-NH-, -C(O)N(Ra1)-, -NH-C(O)-, -N(Ral)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14-Attorney Docket No.: 41827-65012 (045WO)membered bicyclic heterocyclylene; andM is a divalent group with a backbone of 1 -4 carbon atoms in length, wherein one or more carbon atoms are replaced by a divalent group independently selected from -O-, -NH-, -N(Ra1)-, -C(O)-, -C(O)-NH-, -C(O)N(Ral)-, -NH-C(O)-, -N(Ral)-C(O)-, 3- to 9-membered heterocyclylene, and 7- to 14- membered bicyclic heterocyclylene.

71. The compound of claim 70, wherein G is NH.

72. The compound of claim 70, wherein G is N(Ci-C6)alkyl.

73. The compound of claim 70, wherein X is CH.

74. The compound of claim 70, wherein X is N.

75. The compound of claim 70, wherein Rdis selected from -CH3, -CH2CH3, and -CH2CH2CH3.

76. The compound of claim 70, wherein each Y is independently selected from F, Cl, Br, and I.

77. The compound of claim 70, wherein L is selected from78. The compound of claim 77, wherein L is79. The compound of claim 70, wherein M is selected fromAttorney Docket No.: 41827-65012 (045WO)80. The compound of claim 79, wherein M is81. The compound of claim 1, wherein Q is a divalent group of 1-4 carbon atoms in length,wherein one or more carbon atoms are replaced by a divalent group independently selected from Cg-Cio monocyclic arylene and 5- to 10-membered bicyclic heteroarylene, and wherein each of the Cg- C10 monocyclic arylene and 5- to 10-membered bicyclic heteroarylene is independently substituted with 0, 1, 2, or 3 Rd; andeach Rdis independently selected from hydrogen, halogen, Ci-Cg alkyl, hydroxyl, -OCi-Cg alkyl, oxo, and -NH2.

82. The compound according to claim 1 or 48, wherein Q is selected from:Rdis selected from hydrogen, Ci-Cg alkyl, and -OCi-Cg alkyl, and wherein the Ci-Ce alkyl is substituted with one or more of halogen, Ci-Cg alkyl, hydroxyl, oxo, and -NH2;Attorney Docket No.: 41827-65012 (045WO) each X1is independently selected from hydrogen, halogen, C₁-C₆ alkyl, and -OC₁-C₃ alkyl; and n is 0, 1, 2, or 3.

83. The compound according to claim 1 or 49, wherein Q is selected from:

84. The compound according to claim 1, wherein L is selected from85. The compound according to claim 1, wherein M is selected fromAttorney Docket No.: 41827-65012 (045WO) 86. The compound of claim 1, wherein P is selected from87. The compound of claim 1, wherein n is 2 and each Y is F.

88. The compound of claim 1, wherein X is CH.

89. The compound of claim 1, wherein X is N.

90. The compound of claim 1, wherein R1is selected from -CH3, -CH2CH3, and -CH2CH2CH391. The compound of claim 1 or 57, wherein R1is -CH3.

92. The compound of claim 1, wherein the compound is selected from:Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)noo^ / Z OZ A^ A) IZW\Z x—z > —O\ ) Q20q Vdz—Kf L Cl\ \2Z H Z-- A Hf 1T wx' CK.hk.0H2N r- / 1Z z" X_ O V^O e 1 1 J LL - |TMM C T T Cg^N^N^'Y'Ay-N!A / NxAx0. _ (J! 'A, — FF~V / 1H2N'X^ F^O 0V '^hszX A.er / \ A A. / ON' N > r NVN!k / N\ L / NHJ ¥FJ' V-F0FVAAttorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)0 0 / --NHi T N— < > O..sN-^PPp CX / P,»Y NYsA-<h2npF0 0y-NHf jT N— < y=Q0. / N RO^N'Ny_p°1 'NH20 0YtLk J _,NAA N" —NO^N'% / AAK==\F*)(NH2Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)0 HN'A O'X J f[ NS N-^ H2N^X _ JJNO / SANZ0SA N JM1O JU oxF" \ ___ / Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO)Attorney Docket No.: 41827-65012 (045WO) / A H Q H2N~-\ \___ / N— o Az>jAr°r>o -Q i"F\ / F1~ / / / I z^~N L M o H Y 'YCyty / N-N FA>H2N~A C )>' —, \=^ H 0 S X N-A?N. ON" Y °x ) F-HX”1^? N'-CN'CHNf / — O H2N— X ( / \ / / \ _ \~~ / HN-^< y / Q O=\ / S^NN" A nN”~^ / W A \ rA.F'~V Vr VhL / AyF\Attorney Docket No.: 41827-65012 (045WO)or a pharmaceutically acceptable salt of any of the above.

93. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 92 and one or more pharmaceutically acceptable carriers, pharmaceutically acceptable vehicles, pharmaceutically acceptable excipients, or combinations thereof.

94. A method for inhibiting and / or degrading protein kinesin-like protein KIF11 in a cell, comprising contacting the cell with a compound according to any one of claims 1 to 92, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 62.

95. A method of treating a KIF 11 -mediated disease or disorder in a subject in need thereof, comprising administering an effective amount of a compound according to any one of claims 1 to 92, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 93.

96. The method of claim 95, wherein the KIF 11-mediated disease is cancer.97, The method of claim 96, wherein the cancer is selected from breast cancer, lung cancer, pancreatic cancer, small bowel cancer, colorectal cancer, gall bladder cancer, thyroid cancer, liver cancer, bile duct cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, esophageal cancer, and blood cancer.Attorney Docket No.: 41827-65012 (045WO)98. The method of claim 96 or 97, wherein the cancer is breast cancer, papillary adenocarcinoma, adenocarcinoma, or ductal carcinoma.

99. The method of claim 96 or 97, wherein the cancer is a primary cancer or a metastatic cancer.

100. A method of inhibiting the production of kinesin-like protein (KIF11) in a subject, the method comprising administering an effective amount of a compound according to any one of claims 1 to 96, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 97.

101. Use of a compound of any one of claims 1 to 92, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 93, in the manufacture of a medicament for the treatment of a disease or disorder.

102. The use of claim 101, wherein the KIF11-mediated disease is cancer.

103. The use of claim 102, wherein the cancer is selected from breast cancer, lung cancer, pancreatic cancer, small bowel cancer, colorectal cancer, gall bladder cancer, thyroid cancer, liver cancer, bile duct cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, esophageal cancer, and blood cancer.

104. The use of claim 102 or 103, wherein the cancer is breast cancer, papillary adenocarcinoma, adenocarcinoma, or ductal carcinoma.

105. The use of claim 102 or 103, wherein the cancer is a primary cancer or a metastatic cancer

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